Neurophysiological mechanisms of transcranial alternating current stimulation

Neuronal oscillations are the primary basis for precise temporal coordination of neuronal processing and are linked to different brain functions. Transcranial alternating current stimulation (tACS) has demonstrated promising potential in improving cognition by entraining neural oscillations. Despite positive findings in recent decades, the results obtained are sometimes rife with variance and replicability problems, and the findings translation to humans is quite challenging. A thorough understanding of the mechanisms underlying tACS is necessitated for accurate interpretation of experimental results. Animal models are useful for understanding tACS mechanisms, optimizing parameter administration, and improving rational design for broad horizons of tACS. Here, we review recent electrophysiological advances in tACS from animal models, as well as discuss some critical issues for results coordination and translation. We hope to provide an overview of neurophysiological mechanisms and recommendations for future consideration to improve its validity, specificity, and reproducibility

Biophysically grounded mean-field models of neural populations under electrical stimulation

Electrical stimulation of neural systems is a key tool for understanding neural dynamics and ultimately for developing clinical treatments. Many applications of electrical stimulation affect large populations of neurons. However, computational models of large networks of spiking neurons are inherently hard to simulate and analyze. We evaluate a reduced mean-field model of excitatory and inhibitory adaptive exponential integrate-and-fire (AdEx) neurons which can be used to efficiently study the effects of electrical stimulation on large neural populations. The rich dynamical properties of this basic cortical model are described in detail and validated using large network simulations. Bifurcation diagrams reflecting the network's state reveal asynchronous up- and down-states, bistable regimes, and oscillatory regions corresponding to fast excitation-inhibition and slow excitation-adaptation feedback loops. The biophysical parameters of the AdEx neuron can be coupled to an electric field with realistic field strengths which then can be propagated up to the population description.We show how on the edge of bifurcation, direct electrical inputs cause network state transitions, such as turning on and off oscillations of the population rate. Oscillatory input can frequency-entrain and phase-lock endogenous oscillations. Relatively weak electric field strengths on the order of 1 V/m are able to produce these effects, indicating that field effects are strongly amplified in the network. The effects of time-varying external stimulation are well-predicted by the mean-field model, further underpinning the utility of low-dimensional neural mass models.Comment: A Python package with an implementation of the AdEx mean-field model can be found at https://github.com/neurolib-dev/neurolib - code for simulation and data analysis can be found at https://github.com/caglarcakan/stimulus_neural_population

Differential polarization of cortical pyramidal neuron dendrites through weak extracellular fields

<div><p>The rise of transcranial current stimulation (tCS) techniques have sparked an increasing interest in the effects of weak extracellular electric fields on neural activity. These fields modulate ongoing neural activity through polarization of the neuronal membrane. While the somatic polarization has been investigated experimentally, the frequency-dependent polarization of the dendritic trees in the presence of alternating (AC) fields has received little attention yet. Using a biophysically detailed model with experimentally constrained active conductances, we analyze the subthreshold response of cortical pyramidal cells to weak AC fields, as induced during tCS. We observe a strong frequency resonance around 10-20 Hz in the apical dendrites sensitivity to polarize in response to electric fields but not in the basal dendrites nor the soma. To disentangle the relative roles of the cell morphology and active and passive membrane properties in this resonance, we perform a thorough analysis using simplified models, e.g. a passive pyramidal neuron model, simple passive cables and reconstructed cell model with simplified ion channels. We attribute the origin of the resonance in the apical dendrites to (i) a locally increased sensitivity due to the morphology and to (ii) the high density of h-type channels. Our systematic study provides an improved understanding of the subthreshold response of cortical cells to weak electric fields and, importantly, allows for an improved design of tCS stimuli.</p></div

Beyond the target area: an integrative view of tDCS-induced motor cortex modulation in patients and athletes

Transcranial Direct Current Stimulation (tDCS) is a non-invasive technique used to modulate neural tissue. Neuromodulation apparently improves cognitive functions in several neurologic diseases treatment and sports performance. In this study, we present a comprehensive, integrative review of tDCS for motor rehabilitation and motor learning in healthy individuals, athletes and multiple neurologic and neuropsychiatric conditions. We also report on&nbsp;neuromodulation mechanisms, main applications, current knowledge including areas such as language, embodied cognition, functional and social aspects, and future directions. We present the use and perspectives of new developments in tDCS technology, namely high-definition tDCS (HD-tDCS) which promises to overcome one of&nbsp;the main tDCS limitation (i.e., low focality) and its application for neurological disease, pain relief, and motor learning/rehabilitation. Finally, we provided information regarding the Transcutaneous Spinal Direct Current Stimulation (tsDCS) in clinical applications, Cerebellar tDCS (ctDCS) and its&nbsp;influence on motor learning, and TMS combined with electroencephalography (EEG) as a tool to evaluate tDCS effects on brain function

Beyond the target area: an integrative view of tDCS-induced motor cortex modulation in patients and athletes

Transcranial Direct Current Stimulation (tDCS) is a non-invasive technique used to modulate neural tissue. Neuromodulation apparently improves cognitive functions in several neurologic diseases treatment and sports performance. In this study, we present a comprehensive, integrative review of tDCS for motor rehabilitation and motor learning in healthy individuals, athletes and multiple neurologic and neuropsychiatric conditions. We also report on neuromodulation mechanisms, main applications, current knowledge including areas such as language, embodied cognition, functional and social aspects, and future directions. We present the use and perspectives of new developments in tDCS technology, namely high-definition tDCS (HD-tDCS) which promises to overcome one of the main tDCS limitation (i.e., low focality) and its application for neurological disease, pain relief, and motor learning/rehabilitation. Finally, we provided information regarding the Transcutaneous Spinal Direct Current Stimulation (tsDCS) in clinical applications, Cerebellar tDCS (ctDCS) and its influence on motor learning, and TMS combined with electroencephalography (EEG) as a tool to evaluate tDCS effects on brain function161CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP465686/2014-1Não tem2014/50909-8; 13/10187–0; 14/10134–7The authors thank the Ministry of Education (MEC), FAPESP - São Paulo Research Foundation, Universidade Estadual de Londrina, Universidade Federal do Rio Grande do Norte and Universidade Federal do ABC for its support. Postdoctoral scholarships to DGSM from the Coordination for the Improvement of Higher Education Personnel (CAPES). Source(s) of financial support: This study was partially funded by grants to MB from NIH (NIH-NIMH 1R01MH111896, NIH-NINDS 1R01NS101362, NIH-NCI U54CA137788/U54CA132378, R03 NS054783) and New York State Department of Health (NYS DOH, DOH01-C31291GG), CEPID/BRAINN - The Brazilian Institute of Neuroscience and Neurotechnology (Process: 13/07559–3) to LML, Brazilian National Research Council (CNPq, Grant # 465686/2014-1) and the São Paulo Research Foundation (Grant # 2014/50909-8) to MSC, and Postdoctoral scholarships to AHO from FAPESP - Sao Paulo Research Foundation (Process: 13/10187–0 and 14/10134–7

Modulation of cerebellar purkinje cell activity with low intensity electric and ultrasound stimulation

Non-invasive brain stimulation (NIBS) techniques garner significant interest due to their potential to offer instantaneous and region-specific treatments to neurological disorders. The cerebellum is one of the target sites for NIBS methods due to its central role in motor and cognitive functions. Among several modulation techniques, transcranial electric stimulations (tEs), in particular, transcranial direct and alternating current stimulations (tDCs/tACs), and low intensity focused ultrasound stimulation (LIFUS) show encouraging outcomes in clinical applications. tDCs and tACs are favored due to their low cost and accessibility while LIFUS offers high spatial resolution and deeper penetration without affecting the surrounding structures. In order to better understand the underlying mechanism of these methods in the cerebellum, animal studies are needed since these experiments require invasive surgeries. The goal of this study is to investigate the response of cerebellar PCs to electric and ultrasound stimulation in an animal model. The first objective is to measure the electric field (e-field) distribution inside the brain parenchyma since e-field is the main parameter that determines the local effects of electrical stimulation. The results of this part show that e-field decays exponentially through horizontal and vertical directions from the stimulating electrode and scattered by the skin up to 80%. Then, tACS and tDCS are applied to the cerebellar cortex respectively while recording the extracellular spike activity from the cerebellar PCs. The activity of PCs is important because they generate the sole output from the cerebellar cortex, which in turn modifies the output of the deep cerebellar nuclei (DCN). The results of this part demonstrate that the direction of e-field is highly correlated with the level of modulation measured on the PCs. Applying the e-field parallel to the dendritic tree of the PCs generates the highest modulation level. Our data show that PCs have a characteristic response to both DC and AC fields, including entrainment of the simple spike activity at high frequencies. Our findings for the LIFUS also show that spike timing of PCs is strongly entrained with the pulsed ultrasound stimulation, and the level of the entrainment is inversely correlated with the pulse width. In summary, the low intensity electric and ultrasound stimulation are able to effectively modulate the PC activity in the cerebellar cortex. This warrants research to further look into the mechanism of tES and LIFUS acting on the cerebellar cortex at the cellular level

Effects of weak electric fields on long-term synaptic plasticity

Transcranial direct current stimulation (tDCS) is a technique where a weak direct electrical current is applied to the scalp with the goal of stimulating the brain. There is tremendous interest in the use of tDCS for treating brain disorders and improving brain function. However, the effects of tDCS have been highly variable across studies, leading to a debate over its efficacy. A major challenge is therefore to design tDCS protocols that yield predictable effects, which will require a better understanding of its basic mechanisms of action. One commonly discussed mechanism is that tDCS may alter synaptic plasticity, but the biophysics that support this interaction between tDCS and synaptic plasticity remain unclear. This dissertation is centered around a fundamental hypothesis; that tDCS can modulate the brain’s ongoing endogenous synaptic plasticity by altering the voltage dynamics in postsynaptic neurons. In chapters 1 and 2, I discuss how this hypothesis is built on decades of research characterizing effects of weak electric fields on neuronal membrane potential and the dependence of synaptic plasticity on membrane potential. In chapters 3 and 4, several experimental predictions of this theory are tested using a canonical model system for studying synaptic plasticity, the hippocampal brain slice. The theory accounts for the dependence of DCS effects on the temporal pattern of synaptic inputs and their location along a dendritic arbor, which may be sources of unexplained variability in human tDCS studies. An essential part of the proposed theory is that the effects of tDCS are mediated by the same cellular machinery that implements Hebbian synaptic plasticity. In chapter 4, we show that the effects of DCS therefore exhibit Hebbian properties, such as pathway specificity and associativity, whose role in associative learning has been studied extensively. These results suggest that tDCS can enhance associative learning and remain functionally specific by interacting with endogenous plasticity mechanisms. We further propose that clinical tDCS should be paired with tasks that induce plasticity to harness this phenomenon. In chapters 4 and 5, I present a computational model that incorporates established biophysical mechanisms for neuronal voltage dynamics, Hebbian synaptic plasticity, and membrane polarization due to weak electric fields. The model is in good agreement with our experimental results, demonstrating their consistency with the proposed theory. The model is then used to predict effects of tDCS with new synaptic input patterns and propose future brain slice experiments. The remaining chapters, 6 through 8, discuss the advances made by this work and important limitations. The theory and accompanying model provide a principled method for predicting effects on synaptic plasticity when tDCS is applied during training. However, it does not account for several observed effects of tDCS, such as on plasticity that is induced after stimulation has ended. Integrating the present theory with other potential mechanisms is therefore an important area for future research. Nonetheless, this work establishes a mechanistic framework for interpreting the effects of tDCS on synaptic plasticity and should aid in the design of tDCS protocols to facilitate associative learning

PERTURBING THE NEURONAL NETWORK DYNAMICS IN THE HIGHER-ORDER THALAMO-CORTICAL NETWORK

Understanding the brain’s dynamics and its role in cognitive functions will open up new avenues for the treatment of psychiatric illnesses. Oscillations reveal rhythmic features in the dynamics that are associated with different mental states and cognitive processes. One cognitive function of transdiagnostic importance is sustained attention. Sustained attention is the ability to focus our cognitive resources to process unpredictable information for an extended period of time. Temporary loss of sustained attention could lead to accidents while driving, and long-term sustained attention deficit is linked to many psychiatric disorders. Sustained visual attention requires an active engagement of higher-order visual circuitry to maintain a mental state for processing unpredictable visual inputs. The coordinated activity of groups of neurons in such circuitry gives rise to cortico-thalamo-cortical oscillations, which are crucial for mediating top-down control signals and bottom-up information transduction. Through its widespread interconnection with the cortex, the higher-order visual thalamus is ideally positioned to serve such a role by coordinating cortico-cortical synchrony that supports attentional engagement. However, the causal mechanisms underlying the oscillatory synchronization in the posterior visual thalamo-cortical network as well as their function during sustained attention remains unknown. Thus, basic science and translational work with causal perturbation is needed to shine a light on the role of these oscillatory dynamics in neuronal processing and behavior. The studies in this dissertation attempted to address this question by targeting the higher-order thalamo-cortical visual system and combining multiple causal perturbation tools (eg. optogenetics and transcranial brain stimulation), simultaneous multisite electrophysiological recordings, and a sustained attention task. Through a logical process of target identification, engagement, and validation, our work contributes to understanding: 1. how does the higher-order visual thalamus causally coordinate thalamo-cortical communications to enhance attentional behavior, and 2. how does transcranial alternating current stimulation affect single-neuron activity as well as long-range circuit dynamics in this network? Taken together, this work provides causal evidence underlying the mechanism of brain stimulations and its effect on behavior, which ultimately could inform the broader scientific community on how to rationally refine targeted circuit-based therapeutics for treating cognitive deficits.Doctor of Philosoph

Brain and Human Body Modeling

This open access book describes modern applications of computational human modeling with specific emphasis in the areas of neurology and neuroelectromagnetics, depression and cancer treatments, radio-frequency studies and wireless communications. Special consideration is also given to the use of human modeling to the computational assessment of relevant regulatory and safety requirements. Readers working on applications that may expose human subjects to electromagnetic radiation will benefit from this book’s coverage of the latest developments in computational modelling and human phantom development to assess a given technology’s safety and efficacy in a timely manner. Describes construction and application of computational human models including anatomically detailed and subject specific models; Explains new practices in computational human modeling for neuroelectromagnetics, electromagnetic safety, and exposure evaluations; Includes a survey of modern applications for which computational human models are critical; Describes cellular-level interactions between the human body and electromagnetic fields

Brain and Human Body Modeling

This open access book describes modern applications of computational human modeling with specific emphasis in the areas of neurology and neuroelectromagnetics, depression and cancer treatments, radio-frequency studies and wireless communications. Special consideration is also given to the use of human modeling to the computational assessment of relevant regulatory and safety requirements. Readers working on applications that may expose human subjects to electromagnetic radiation will benefit from this book’s coverage of the latest developments in computational modelling and human phantom development to assess a given technology’s safety and efficacy in a timely manner. Describes construction and application of computational human models including anatomically detailed and subject specific models; Explains new practices in computational human modeling for neuroelectromagnetics, electromagnetic safety, and exposure evaluations; Includes a survey of modern applications for which computational human models are critical; Describes cellular-level interactions between the human body and electromagnetic fields