2026-10-07

Electrophysiological recordings provide powerful tools for characterizing the dynamics of neuronal networks. In vitro neuronal cultures offer a controlled setting for investigating network responses to diverse interventions, including pharmacological and optogenetic stimulation. However, conventional analyses often reduce electrophysiological activity to aggregate measures calculated over fixed temporal windows, providing only a static representation of the network state. Here, we introduce a comprehensive, multiparametric analytical framework designed to characterize both the temporal evolution of network activity and the transitional states induced by external interventions. The framework combines multiple network discriminators with a compositional analysis that resolves electrode-level responses into excited, inhibited, and unchanged states over successive temporal segments. We apply the framework to electrophysiological recordings obtained under pharmacological interventions with 4-aminopyridine (4-AP), optogenetic stimulation, and additional benchmark conditions. The results demonstrate that the proposed analysis can reveal subtle and transient responses that may be difficult to detect using conventional aggregate measures, including responses to low-dose pharmacological interventions. These findings highlight the value of temporally resolved and compositional analyses for characterizing heterogeneous neuronal network responses in vitro.

Where generalization capacity--the ability to extract context-invariant relational structures--first emerges remains a central question in AI and neuroscience. The foundation for this capacity lies upstream of the hippocampus, within the entorhinal cortex, where parallel pathways dissociate relational structure in the medial entorhinal cortex (MEC) from sensory content in the lateral entorhinal cortex. However, as Eichenbaum argued, such factorization likely originates earlier, driven by the segregation of the dorsal ('where') and ventral ('what') visual streams. Supporting this, grid-like firing patterns--a signature of MEC (context-invariant codes)--also appear in preceding neocortical regions along the dorsal pathway. Yet, how such representations are computationally formed along upstream pathways remains unknown. To investigate this in silico, we developed ReGraph, a recurrent dual-stream graph model with biological inductive biases, including retina-driven stream-specialized encoding, dorsal-to-ventral modulation, and dynamic lateral connectivity. Trained on the action benchmark Something-Something V2, ReGraph revealed a pathway-specific emergence of relational mapping: context-invariant codes and grid-like spatial bases uniquely co-emerged along the extended dorsal stream. In contrast, their absence in single-stream, unmodulated variants, and standard baselines implies that these inductive biases are prerequisites for relational structures. Crucially, our post-hoc analyses demonstrated that these grid-like bases serve as reusable routing templates for information processing via lateral connectivity. Together, our findings provide a computational account that generalization may not be a faculty that emerges abruptly within a dedicated region, but a property that already takes shape as sensory information is parsed into factorized streams of hierarchical visual processing.

Electrophysiological source imaging (ESI) aims to estimate cortical source activity from noninvasive electrophysiological measurements such as electroencephalogram (EEG). However, ESI is fundamentally ill-posed because source activity is substantially higher-dimensional than sensor observations, resulting in non-unique solutions. Recent learning-based approaches address this ambiguity by learning data-driven source priors, yet they often struggle to generalize across subject-specific cortical geometries. To address this, we propose CANDLE, a learning-based ESI model that estimates source activity on subject-specific cortical geometries. CANDLE learns a prior over the null space induced by the source-to-sensor mapping derived from T1-weighted MRI, restricting learning to unobservable source components while preserving geometric constraints. To train CANDLE, we develop a whole-brain simulator spanning over 1,100 subject-specific cortical geometries with source configurations derived from over 26,000 statistical brain maps. Trained exclusively on simulated data, CANDLE outperformed prior ESI methods on simulated source activity estimation and generalized to two empirical tasks: (i) intracranial stimulation localization from simultaneously recorded scalp EEG and (ii) epileptogenic zone estimation from presurgical interictal EEG. Our project page is available at https://candle-esi.pages.dev}{https://candle-esi.pages.dev.