Stimulation Physiology

Modeling the response of ON and OFF retinal bipolar cells during electric stimulation

P. Werginz and H. Benav and E. Zrenner and F. Rattay

Vision Res      (2014)

Retinal implants allowing blind people suffering from diseases like retinitis pigmentosa and macular degeneration to regain rudimentary vision are struggling with several obstacles. One of the main problems during external electric stimulation is the co-activation of the ON and OFF pathways which results in mutual impairment. In this study the response of ON and OFF cone retinal bipolar cells during extracellular electric stimulation from the subretinal space was examined. To gain deeper insight into the behavior of these cells sustained L-type and transient T-type calcium channels were integrated in the synaptic terminals of reconstructed 3D morphologies of ON and OFF cone bipolar cells. Intracellular calcium concentration in the synaptic regions of the model neurons was investigated as well since calcium influx is a crucial parameter for cell-to-cell activity between bipolar cells and retinal ganglion cells. It was shown that monophasic stimulation results in significant different calcium concentrations in the synaptic terminals of ON and OFF bipolar cells. Intracellular calcium increased to values up to fourfold higher in the OFF bipolar model neuron in comparison to the ON bipolar cell. Furthermore, geometric properties strongly influence the activation of bipolar cells. Monophasic, biphasic, single and repetitive pulses with similar lengths, amplitudes and polarities were applied to the two model neurons.

Physiological observations validate finite element models for estimating subject-specific electric field distributions induced by transcranial magnetic stimulation of the human motor cortex

A. Opitz and W. Legon and A. Rowlands and W. K. Bickel and W. Paulus and W. J. Tyler

Neuroimage  81  253-64  (2013)

Recent evidence indicates subject-specific gyral folding patterns and white matter anisotropy uniquely shape electric fields generated by TMS. Current methods for predicting the brain regions influenced by TMS involve projecting the TMS coil position or center of gravity onto realistic head models derived from structural and functional imaging data. Similarly, spherical models have been used to estimate electric field distributions generated by TMS pulses delivered from a particular coil location and position. In the present paper we inspect differences between electric field computations estimated using the finite element method (FEM) and projection-based approaches described above. We then more specifically examined an approach for estimating cortical excitation volumes based on individualistic FEM simulations of electric fields. We evaluated this approach by performing neurophysiological recordings during MR-navigated motormapping experiments. We recorded motor evoked potentials (MEPs) in response to single pulse TMS using two different coil orientations (45$\,^{\circ}$ and 90$\,^{\circ}$ to midline) at 25 different locations (5×5 grid, 1cm spacing) centered on the hotspot of the right first dorsal interosseous (FDI) muscle in left motor cortex. We observed that motor excitability maps varied within and between subjects as a function of TMS coil position and orientation. For each coil position and orientation tested, simulations of the TMS-induced electric field were computed using individualistic FEM models and compared to MEP amplitudes obtained during our motormapping experiments. We found FEM simulations of electric field strength, which take into account subject-specific gyral geometry and tissue conductivity anisotropy, significantly correlated with physiologically observed MEP amplitudes (rmax=0.91, p=1.8×10(-5) rmean=0.81, p=0.01). These observations validate the implementation of individualistic FEM models to account for variations in gyral folding patterns and tissue conductivity anisotropy, which should help improve the targeting accuracy of TMS in the mapping or modulation of human brain circuits.

Current approaches to model extracellular electrical neural microstimulation

S. Joucla and A. Glière and B. Yvert

Front Comput Neurosci  8  13  (2014)

Nowadays, high-density microelectrode arrays provide unprecedented possibilities to precisely activate spatially well-controlled central nervous system (CNS) areas. However, this requires optimizing stimulating devices, which in turn requires a good understanding of the effects of microstimulation on cells and tissues. In this context, modeling approaches provide flexible ways to predict the outcome of electrical stimulation in terms of CNS activation. In this paper, we present state-of-the-art modeling methods with sufficient details to allow the reader to rapidly build numerical models of neuronal extracellular microstimulation. These include (1) the computation of the electrical potential field created by the stimulation in the tissue, and (2) the response of a target neuron to this field. Two main approaches are described: First we describe the classical hybrid approach that combines the finite element modeling of the potential field with the calculation of the neuron's response in a cable equation framework (compartmentalized neuron models). Then, we present a "whole finite element" approach allowing the simultaneous calculation of the extracellular and intracellular potentials, by representing the neuronal membrane with a thin-film approximation. This approach was previously introduced in the frame of neural recording, but has never been implemented to determine the effect of extracellular stimulation on the neural response at a sub-compartment level. Here, we show on an example that the latter modeling scheme can reveal important sub-compartment behavior of the neural membrane that cannot be resolved using the hybrid approach. The goal of this paper is also to describe in detail the practical implementation of these methods to allow the reader to easily build new models using standard software packages. These modeling paradigms, depending on the situation, should help build more efficient high-density neural prostheses for CNS rehabilitation.

Transcranial magnetic stimulation elicits coupled neural and hemodynamic consequences

E. A. Allen and B. N. Pasley and T. Duong and R. D. Freeman

Science  317  1918-21  (2007)

Transcranial magnetic stimulation (TMS) is an increasingly common technique used to selectively modify neural processing. However, application of TMS is limited by uncertainty concerning its physiological effects. We applied TMS to the cat visual cortex and evaluated the neural and hemodynamic consequences. Short TMS pulse trains elicited initial activation (approximately 1 minute) and prolonged suppression (5 to 10 minutes) of neural responses. Furthermore, TMS disrupted the temporal structure of activity by altering phase relationships between neural signals. Despite the complexity of this response, neural changes were faithfully reflected in hemodynamic signals; quantitative coupling was present over a range of stimulation parameters. These results demonstrate long-lasting neural responses to TMS and support the use of hemodynamic-based neuroimaging to effectively monitor these changes over time.

Transcranial electric stimulation entrains cortical neuronal populations in rats

S. Ozen and A. Sirota and M. A. Belluscio and C. A. Anastassiou and E. Stark and C. Koch and G. Buzsáki

J Neurosci  30  11476-85  (2010)

Low intensity electric fields have been suggested to affect the ongoing neuronal activity in vitro and in human studies. However, the physiological mechanism of how weak electrical fields affect and interact with intact brain activity is not well understood. We performed in vivo extracellular and intracellular recordings from the neocortex and hippocampus of anesthetized rats and extracellular recordings in behaving rats. Electric fields were generated by sinusoid patterns at slow frequency (0.8, 1.25 or 1.7 Hz) via electrodes placed on the surface of the skull or the dura. Transcranial electric stimulation (TES) reliably entrained neurons in widespread cortical areas, including the hippocampus. The percentage of TES phase-locked neurons increased with stimulus intensity and depended on the behavioral state of the animal. TES-induced voltage gradient, as low as 1 mV/mm at the recording sites, was sufficient to phase-bias neuronal spiking. Intracellular recordings showed that both spiking and subthreshold activity were under the combined influence of TES forced fields and network activity. We suggest that TES in chronic preparations may be used for experimental and therapeutic control of brain activity.

Transcranial direct-current stimulation modulates synaptic mechanisms involved in associative learning in behaving rabbits

J. Márquez-Ruiz and R. Leal-Campanario and R. Sánchez-Campusano and B. Molaee-Ardekani and F. Wendling and P. C. Miranda and G. Ruffini and A. Gruart and J. M. Delgado-García

Proc Natl Acad Sci U S A  109  6710-5  (2012)

Transcranial direct-current stimulation (tDCS) is a noninvasive brain stimulation technique that has been successfully applied for modulation of cortical excitability. tDCS is capable of inducing changes in neuronal membrane potentials in a polarity-dependent manner. When tDCS is of sufficient length, synaptically driven after-effects are induced. The mechanisms underlying these after-effects are largely unknown, and there is a compelling need for animal models to test the immediate effects and after-effects induced by tDCS in different cortical areas and evaluate the implications in complex cerebral processes. Here we show in behaving rabbits that tDCS applied over the somatosensory cortex modulates cortical processes consequent to localized stimulation of the whisker pad or of the corresponding area of the ventroposterior medial (VPM) thalamic nucleus. With longer stimulation periods, poststimulation effects were observed in the somatosensory cortex only after cathodal tDCS. Consistent with the polarity-specific effects, the acquisition of classical eyeblink conditioning was potentiated or depressed by the simultaneous application of anodal or cathodal tDCS, respectively, when stimulation of the whisker pad was used as conditioned stimulus, suggesting that tDCS modulates the sensory perception process necessary for associative learning. We also studied the putative mechanisms underlying immediate effects and after-effects of tDCS observed in the somatosensory cortex. Results when pairs of pulses applied to the thalamic VPM nucleus (mediating sensory input) during anodal and cathodal tDCS suggest that tDCS modifies thalamocortical synapses at presynaptic sites. Finally, we show that blocking the activation of adenosine A1 receptors prevents the long-term depression (LTD) evoked in the somatosensory cortex after cathodal tDCS.

Transcranial alternating current stimulation modulates large-scale cortical network activity by network resonance

M. M. Ali and K. K. Sellers and F. Fröhlich

J Neurosci  33  11262-75  (2013)

Transcranial direct current stimulation (tDCS) has emerged as a potentially safe and effective brain stimulation modality that alters cortical excitability by passing a small, constant electric current through the scalp. tDCS creates an electric field that weakly modulates the membrane voltage of a large number of cortical neurons. Recent human studies have suggested that sine-wave stimulation waveforms [transcranial alternating current stimulation (tACS)] represent a more targeted stimulation paradigm for the enhancement of cortical oscillations. Yet, the underlying mechanisms of how periodic, weak global perturbations alter the spatiotemporal dynamics of large-scale cortical network dynamics remain a matter of debate. Here, we simulated large-scale networks of spiking neuron models to address this question in endogenously rhythmic networks. We identified distinct roles of the depolarizing and hyperpolarizing phases of tACS in entrainment, which entailed moving network activity toward and away from a strong nonlinearity provided by the local excitatory coupling of pyramidal cells. Together, these mechanisms gave rise to resonance dynamics characterized by an Arnold tongue centered on the resonance frequency of the network. We then performed multichannel extracellular recordings of multiunit firing activity during tACS in anesthetized ferrets (Mustela putoris furo), a model species with a gyrencephalic brain, to verify that weak global perturbations can selectively enhance oscillations at the applied stimulation frequency. Together, these results provide a detailed mechanistic understanding of tACS at the level of large-scale network dynamics and support the future design of activity-dependent feedback tACS paradigms that dynamically tailor stimulation frequency to the spectral peak of ongoing brain activity.


The effect of transcranial direct current stimulation: a role for cortical excitation/inhibition balance?

B. Krause and J. Márquez-Ruiz and R. Cohen Kadosh

Front Hum Neurosci  7  602  (2013)

Transcranial direct current stimulation (tDCS) is a promising tool for cognitive enhancement and neurorehabilitation in clinical disorders in both cognitive and clinical domains (e.g., chronic pain, tinnitus). Here we suggest the potential role of tDCS in modulating cortical excitation/inhibition (E/I) balance and thereby inducing improvements. We suggest that part of the mechanism of action of tDCS can be explained by non-invasive modulations of the E/I balance.

tDCS-induced alterations in GABA concentration within primary motor cortex predict motor learning and motor memory: a 7 T magnetic resonance spectroscopy study

S. Kim and M. C. Stephenson and P. G. Morris and S. R. Jackson

Neuroimage  99  237-43  (2014)

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that alters cortical excitability in a polarity specific manner and has been shown to influence learning and memory. tDCS may have both on-line and after-effects on learning and memory, and the latter are thought to be based upon tDCS-induced alterations in neurochemistry and synaptic function. We used ultra-high-field (7 T) magnetic resonance spectroscopy (MRS), together with a robotic force adaptation and de-adaptation task, to investigate whether tDCS-induced alterations in GABA and Glutamate within motor cortex predict motor learning and memory. Note that adaptation to a robot-induced force field has long been considered to be a form of model-based learning that is closely associated with the computation and 'supervised' learning of internal 'forward' models within the cerebellum. Importantly, previous studies have shown that on-line tDCS to the cerebellum, but not to motor cortex, enhances model-based motor learning. Here we demonstrate that anodal tDCS delivered to the hand area of the left primary motor cortex induces a significant reduction in GABA concentration. This effect was specific to GABA, localised to the left motor cortex, and was polarity specific insofar as it was not observed following either cathodal or sham stimulation. Importantly, we show that the magnitude of tDCS-induced alterations in GABA concentration within motor cortex predicts individual differences in both motor learning and motor memory on the robotic force adaptation and de-adaptation task.

State-dependent variability of neuronal responses to transcranial magnetic stimulation of the visual cortex

B. N. Pasley and E. A. Allen and R. D. Freeman

Neuron  62  291-303  (2009)

Electrical brain stimulation is a promising tool for both experimental and clinical applications. However, the effects of stimulation on neuronal activity are highly variable and poorly understood. To investigate the basis of this variability, we performed extracellular recordings in the visual cortex following application of transcranial magnetic stimulation (TMS). Our measurements of spiking and local field potential activity exhibit two types of response patterns which are characterized by the presence or absence of spontaneous discharge following stimulation. This variability can be partially explained by state-dependent effects, in which higher pre-TMS activity predicts larger post-TMS responses. These results reveal the possibility that variability in the neural response to TMS can be exploited to optimize the effects of stimulation. It is conceivable that this feature could be utilized in real time during the treatment of clinical disorders.

Remote excitation of neuronal circuits using low-intensity, low-frequency ultrasound

W. J. Tyler and Y. Tufail and M. Finsterwald and M. L. Tauchmann and E. J. Olson and C. Majestic

PLoS One  3  e3511  (2008)

Possessing the ability to noninvasively elicit brain circuit activity yields immense experimental and therapeutic power. Most currently employed neurostimulation methods rely on the somewhat invasive use of stimulating electrodes or photon-emitting devices. Due to its ability to noninvasively propagate through bone and other tissues in a focused manner, the implementation of ultrasound (US) represents a compelling alternative approach to current neuromodulation strategies. Here, we investigated the influence of low-intensity, low-frequency ultrasound (LILFU) on neuronal activity. By transmitting US waveforms through hippocampal slice cultures and ex vivo mouse brains, we determined LILFU is capable of remotely and noninvasively exciting neurons and network activity. Our results illustrate that LILFU can stimulate electrical activity in neurons by activating voltage-gated sodium channels, as well as voltage-gated calcium channels. The LILFU-induced changes in neuronal activity were sufficient to trigger SNARE-mediated exocytosis and synaptic transmission in hippocampal circuits. Because LILFU can stimulate electrical activity and calcium signaling in neurons as well as central synaptic transmission we conclude US provides a powerful tool for remotely modulating brain circuit activity.

Paired associative transcranial alternating current stimulation increases the excitability of corticospinal projections in humans

E. McNickle and R. G. Carson

J Physiol      (2014)

Many types of non-invasive brain stimulation alter corticospinal excitability (CSE). Paired associative stimulation (PAS) attracts particular attention as its effects ostensibly adhere to Hebbian principles of neural plasticity. In prototypical form, a single electrical stimulus is directed to a peripheral nerve in close temporal contiguity with transcranial magnetic stimulation (TMS) delivered to the contralateral primary motor cortex (M1). Repeated pairing of the two discrete stimulus events (i.e. association) over an extended period either increases or decreases the excitability of corticospinal projections from M1, contingent on the interstimulus interval (ISI). We studied a novel form of associative stimulation, consisting of brief trains of peripheral afferent stimulation paired with short bursts of high frequency (≥ 80 Hz) transcranial alternating current stimulation (tACS) over contralateral M1. Elevations in the excitability of corticospinal projections to the forearm were observed for a range of tACS frequency (80 Hz, 140 Hz and 250 Hz), current (1 mA, 2 mA and 3 mA) and duration (500 ms, and 1000 ms) parameters. The effects were at least as reliable as those brought about by PAS or transcranial direct current stimulation (tDCS). When paired with tACS, muscle tendon vibration also induced elevations of CSE. No such changes were brought about by the tACS or peripheral afferent stimulation alone. In demonstrating that associative effects are expressed when the timing of the peripheral and cortical events is not precisely circumscribed, these findings suggest that multiple cellular pathways may contribute to a LTP-type response. Their relative contributions will differ depending on the nature of the induction protocol that is used. This article is protected by copyright. All rights reserved.

Low-intensity electrical stimulation affects network dynamics by modulating population rate and spike timing

D. Reato and A. Rahman and M. Bikson and L. C. Parra

J Neurosci  30  15067-79  (2010)

Clinical effects of transcranial electrical stimulation with weak currents are remarkable considering the low amplitude of the electric fields acting on the brain. Elucidating the processes by which small currents affect ongoing brain activity is of paramount importance for the rational design of noninvasive electrotherapeutic strategies and to determine the relevance of endogenous fields. We propose that in active neuronal networks, weak electrical fields induce small but coherent changes in the firing rate and timing of neuronal populations that can be magnified by dynamic network activity. Specifically, we show that carbachol-induced gamma oscillations (25-35 Hz) in rat hippocampal slices have an inherent rate-limiting dynamic and timing precision that govern susceptibility to low-frequency weak electric fields (<50 Hz; <10 V/m). This leads to a range of nonlinear responses, including the following: (1) asymmetric power modulation by DC fields resulting from balanced excitation and inhibition; (2) symmetric power modulation by lower frequency AC fields with a net-zero change in firing rate; and (3) half-harmonic oscillations for higher frequency AC fields resulting from increased spike timing precision. These underlying mechanisms were elucidated by slice experiments and a parsimonious computational network model of single-compartment spiking neurons responding to electric field stimulation with small incremental polarization. Intracellular recordings confirmed model predictions on neuronal timing and rate changes, as well as spike phase-entrainment resonance at 0.2 V/m. Finally, our data and mechanistic framework provide a functional role for endogenous electric fields, specifically illustrating that modulation of gamma oscillations during theta-modulated gamma activity can result from field effects alone.

Effects of transcranial Direct Current Stimulation (tDCS) on cortical activity: a computational modeling study

B. Molaee-Ardekani and J. Márquez-Ruiz and I. Merlet and R. Leal-Campanario and A. Gruart and R. Sánchez-Campusano and G. Birot and G. Ruffini and J.-M. Delgado-García and F. Wendling

Brain Stimul  6  25-39  (2013)

Although it is well-admitted that transcranial Direct Current Stimulation (tDCS) allows for interacting with brain endogenous rhythms, the exact mechanisms by which externally-applied fields modulate the activity of neurons remain elusive. In this study a novel computational model (a neural mass model including subpopulations of pyramidal cells and inhibitory interneurons mediating synaptic currents with either slow or fast kinetics) of the cerebral cortex was elaborated to investigate the local effects of tDCS on neuronal populations based on an in-vivo experimental study. Model parameters were adjusted to reproduce evoked potentials (EPs) recorded from the somatosensory cortex of the rabbit in response to air-puffs applied on the whiskers. EPs were simulated under control condition (no tDCS) as well as under anodal and cathodal tDCS fields. Results first revealed that a feed-forward inhibition mechanism must be included in the model for accurate simulation of actual EPs (peaks and latencies). Interestingly, results revealed that externally-applied fields are also likely to affect interneurons. Indeed, when interneurons get polarized then the characteristics of simulated EPs become closer to those of real EPs. In particular, under anodal tDCS condition, more realistic EPs could be obtained when pyramidal cells were depolarized and, simultaneously, slow (resp. fast) interneurons became de- (resp. hyper-) polarized. Geometrical characteristics of interneurons might provide some explanations for this effect.

Direct current stimulation promotes BDNF-dependent synaptic plasticity: potential implications for motor learning

B. Fritsch and J. Reis and K. Martinowich and H. M. Schambra and Y. Ji and L. G. Cohen and B. Lu

Neuron  66  198-204  (2010)

Despite its increasing use in experimental and clinical settings, the cellular and molecular mechanisms underlying transcranial direct current stimulation (tDCS) remain unknown. Anodal tDCS applied to the human motor cortex (M1) improves motor skill learning. Here, we demonstrate in mouse M1 slices that DCS induces a long-lasting synaptic potentiation (DCS-LTP), which is polarity specific, NMDA receptor dependent, and requires coupling of DCS with repetitive low-frequency synaptic activation (LFS). Combined DCS and LFS enhance BDNF-secretion and TrkB activation, and DCS-LTP is absent in BDNF and TrkB mutant mice, suggesting that BDNF is a key mediator of this phenomenon. Moreover, the BDNF val66met polymorphism known to partially affect activity-dependent BDNF secretion impairs motor skill acquisition in humans and mice. Motor learning is enhanced by anodal tDCS, as long as activity-dependent BDNF secretion is in place. We propose that tDCS may improve motor skill learning through augmentation of synaptic plasticity that requires BDNF secretion and TrkB activation within M1.

Cellular effects of acute direct current stimulation: somatic and synaptic terminal effects

A. Rahman and D. Reato and M. Arlotti and F. Gasca and A. Datta and L. C. Parra and M. Bikson

J Physiol  591  2563-78  (2013)

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique to modulate cortical excitability. Although increased/decreased excitability under the anode/cathode electrode is nominally associated with membrane depolarization/hyperpolarization, which cellular compartments (somas, dendrites, axons and their terminals) mediate changes in cortical excitability remains unaddressed. Here we consider the acute effects of DCS on excitatory synaptic efficacy. Using multi-scale computational models and rat cortical brain slices, we show the following. (1) Typical tDCS montages produce predominantly tangential (relative to the cortical surface) direction currents (4-12 times radial direction currents), even directly under electrodes. (2) Radial current flow (parallel to the somatodendritic axis) modulates synaptic efficacy consistent with somatic polarization, with depolarization facilitating synaptic efficacy. (3) Tangential current flow (perpendicular to the somatodendritic axis) modulates synaptic efficacy acutely (during stimulation) in an afferent pathway-specific manner that is consistent with terminal polarization, with hyperpolarization facilitating synaptic efficacy. (4) Maximal polarization during uniform DCS is expected at distal (the branch length is more than three times the membrane length constant) synaptic terminals, independent of and two-three times more susceptible than pyramidal neuron somas. We conclude that during acute DCS the cellular targets responsible for modulation of synaptic efficacy are concurrently somata and axon terminals, with the direction of cortical current flow determining the relative influence.

Baseline effects of transcranial direct current stimulation on glutamatergic neurotransmission and large-scale network connectivity

M. A. Hunter and B. A. Coffman and C. Gasparovic and V. D. Calhoun and M. C. Trumbo and V. P. Clark

Brain Res  1594  92-107  (2015)

Transcranial direct current stimulation (tDCS) modulates glutamatergic neurotransmission and can be utilized as a novel treatment intervention for a multitude of populations. However, the exact mechanism by which tDCS modulates the brain׳s neural architecture, from the micro to macro scales, have yet to be investigated. Using a within-subjects design, resting-state functional magnetic resonance imaging (rs-fMRI) and proton magnetic resonance spectroscopy ((1)H MRS) were performed immediately before and after the administration of anodal tDCS over right parietal cortex. Group independent component analysis (ICA) was used to decompose fMRI scans into 75 brain networks, from which 12 resting-state networks were identified that had significant voxel-wise functional connectivity to anatomical regions of interest. (1)H MRS was used to obtain estimates of combined glutamate and glutamine (Glx) concentrations from bilateral intraparietal sulcus. Paired sample t-tests showed significantly increased Glx under the anodal electrode, but not in homologous regions of the contralateral hemisphere. Increases of within-network connectivity were observed within the superior parietal, inferior parietal, left frontal-parietal, salience and cerebellar intrinsic networks, and decreases in connectivity were observed in the anterior cingulate and the basal ganglia (p<0.05, FDR-corrected). Individual differences in Glx concentrations predicted network connectivity in most of these networks. The observed relationships between glutamatergic neurotransmission and network connectivity may be used to guide future tDCS protocols that aim to target and alter neuroplastic mechanisms in healthy individuals as well as those with psychiatric and neurologic disorders.

A model of the effects of applied electric fields on neuronal synchronization

E.-H. Park and E. Barreto and B. J. Gluckman and S. J. Schiff and P. So

J Comput Neurosci  19  53-70  (2005)

We examine the effects of applied electric fields on neuronal synchronization. Two-compartment model neurons were synaptically coupled and embedded within a resistive array, thus allowing the neurons to interact both chemically and electrically. In addition, an external electric field was imposed on the array. The effects of this field were found to be nontrivial, giving rise to domains of synchrony and asynchrony as a function of the heterogeneity among the neurons. A simple phase oscillator reduction was successful in qualitatively reproducing these domains. The findings form several readily testable experimental predictions, and the model can be extended to a larger scale in which the effects of electric fields on seizure activity may be simulated.