Effects of transcranial alternating current stimulation on spiking activity in computational models of single neocortical neurons.

Neural oscillations are a key mechanism for information transfer in brain circuits. Rhythmic fluctuations of local field potentials control spike timing through cyclic membrane de- and hyperpolarization. Transcranial alternating current stimulation (tACS) is a non-invasive neuromodulation method which can directly interact with brain oscillatory activity by imposing an oscillating electric field on neurons. Despite its increasing use, the basic mechanisms of tACS are still not fully understood. Here, we investigate in a computational study the effects of tACS on morphologically realistic neurons with ongoing spiking activity. We characterize the membrane polarization as a function of electric field strength and subsequent effects on spiking activity in a set of 25 neurons from different neocortical layers. We find that tACS does not affect the firing rate of investigated neurons for electric field strengths applicable to human studies. However, we find that the applied electric fields entrain the spiking activity of large pyramidal neurons and large basket neurons at < 1 mV/mm field strengths. Our model results are in line with recent experimental studies and can provide a mechanistic framework to understand the effects of oscillating electric fields on single neuron activity. They highlight the importance of neuron morphology and biophysics in responsiveness to electrical stimulation.

Fast simulation of extracellular action potential signatures based on a morphological filtering approximation.

Simulating extracellular recordings of neuronal populations is an important and challenging task both for understanding the nature and relationships between extracellular field potentials at different scales, and for the validation of methodological tools for signal analysis such as spike detection and sorting algorithms. Detailed neuronal multicompartmental models with active or passive compartments are commonly used in this objective. Although using such realistic NEURON models could lead to realistic extracellular potentials, it may require a high computational burden making the simulation of large populations difficult without a workstation. We propose in this paper a novel method to simulate extracellular potentials of firing neurons, taking into account the NEURON geometry and the relative positions of the electrodes. The simulator takes the form of a linear geometry based filter that models the shape of an action potential by taking into account its generation in the cell body / axon hillock and its propagation along the axon. The validity of the approach for different NEURON morphologies is assessed. We demonstrate that our method is able to reproduce realistic extracellular action potentials in a given range of axon/dendrites surface ratio, with a time-efficient computational burden.

intensity- and frequency-specific effects of transcranial alternating current stimulation are explained by network dynamics.

Objective. Transcranial alternating current stimulation (tACS) can be used to non-invasively entrain neural activity and thereby cause changes in local neural oscillatory power. Despite its increased use in cognitive and clinical neuroscience, the fundamental mechanisms of tACS are still not fully understood.Approach. We developed a computational neuronal network model of two-compartment pyramidal neurons (PY) and inhibitory interneurons, which mimic the local cortical circuits. We modeled tACS with electric field strengths that are achievable in human applications. We then simulated intrinsic network activity and measured neural entrainment to investigate how tACS modulates ongoing endogenous oscillations.Main results. The intensity-specific effects of tACS are non-linear. At low intensities (<0.3 mV mm-1), tACS desynchronizes neural firing relative to the endogenous oscillations. At higher intensities (>0.3 mV mm-1), neurons are entrained to the exogenous electric field. We then further explore the stimulation parameter space and find that the entrainment of ongoing cortical oscillations also depends on stimulation frequency by following an Arnold tongue. Moreover, neuronal networks can amplify the tACS-induced entrainment via synaptic coupling and network effects. Our model shows that PY are directly entrained by the exogenous electric field and drive the inhibitory neurons.Significance. The results presented in this study provide a mechanistic framework for understanding the intensity- and frequency-specific effects of oscillating electric fields on neuronal networks. This is crucial for rational parameter selection for tACS in cognitive studies and clinical applications.

Induced neural phase precession through exogenous electric fields.

The gradual shifting of preferred neural spiking relative to local field potentials (LFPs), known as phase precession, plays a prominent role in neural coding. Correlations between the phase precession and behavior have been observed throughout various brain regions. As such, phase precession is suggested to be a global neural mechanism that promotes local neuroplasticity. However, causal evidence and neuroplastic mechanisms of phase precession are lacking so far. Here we show a causal link between LFP dynamics and phase precession. In three experiments, we modulated LFPs in humans, a non-human primate, and computational models using alternating current stimulation. We show that continuous stimulation of motor cortex oscillations in humans lead to a gradual phase shift of maximal corticospinal excitability by ~90°. Further, exogenous alternating current stimulation induced phase precession in a subset of entrained neurons (~30%) in the non-human primate. Multiscale modeling of realistic neural circuits suggests that alternating current stimulation-induced phase precession is driven by NMDA-mediated synaptic plasticity. Altogether, the three experiments provide mechanistic and causal evidence for phase precession as a global neocortical process. Alternating current-induced phase precession and consequently synaptic plasticity is crucial for the development of novel therapeutic neuromodulation methods.

Multi-scale modeling toolbox for single neuron and subcellular activity under Transcranial Magnetic Stimulation.

BACKGROUND: Transcranial Magnetic Stimulation (TMS) is a widely used non-invasive brain stimulation method. However, its mechanism of action and the neural response to TMS are still poorly understood. Multi-scale modeling can complement experimental research to study the subcellular neural effects of TMS. At the macroscopic level, sophisticated numerical models exist to estimate the induced electric fields. However, multi-scale computational modeling approaches to predict TMS cellular and subcellular responses, crucial to understanding TMS plasticity inducing protocols, are not available so far. OBJECTIVE: We develop an open-source multi-scale toolbox Neuron Modeling for TMS (NeMo-TMS) to address this problem. METHODS: NeMo-TMS generates accurate neuron models from morphological reconstructions, couples them to the external electric fields induced by TMS, and simulates the cellular and subcellular responses of single-pulse and repetitive TMS. RESULTS: We provide examples showing some of the capabilities of the toolbox. CONCLUSION: NeMo-TMS toolbox allows researchers a previously not available level of detail and precision in realistically modeling the physical and physiological effects of TMS.

Effects of inhibition of neuronal nitric oxide synthase on basal retinal blood flow regulation.

Nitric oxide (NO) has been observed to regulate blood flow under basal and stimulated conditions in the retina. Recent evidence suggests that NO produced by neuronal nitric oxide synthase (nNOS) may regulate blood flow in addition to that produced by endothelial nitric oxide synthase (eNOS). The objective of the current study was to investigate the contribution of NO produced by nNOS in the regulation of basal retinal blood flow. A non-specific NOS inhibitor N (G)-nitro-l-arginine methyl ester (l-NAME) and the specific nNOS inhibitors 1-(2-trifluoromethylphenyl) imidazole (TRIM) and (4S)-N-(4-amino-5 [aminoethyl] aminopentyl)-N-nitroguanidine (AAAN) were injected into the vitreous (intravitreal) of Long-Evans rats. Vessel diameters, velocities and volumetric blood flow rates (VBF) in the retinal circulation were determined prior to and in 30-min intervals for 4-4.5h after injection. In addition, the basal amount of nNOS in the rat retina was quantified using a specific enzyme linked immunoassay (ELISA). Treatment with l-NAME and TRIM significantly decreased diameters and VBF. Compared with saline, treatment with l-NAME and TRIM produced a significant (p<0.001) decrease of approximately 12-17% in vessel diameters. Treatment with AAAN significantly decreased vessel diameters and venous VBF. Compared with saline AAAN produced a significant decrease of approximately 7% in arterial (p<0.001) and 5% in venous (p=0.011) diameters, respectively. The amount of nNOS in the rat retina was 0.17+/- 0.0147 pmol mg(-1) of dry retina. The results suggest that though inhibition of nNOS decreases basal diameters, constant VBF is maintained in the retinal circulation.