Cortical function emerges from the interactions of multi-scale networks that may be studied at a high level using neural mass models (NMM) that represent the mean activity of large numbers of neurons. Here, we provide first a new framework called laminar NMM, or LaNMM for short, where we combine conduction physics with NMMs to simulate electrophysiological measurements. Then, we employ this framework to infer the location of oscillatory generators from laminar-resolved data collected from the prefrontal cortex in the macaque monkey. We define a minimal model capable of generating coupled slow and fast oscillations, and we optimize LaNMM-specific parameters to fit multi-contact recordings. We rank the candidate models using an optimization function that evaluates the match between the functional connectivity (FC) of the model and data, where FC is defined by the covariance between bipolar voltage measurements at different cortical depths. The family of best solutions reproduces the FC of the observed electrophysiology by selecting locations of pyramidal cells and their synapses that result in the generation of fast activity at superficial layers and slow activity across most depths, in line with recent literature proposals. In closing, we discuss how this hybrid modeling framework can be more generally used to infer cortical circuitry.

Several decades of research suggest that weak electric fields may influence neural processing, including those induced by neuronal activity and proposed as a substrate for a potential new cellular communication system, i.e., ephaptic transmission. Here we aim to model mesoscopic ephaptic activity in the human brain and explore its trajectory during aging by characterizing the electric field generated by cortical dipoles using realistic finite element modeling. Extrapolating from electrophysiological measurements, we first observe that modeled endogenous field magnitudes are comparable to those in measurements of weak but functionally relevant self-generated fields and to those produced by noninvasive transcranial brain stimulation, and therefore possibly able to modulate neuronal activity. Then, to evaluate the role of these fields in the human cortex in large MRI databases, we adapt an interaction approximation that considers the relative orientation of neuron and field to estimate the membrane potential perturbation in pyramidal cells. We use this approximation to define a simplified metric (EMOD1) that weights dipole coupling as a function of distance and relative orientation between emitter and receiver and evaluate it in a sample of 401 realistic human brain models from healthy subjects aged 16–83. Results reveal that ephaptic coupling, in the simplified mesoscopic modeling approach used here, significantly decreases with age, with higher involvement of sensorimotor regions and medial brain structures. This study suggests that by providing the means for fast and direct interaction between neurons, ephaptic modulation may contribute to the complexity of human function for cognition and behavior, and its modification across the lifespan and in response to pathology. We study the potential role of a less understood type of communication between neurons in the brain. While the principal mechanism for neuron communication is synaptic, active neurons generate electric fields. Whether this is physiologically relevant at the systems level or merely an epiphenomenon is uncertain because these fields are rather weak at the mesoscopic scale (i.e., between single neuron and entire brain scales). We first review converging evidence from in-vitro and in-vivo studies that suggest the former, and then, using realistic finite element modeling, we show that the electric fields generated by transcranial electrical current stimulation are of the same magnitude as endogenous ones in this scale. We then develop a method to estimate the amount of potential ephaptic or electric-field interaction in an individual brain using finite element modeling and show its decrease with age in a large cohort of 401 subjects. Ephaptic interaction may be important for complex processing in biological neural networks, because it travels at very fast speeds and provides a potential communication link across distant neurons in the cortex. Assessing the physiological relevance of this mechanism may be key in understanding some brain disorders and to design improved tES protocols.

Work in the last two decades has shown that neural mass models (NMM) can realistically reproduce and explain epileptic seizure transitions as recorded by electrophysiological methods (EEG, SEEG). In previous work, advances were achieved by increasing excitation and heuristically varying network inhibitory coupling parameters in the models. Based on these early studies, we provide a laminar NMM capable of realistically reproducing the electrical activity recorded by SEEG in the epileptogenic zone during interictal to ictal states. With the exception of the external noise input into the pyramidal cell population, the model dynamics are autonomous. By setting the system at a point close to bifurcation, seizure-like transitions are generated, including pre-ictal spikes, low voltage fast activity, and ictal rhythmic activity. A novel element in the model is a physiologically motivated algorithm for chloride dynamics: the gain of GABAergic post-synaptic potentials is modulated by the pathological accumulation of chloride in pyramidal cells due to high inhibitory input and/or dysfunctional chloride transport. In addition, in order to simulate SEEG signals for comparison with real seizure recordings, the NMM is embedded first in a layered model of the neocortex and then in a realistic physical model. We compare modeling results with data from four epilepsy patient cases. By including key pathophysiological mechanisms, the proposed framework captures succinctly the electrophysiological phenomenology observed in ictal states, paving the way for robust personalization methods based on NMMs.

Major Depressive Disorder (MDD) is a complex, heterogeneous condition affecting millions worldwide. Computational neuropsychiatry offers potential breakthroughs through the mechanistic modeling of this disorder. Using the Kolmogorov theory (KT) of consciousness, we developed a foundational model where algorithmic agents interact with the world to maximize an Objective Function evaluating affective valence. Depression, defined in this context by a state of persistently low valence, may arise from various factors—including inaccurate world models (cognitive biases), a dysfunctional Objective Function (anhedonia, anxiety), deficient planning (executive deficits), or unfavorable environments. Integrating algorithmic, dynamical systems, and neurobiological concepts, we map the agent model to brain circuits and functional networks, framing potential etiological routes and linking with depression biotypes. Finally, we explore how brain stimulation, psychotherapy, and plasticity-enhancing compounds such as psychedelics can synergistically repair neural circuits and optimize therapies using personalized computational models.

We explore the intersection of neural dynamics and the effects of psychedelics in light of distinct timescales in a framework integrating concepts from dynamics, complexity, and plasticity. We call this framework neural geometrodynamics for its parallels with general relativity’s description of the interplay of spacetime and matter. The geometry of trajectories within the dynamical landscape of “fast time” dynamics are shaped by the structure of a differential equation and its connectivity parameters, which themselves evolve over “slow time” driven by state-dependent and state-independent plasticity mechanisms. Finally, the adjustment of plasticity processes (metaplasticity) takes place in an “ultraslow” time scale. Psychedelics flatten the neural landscape, leading to heightened entropy and complexity of neural dynamics, as observed in neuroimaging and modeling studies linking increases in complexity with a disruption of functional integration. We highlight the relationship between criticality, the complexity of fast neural dynamics, and synaptic plasticity. Pathological, rigid, or “canalized” neural dynamics result in an ultrastable confined repertoire, allowing slower plastic changes to consolidate them further. However, under the influence of psychedelics, the destabilizing emergence of complex dynamics leads to a more fluid and adaptable neural state in a process that is amplified by the plasticity-enhancing effects of psychedelics. This shift manifests as an acute systemic increase of disorder and a possibly longer-lasting increase in complexity affecting both short-term dynamics and long-term plastic processes. Our framework offers a holistic perspective on the acute effects of these substances and their potential long-term impacts on neural structure and function.