Spherical harmonics representation of the steady-state membrane potential shift induced by tDCS in realistic neuron models.

Objective.We provide a systematic framework for quantifying the effect of externally applied weak electric fields on realistic neuron compartment models as captured by physiologically relevant quantities such as the membrane potential or transmembrane current as a function of the orientation of the field.Approach.We define a response function as the steady-state change of the membrane potential induced by a canonical external field of 1 V m-1as a function of its orientation. We estimate the function values through simulations employing reconstructions of the rat somatosensory cortex from the Blue Brain Project. The response of different cell types is simulated using the NEURON simulation environment. We represent and analyze the angular response as an expansion in spherical harmonics.Main results.We report membrane perturbation values comparable to those in the literature, extend them to different cell types, and provide their profiles as spherical harmonic coefficients. We show that at rest, responses are dominated by their dipole terms (ℓ=1), in agreement with experimental findings and compartment theory. Indeed, we show analytically that for a passive cell, only the dipole term is nonzero. However, while minor, other terms are relevant for states different from resting. In particular, we show howℓ=0andℓ=2terms can modify the function to induce asymmetries in the response.Significance.This work provides a practical framework for the representation of the effects of weak electric fields on different neuron types and their main regions-an important milestone for developing micro- and mesoscale models and optimizing brain stimulation solutions.

Towards a mesoscale physical modeling framework for stereotactic-EEG recordings.

Objective.Stereotactic-electroencephalography (SEEG) and scalp EEG recordings can be modeled using mesoscale neural mass population models (NMMs). However, the relationship between those mathematical models and the physics of the measurements is unclear. In addition, it is challenging to represent SEEG data by combining NMMs and volume conductor models due to the intermediate spatial scale represented by these measurements.Approach.We provide a framework combining the multi-compartmental modeling formalism and a detailed geometrical model to simulate the transmembrane currents that appear in layer 3, 5 and 6 pyramidal cells due to a synaptic input. With this approach, it is possible to realistically simulate the current source density (CSD) depth profile inside a cortical patch due to inputs localized into a single cortical layer and the induced voltage measured by two SEEG contacts using a volume conductor model. Based on this approach, we built a framework to connect the activity of a NMM with a volume conductor model and we simulated an example of SEEG signal as a proof of concept.Main results.CSD depends strongly on the distribution of the synaptic inputs onto the different cortical layers and the equivalent current dipole strengths display substantial differences (of up to a factor of four in magnitude in our example). Thus, the inputs coming from different neural populations do not contribute equally to the electrophysiological recordings. A direct consequence of this is that the raw output of NMMs is not a good proxy for electrical recordings. We also show that the simplest CSD model that can accurately reproduce SEEG measurements can be constructed from discrete monopolar sources (one per cortical layer).Significance.Our results highlight the importance of including a physical model in NMMs to represent measurements. We provide a framework connecting microscale neuron models with the neural mass formalism and with physical models of the measurement process that can improve the accuracy of predicted electrophysiological recordings.

Reduced serial dependence suggests deficits in synaptic potentiation in anti-NMDAR encephalitis and schizophrenia.

A mechanistic understanding of core cognitive processes, such as working memory, is crucial to addressing psychiatric symptoms in brain disorders. We propose a combined psychophysical and biophysical account of two symptomatologically related diseases, both linked to hypofunctional NMDARs: schizophrenia and autoimmune anti-NMDAR encephalitis. We first quantified shared working memory alterations in a delayed-response task. In both patient groups, we report a markedly reduced influence of previous stimuli on working memory contents, despite preserved memory precision. We then simulated this finding with NMDAR-dependent synaptic alterations in a microcircuit model of prefrontal cortex. Changes in cortical excitation destabilized within-trial memory maintenance and could not account for disrupted serial dependence in working memory. Rather, a quantitative fit between data and simulations supports alterations of an NMDAR-dependent memory mechanism operating on longer timescales, such as short-term potentiation.

Interplay between persistent activity and activity-silent dynamics in the prefrontal cortex underlies serial biases in working memory.

Persistent neuronal spiking has long been considered the mechanism underlying working memory, but recent proposals argue for alternative 'activity-silent' substrates. Using monkey and human electrophysiology data, we show here that attractor dynamics that control neural spiking during mnemonic periods interact with activity-silent mechanisms in the prefrontal cortex (PFC). This interaction allows memory reactivations, which enhance serial biases in spatial working memory. Stimulus information was not decodable between trials, but remained present in activity-silent traces inferred from spiking synchrony in the PFC. Just before the new stimulus, this latent trace was reignited into activity that recapitulated the previous stimulus representation. Importantly, the reactivation strength correlated with the strength of serial biases in both monkeys and humans, as predicted by a computational model that integrates activity-based and activity-silent mechanisms. Finally, single-pulse transcranial magnetic stimulation applied to the human PFC between successive trials enhanced serial biases, thus demonstrating the causal role of prefrontal reactivations in determining working-memory behavior.