Arturo G. Isla

Childhood epilepsy may affect language development during the preschool years, a critical period for the acquisition of receptive vocabulary, expressive language, phonological skills, and early communication abilities; however, evidence focused specifically on preschool-aged populations remains scarce and inconsistent. This systematic review with exploratory meta-analysis, conducted following PRISMA 2020 guidelines, aimed to synthesize available evidence on the impact of active epilepsy on oral language development in preschool-aged children, examining receptive and expressive language, vocabulary, phonological processing, and auditory-verbal memory outcomes. Literature published between 2008 and 2025 addressing oral language performance in young children with epilepsy was retrieved from relevant databases, and random-effects models were applied where sufficient comparable data existed: continuous variables were pooled as Hedges' g standardized mean differences, binary outcomes as odds ratios, and prevalence data as pooled proportions. Seven independent study populations, reported across eight publications, met the eligibility criteria. Relative to typically developing peers, children with epilepsy showed markedly poorer receptive/comprehension performance. Language delay or disorder had a pooled prevalence of 0.50 (95% CI, 0.26-0.74), although heterogeneity across studies was high. Exploratory analyses further indicated greater likelihood of expressive impairment and receptive delay. These findings indicate that preschool-aged children with epilepsy experience meaningful vulnerability across multiple oral language domains, supporting the need for early speech-language screening and coordinated interdisciplinary follow-up in this population.

The interaction of retinal center-surround processes with early visual subcortical and cortical circuits forms the basis for saliency computations. The subcortical circuit mechanisms contributing to surround modulation, however, remain unclear. We developed an optogenetic approach to functionally delineate visual center and surround zones of individual neurons in the superficial layers of the superior colliculus (SCs). We demonstrate that local circuit interactions within the SCs are sufficient to generate visual surround suppression. Notably, surround network activation leads to decreases in center excitation rather than increases in synaptic inhibition. Using a range of complementary methods, we reveal the identity of a SCs-based circuit with two key interacting circuit motifs, recurrent excitation and feedback inhibition, capable of modulating levels of center excitation when the visual surround is active. We propose that subcortical and cortical visual circuits are both recurrent-based and have evolved to independently perform surround modulation, thus enabling parallel saliency computations across multiple levels.

Center-surround interactions are fundamental to visual saliency computation, but debate continues over whether and how subcortical visual circuits actively contribute. To address this, we developed an optogenetic approach to delineate the visual center and surround zones of individual neurons in the superficial layer of the superior colliculus (SCs) using only retinal ganglion cell input. Using whole-cell recordings, we demonstrate that surround network activation suppresses center excitability, indicating that SCs circuitry is self-sufficient in driving center-surround dynamics. Through cell-type-specific trans-synaptic tracing and large-scale modeling, we identified an SCs-based circuit with two key motifs driving surround modulation: recurrent excitation and feedback inhibition. We propose that subcortical visual circuits in the SCs have evolved to perform surround suppression alongside retinal and cortical suppression, facilitating the distribution of parallel saliency computations across different levels. Significance statement: This study questions the notion that the superior colliculus (SC) merely acts as a passive recipient of saliency information from upstream circuits. We demonstrate that the SC can independently generate center-surround interactions that could contribute to visual saliency through local circuits without top-down input. This ability represents a computation that has been conserved since the dawn of vertebrate evolution. By mapping these interactions, we reveal that the mouse SC actively induces visual surround suppression. These findings suggest that phylogenetically older circuits in the SC may play a more independent role in active vision than previously acknowledged, prompting a reevaluation of visual saliency processing across subcortical brain regions.

In Alzheimer’s disease (AD) the accumulation of amyloid-β (Aβ) correlates with degradation of cognition-relevant gamma oscillations. The gamma rhythm relies on proper neuronal spike-gamma coupling, specifically of fast-spiking interneurons (FSN). Here we tested the hypothesis that decrease in gamma power and FSN synchrony precede amyloid plaque deposition and cognitive impairment in App^NL-G-F knock-in mice (App^NL-G-F). The aim of the study was to evaluate the amyloidogenic pathology progression in the novel App^NL-G-F mouse model using in vitro electrophysiological network analysis. Using patch clamp of FSNs and pyramidal cells (PCs) with simultaneous gamma oscillation recordings, we compared the activity of the hippocampal network of wild-type mice (WT) and the App^NL-G-F mice at four disease stages (1, 2, 4, and 6 months of age). We found a severe degradation of gamma oscillation power that is independent of, and precedes Aβ plaque formation, and the cognitive impairment reported previously in this animal model. The degradation correlates with increased Aβ_1-42 concentration in the brain. Analysis on the cellular level showed an impaired spike-gamma coupling of FSN from 2 months of age that correlates with the degradation of gamma oscillations. From 6 months of age PC firing becomes desynchronized also, correlating with reports in the literature of robust Aβ plaque pathology and cognitive impairment in the App^NL-G-F mice. This study provides evidence that impaired FSN spike-gamma coupling is one of the earliest functional impairment caused by the amyloidogenic pathology progression likely is the main cause for the degradation of gamma oscillations and consequent cognitive impairment. Our data suggests that therapeutic approaches should be aimed at restoring normal FSN spike-gamma coupling and not just removal of Aβ.

Alzheimer’s disease (AD) is characterized in the late stages by amyloid-β (Aβ) plaques and neurofibrillary tangles. Nevertheless, recent evidence has indicated that early changes in cerebral connectivity could compromise cognitive functions even before the appearance of the classical neuropathological features. Diffusion tensor imaging (DTI), resting-state functional magnetic resonance imaging (rs-fMRI) and volumetry were performed in the triple transgenic mouse model of AD (3xTg-AD) at 2 months of age, prior to the development of intraneuronal plaque accumulation. We found the 3xTg-AD had significant fractional anisotropy (FA) increase and radial diffusivity (RD) decrease in the cortex compared with wild-type controls, while axial diffusivity (AD) and mean diffusivity (MD) were similar. Interhemispheric hippocampal connectivity was decreased in the 3xTg-AD while connectivity in the caudate putamen (CPu) was similar to controls. Most surprising, ventricular volume in the 3xTg-AD was four times larger than controls. The results obtained in this study characterize the early stage changes in interhemispheric hippocampal connectivity in the 3xTg-AD mouse that could represent a translational biomarker to human models in preclinical stages of the AD.

Background: Amyloid beta inhibits olfactory bulb function. The mechanisms involved in this effect must include alterations in network excitability, inflammation and the activation of different transduction pathways. Thus, here we tested whether tolfenamic acid, a drug that modulates several of these pathological processes, could prevent amyloid beta-induced olfactory bulb dysfunction. Objective: To test whether tolfenamic acid prevents amyloid beta-induced alterations in olfactory bulb network function, olfaction and GSK3β activity. Method: The protective effects of tolfenamic acid against amyloid beta-induced population activity inhibition were tested in olfactory bulb slices from adult mice, while tolfenamic acid and amyloid beta were bath-applied. We also tested the effects of amyloid-beta in slices obtained from animals pre-treated chronically (21 days) with tolfenamic acid. The effects of amyloid beta micro-injected into the olfactory bulbs were also tested, after two weeks, on olfactory bulb population activity and olfaction in control and tolfenamic acid chronically treated animals. Olfaction was assessed with the odor-avoidance and the habituation/cross-habituation tests. GSK3β activation was evaluated with Western-blot. Results: Acute bath application of tolfenamic acid does not prevent amyloid beta-induced inhibition of olfactory bulb network activity in vitro. In contrast, chronic treatment with tolfenamic acid renders the olfactory bulb resistant to amyloid beta-induced network activity inhibition in vitro and in vivo, which correlates with the inhibition of GSK3β activation and the protection against amyloid beta-induced olfactory dysfunction. Conclusion: Our data further support the use of tolfenamic acid to prevent amyloid beta-induced pathology and the early symptoms of Alzheimer Disease.

These authors contributed equally to this work. Exercise is becoming a promising therapeutic approach to prevent alterations both in Alzheimer’s disease (AD) patients and in transgenic models of AD. This neuroprotection has been associated with chang