Davide Reato

Low-Intensity Electrical Stimulation Affects Network Dynamics by Modulating Population Rate and Spike Timing

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.

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

•  The diversity of cellular targets of direct current stimulation (DCS), including somas, dendrites and axon terminals, determine the modulation of synaptic efficacy. •  Axon terminals of cortical pyramidal neurons are two–three times more susceptible to polarization than somas. •  DCS in humans results in current flow dominantly parallel to the cortical surface, which in animal models of cortical stimulation results in synaptic pathway‐specific modulation of neuronal excitability. •  These results suggest that somatic polarization together with axon terminal polarization may be important for synaptic pathway‐specific modulation of DCS, which underlies modulation of neuronal excitability during transcranial DCS.

Effects of weak transcranial alternating current stimulation on brain activity—a review of known mechanisms from animal studies

Rhythmic neuronal activity is ubiquitous in the human brain. These rhythms originate from a variety of different network mechanisms, which give rise to a wide-ranging spectrum of oscillation frequencies. In the last few years an increasing number of clinical research studies have explored transcranial alternating current stimulation (tACS) with weak current as a tool for affecting brain function. The premise of these interventions is that tACS will interact with ongoing brain oscillations. However, the exact mechanisms by which weak currents could affect neuronal oscillations at different frequency bands are not well known and this, in turn, limits the rational optimization of human experiments. Here we review the available in vitro and in vivo animal studies that attempt to provide mechanistic explanations. The findings can be summarized into a few generic principles, such as periodic modulation of excitability, shifts in spike timing, modulation of firing rate, and shifts in the balance of excitation and inhibition. These effects result from weak but simultaneous polarization of a large number of neurons. Whether this can lead to an entrainment or a modulation of brain oscillations, or whether AC currents have no effect at all, depends entirely on the specific dynamic that gives rise to the different brain rhythms, as discussed here for slow wave oscillations (∼1 Hz) and gamma oscillations (∼30 Hz). We conclude with suggestions for further experiments to investigate the role of AC stimulation for other physiologically relevant brain rhythms.

Toward rational design of electrical stimulation strategies for epilepsy control

Electrical stimulation is emerging as a viable alternative for patients with epilepsy whose seizures are not alleviated by drugs or surgery. Its attractions are temporal and spatial specificity of action, flexibility of waveform parameters and timing, and the perception that its effects are reversible unlike resective surgery. However, despite significant advances in our understanding of mechanisms of neural electrical stimulation, clinical electrotherapy for seizures relies heavily on empirical tuning of parameters and protocols. We highlight concurrent treatment goals with potentially conflicting design constraints that must be resolved when formulating rational strategies for epilepsy electrotherapy, namely, seizure reduction versus cognitive impairment, stimulation efficacy versus tissue safety, and mechanistic insight versus clinical pragmatism. First, treatment markers, objectives, and metrics relevant to electrical stimulation for epilepsy are discussed from a clinical perspective. Then the experimental perspective is presented, with the biophysical mechanisms and modalities of open-loop electrical stimulation, and the potential benefits of closed-loop control for epilepsy.

Transcranial electrical stimulation accelerates human sleep homeostasis.

The sleeping brain exhibits characteristic slow-wave activity which decays over the course of the night. This decay is thought to result from homeostatic synaptic downscaling. Transcranial electrical stimulation can entrain slow-wave oscillations (SWO) in the human electro-encephalogram (EEG). A computational model of the underlying mechanism predicts that firing rates are predominantly increased during stimulation. Assuming that synaptic homeostasis is driven by average firing rates, we expected an acceleration of synaptic downscaling during stimulation, which is compensated by a reduced drive after stimulation. We show that 25 minutes of transcranial electrical stimulation, as predicted, reduced the decay of SWO in the remainder of the night. Anatomically accurate simulations of the field intensities on human cortex precisely matched the effect size in different EEG electrodes. Together these results suggest a mechanistic link between electrical stimulation and accelerated synaptic homeostasis in human sleep.

Lasting modulation of in vitro oscillatory activity with weak direct current stimulation

Transcranial direct current stimulation (tDCS) is emerging as a versatile tool to affect brain function. While the acute neurophysiological effects of stimulation are well understood, little is know about the long-term effects. One hypothesis is that stimulation modulates ongoing neural activity, which then translates into lasting effects via physiological plasticity. Here we used carbachol-induced gamma oscillations in hippocampal rat slices to establish whether prolonged constant current stimulation has a lasting effect on endogenous neural activity. During 10 min of stimulation, the power and frequency of gamma oscillations, as well as multiunit activity, were modulated in a polarity specific manner. Remarkably, the effects on power and multiunit activity persisted for more than 10 min after stimulation terminated. Using a computational model we propose that altered synaptic efficacy in excitatory and inhibitory pathways could be the source of these lasting effects. Future experimental studies using this novel in vitro preparation may be able to confirm or refute the proposed hypothesis.

Transcranial Electrical Stimulation: Transcranial Direct Current Stimulation (tDCS), Transcranial Alternating Current Stimulation (tACS), Transcranial Pulsed Current Stimulation (tPCS), and Transcranial Random Noise Stimulation (tRNS)

Transcranial electrical stimulation (tES) includes a range of devices where electric current is applied to electrodes on the head to modulate brain function. Various tES devices are applied to indications spanning neurological and psychiatric disorders, neuro-rehabilitation after injury, and altering cognition in healthy adults. All tES devices share certain common features including a waveform generator (typically current controlled), disposable electrodes or electrolyte, and an adhesive or headgear to position the electrodes. tES “dose” is defined by the size and position of electrodes and the waveform (current pattern, duration, and intensity). Many subclasses of tES are named based on dose. This chapter is largely focused on low-intensity (few mA) tES. Low-intensity tES includes transcranial direct-current stimulation (tDCS), transcranial alternating-current stimulation (tACS), and transcranial pulsed-current stimulation (tPCS). Electrode design is important for reproducibility, tolerability, and influences when and what dose can be applied. Stimulation impedance measurements monitor contact quality, while current control is typically used to ensure consistent current delivery despite electrode impedance unknowns. Computational current flow models support device design and programming by informing dose selection for a given outcome. Consensus on the safety and tolerability of tES is protocol-specific, but medical-grade tES devices minimize risk.

Long-term effects of weak electrical stimulation on active neuronal networks

Transcranial direct-current stimulation induces cortically sub-millivolt electric fields that modulate brain activity and induce long-term (plastic) effects measurable as improved cognitive and behavioral performances in human experiments [1]. However, the basic mechanisms by which a weak electric field can induce long term effects are not clear yet. This is a limitation for developing more targeted stimulation protocols or to maximize the outcome of the stimulation. In particular, considering that 1 V/m electric field can polarize the neuronal membrane at most 0.2 mV [2], it is still a mystery how such a small voltage fluctuation can mediate any significant long-term effect. Here we combine experiments in rat brain slices and computational models of neuronal networks to determine how fields can induce long-term effects. Our hypothesis is that basal neuronal depolarization and network activity are required to amplify the effects of the electric field and so to mediate plasticity. Network activity can be induced in hippocampal rat slices by applying carbachol, a cholinergic agonist [3]. The coherent network activity can be measured extracellularly in the high beta/low gamma frequency band. The activity persists for many hours and is generated from the interplay of excitation of pyramidal neurons and inhibitory feedback. We have previously characterized the effects of fields on gamma oscillations during stimulation [4]. Gamma power is modulated depending on the frequency and amplitude of the stimulation. A computational model based on Izhikevichs single neuron dynamics describing synaptically connected excitatory and inhibitory neurons was parameterized based on the results of the extracellular recordings in slices. The model explained the effects of the electric field on firing rate and spike timing and made precise predictions about intracellular experiments that were confirmed. However, how these acute effects of stimulation translate to long-term was not investigated. Previous experimental and theoretical studies have shown that small injected currents on post-synaptic neurons can strongly modulate LTP/LTD induction in paired pre- and post-synaptic neurons intracellular recordings and even result in plastic effects despite timing discrepancy between the two spike timings [5,6]. The effects are thought to be mediated by dendritic depolarization [6]. Based on these results and considering that weak electrical stimulation induce small membrane polarizations, we investigate how small currents can induce long term plastic effect. We applied DC electric fields for 10 minutes during carbachol-induced gamma oscillations in hippocampal brain slices and record the oscillations for 1 hour after stimulation. The basal depolarization induced by carbachol (~10 mV) is a range that is plasticity-permissive. To further investigate how electric fields affect neuronal somatic and dendritic compartments, we use current source density to estimate sink and source dynamics during oscillations and stimulation. Our preliminary results show that indeed, electrical stimulation not only acutely modulates the power of the oscillations but also produces after-stimulation effects. We also perfuse slices with synaptic blockers to determine which receptors mediate possible long-term effects induced by the electrical stimulation. The experimental results are then combined to model the effect of electric field on gamma oscillations and plastic synapses at a network level.