Elsevier

Clinical Neurophysiology

Volume 127, Issue 11, November 2016, Pages 3425-3454
Clinical Neurophysiology

Review
Animal models of transcranial direct current stimulation: Methods and mechanisms

https://doi.org/10.1016/j.clinph.2016.08.016Get rights and content

Highlights

  • We provide a comprehensive description of methodology for studying cellular mechanisms of tDCS.

  • In vivo and in vitro tDCS animal studies are contextualized by examining experimental methodology.

  • We discuss clinical tDCS at single cell, synaptic, and network levels from studies of animal tDCS.

Abstract

The objective of this review is to summarize the contribution of animal research using direct current stimulation (DCS) to our understanding of the physiological effects of transcranial direct current stimulation (tDCS). We comprehensively address experimental methodology in animal studies, broadly classified as: (1) transcranial stimulation; (2) direct cortical stimulation in vivo and (3) in vitro models. In each case advantages and disadvantages for translational research are discussed including dose translation and the overarching “quasi-uniform” assumption, which underpins translational relevance in all animal models of tDCS. Terminology such as anode, cathode, inward current, outward current, current density, electric field, and uniform are defined. Though we put key animal experiments spanning decades in perspective, our goal is not simply an exhaustive cataloging of relevant animal studies, but rather to put them in context of ongoing efforts to improve tDCS. Cellular targets, including excitatory neuronal somas, dendrites, axons, interneurons, glial cells, and endothelial cells are considered. We emphasize neurons are always depolarized and hyperpolarized such that effects of DCS on neuronal excitability can only be evaluated within subcellular regions of the neuron. Findings from animal studies on the effects of DCS on plasticity (LTP/LTD) and network oscillations are reviewed extensively. Any endogenous phenomena dependent on membrane potential changes are, in theory, susceptible to modulation by DCS. The relevance of morphological changes (galvanotropy) to tDCS is also considered, as we suggest microscopic migration of axon terminals or dendritic spines may be relevant during tDCS. A majority of clinical studies using tDCS employ a simplistic dose strategy where excitability is singularly increased or decreased under the anode and cathode, respectively. We discuss how this strategy, itself based on classic animal studies, cannot account for the complexity of normal and pathological brain function, and how recent studies have already indicated more sophisticated approaches are necessary. One tDCS theory regarding “functional targeting” suggests the specificity of tDCS effects are possible by modulating ongoing function (plasticity). Use of animal models of disease are summarized including pain, movement disorders, stroke, and epilepsy.

Section snippets

Meaningful animal studies of tDCS

This review is an update, with permission, of a previously published work (Bikson et al., 2012).

The basic motivation for tDCS research using animals is similar to other translational medical research efforts: to allow rapid and risk free screening of stimulation protocols in research and clinical settings, and to address the mechanisms of tDCS with the ultimate goal of informing clinical efficacy and safety of tDCS. To have a meaningful relevance for clinical tDCS, animal studies must be

The somatic doctrine and need for amplification

Since seminal clinical neurophysiology in 2000 (Nitsche and Paulus, 2000, Ardolino et al., 2005, Fregni et al., 2005, Fregni et al., 2007), there has been exponential growth in the exploration of tDCS for clinical and cognitive/neuroscience research. Broad adaptation has been encouraged by the apparent simplicity of the technique, and the perception that tDCS protocols can be designed for any application simply by placing an electrode over the targeted brain region. In the next sections,

Synaptic processing and plasticity

There is a clinical need for lasting changes by tDCS, as it is impractical to improve disease/injury by continuously stimulating with electrodes on the head. The desire for lasting change means tDCS should influence plasticity during or after stimulation in cognitively/therapeutically relevant ways (Yoon et al., 2012). This section addresses the contribution of animal studies to understanding plasticity generated by weak DC electric fields.

Animal studies, some decades old, have suggested

Network effects

The consideration of how weak DC electric fields interact with active neuronal networks (e.g. oscillations) is a compelling area of ongoing research. Just as networks of coupled, active neurons exhibit network activity not seen in isolated neurons, the application of electrical stimulation to active networks often produce responses not expected by single neurons. These responses are specific to the network’s architecture and level of activity. Neuronal networks also provide a mechanism for

Interneurons and non-neuronal effects

The role of interneurons and non-neuronal cells, such as glial and endothelial cells, during tDCS remains both an open and critical question. To address their role to tDCS, we distinguish between: (1) primary stimulation effects, reflecting direct membrane polarization and modulation of these cell types by DC electric fields; (2) secondary stimulation effects, reflecting secondary functional changes resulting from direct excitatory neuronal activation that then influence interneurons and other

Pain

tDCS has shown promising results for treating pain symptoms in humans, and studies using animal models of pain have also provided reason for optimism. Pain symptoms are mainly determined by alterations in excitability and connectivity of pain related neural networks (Knotkova and Cruciani, 2010, Knotkova et al., 2013) and increased expression of some pro inflammatory cytokines in the brain vascular system (Spezia Adachi et al., 2012). Recent studies (Laste et al., 2012, Spezia Adachi et al.,

Safety limits for tissue injury

Data for a tDCS lesion threshold in animal models have been used to support the significant safety factor between maximum tDCS and brain damage (Bikson et al., 2009, Liebetanz et al., 2009). As the use of tDCS increases, this data warrants updating. Modeling DC predictions across animal and human are specific to the electric field produced in the brain, so data from animal models are solely based on analysis of brain lesion in this section. In addition, our analyses in this section do not

Summary: 3 tier approach, beyond the somatic doctrine, experimental rigor and dose response

Implicitly or explicitly, tDCS protocols in humans, whether directed toward clinical application, neurophysiology, or cognitive function, continue to be interpreted and designed following what we have termed the somatic doctrine of tDCS. Under the somatic doctrine, brain regions under the anode or cathode electrode are assumed to increase or decrease in neuronal excitability as a result of the polarization of cortical pyramidal cell somas due to radial current flow. Even though this simple

Acknowledgements

Support for this review comes from the Department of Defense (Air Force Office of Scientific Research), The Wallace Coulter Foundation, The Epilepsy Foundation, The Andy Grove Fund, and NIH.

Conflict of interest: MB and LP have equity in Soterix Medical Inc. The City University of New York has patents on brain stimulation with MB and LP as inventors. This review is an update of a previously published chapter (Bikson et al., 2012); portions of that chapter are updated here with permission from

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