Search Results (69)

Sensory processing differences, reported in up to 97% of individuals with autism spectrum disorder (ASD), are increasingly recognized as a defining feature of the condition, shaping perception, cognition, and adaptive behavior. Atypical sensory responsivity, ranging from hyper- to hypo-reactivity and sensory seeking, emerges early in development and contributes to the clinical and neurobiological heterogeneity of autism. Alterations in neural connectivity, the balance of excitation and inhibition, and multisensory integration are thought to underlie these sensory profiles, influencing emotional regulation, attention, and social interaction. Sensory features also interact with co-occurring conditions such as anxiety, attention deficit hyperactivity disorder, and sleep and feeding difficulties, thereby shaping developmental trajectories and influencing adaptive behavior. Clinically, these sensory dysfunctions have a significant impact on daily participation and quality of life, extending their effects to family functioning. Understanding individual sensory phenotypes is therefore essential for accurate assessment and personalized intervention. Current therapeutic approaches include Sensory Integration Therapy, Sensory-Based Interventions, Sequential Oral Sensory Approach, and structured physical activity programs, often complemented by behavioral and mindfulness-based techniques. Emerging neuroplasticity-oriented methods for targeted modulation of sensory processing networks include neurofeedback and non-invasive brain stimulation. Overall, current evidence highlights the central role of sensory processing in ASD and underscores the need for multidisciplinary, individualized approaches to optimize developmental trajectories and enhance adaptive functioning. This review provides an updated synthesis of sensory processing in ASD, integrating neurobiological, developmental, and clinical evidence to highlight established knowledge, unresolved questions, and priorities for future research. Full article

Background: Repetitive transcranial magnetic stimulation (rTMS) is an established neuromodulatory method, yet its multiscale neurophysiological effects in autism spectrum disorder (ASD) remain insufficiently characterized. Recent EEG analytic advances—such as spectral parameterization, long-range temporal correlation (LRTC) assessment, and connectivity modeling—enable quantitative evaluation of excitation–inhibition (E/I) balance and network organization. Objective: This study aimed to examine whether an eight-session, EEG-guided mixed-frequency rTMS protocol—combining inhibitory 1 Hz and excitatory 10 Hz trains individualized to quantitative EEG (qEEG) abnormalities—produces measurable changes in spectral dynamics, temporal correlations, and functional connectivity in a pediatric ASD case. Methods: An 11-year-old right-handed female with ASD (DSM-5-TR, ADOS-2) underwent resting-state EEG one week before and four months after intervention. Preprocessing used a validated automated pipeline, followed by spectral parameterization (FOOOF), detrended fluctuation analysis (DFA), and connectivity analyses (phase-lag index and Granger causality) in MATLAB (2023b). No inferential statistics were applied due to the single-case design. The study was conducted at Cosmos Healthcare (London, UK) with in-kind institutional support and approved by the Atlantic International University IRB (AIU-IRB-22-101). Results: Post-rTMS EEG showed (i) increased delta and reduced theta/alpha/beta power over central regions; (ii) steeper aperiodic slope and higher offset, maximal at Cz, suggesting increased inhibitory tone; (iii) reduced Hurst exponents (1–10 Hz) at Fz, Cz, and Pz, indicating decreased long-range temporal correlations; (iv) reorganization of hubs away from midline with marked Cz decoupling; and (v) strengthened parietal-to-central directional connectivity (Pz→Cz) with reduced Cz→Pz influence. Conclusions: Mixed-frequency, EEG-guided rTMS produced convergent changes across spectral, aperiodic, temporal, and connectivity measures consistent with modulation of cortical E/I balance and network organization. Findings are preliminary and hypothesis-generating. The study was supported by in-kind resources from Cosmos Healthcare, whose authors participated as investigators but had no influence on analysis or interpretation. Controlled trials are warranted to validate these exploratory results. Full article

Rett syndrome (RTT) is a severe neurodevelopmental disorder caused primarily by mutations in the gene encoding the methyl-CpG-binding protein 2 (Mecp2). Mecp2 binds to methylated cytosines, playing a crucial role in chromatin organization and transcriptional regulation. At the neurobiological level, RTT is characterized by dendritic spine dysgenesis and altered excitation–inhibition balance, drawing attention to the mechanisms that scale from mutations in a nuclear protein to altered neuronal connectivity. Although Mecp2 dysfunction disrupts multiple neuronal processes, emerging evidence highlights altered calcium (Ca²⁺) signaling as a central contributor to RTT pathophysiology. This review explores the link between Mecp2 and Ca²⁺ regulation by highlighting how Mecp2 affects Ca²⁺-dependent transcriptional pathways, while Ca²⁺ modulates Mecp2 function by inducing post-translational modifications. We discuss this crosstalk in light of evidence from RTT models, with a particular focus on the brain-derived neurotrophic factor BDNF-miR132-Mecp2 axis and the dysregulation of ryanodine receptors (RyRs). Additionally, we examine how these perturbations contribute to the reduced structural plasticity and the altered activity-driven gene expression that characterizes RTT. Understanding the intersection between Mecp2 function and Ca²⁺ homeostasis will provide critical insights into RTT pathogenesis and potential therapeutic targets aimed at restoring neuronal connectivity. Full article

Schizophrenia (SZ) is a complex neuropsychiatric disorder characterized by heterogeneous symptoms, relatively poor clinical outcome, and widespread disruptions in neural connectivity and oscillatory dynamics. This article attempts to review current evidence linking genomic and proteomic alterations with aberrant neural oscillations observed in SZ, including aberrations in all oscillatory frequency bands obtained via human EEG. The numerous genes discussed are mainly involved in modulating synaptic transmission, synaptic function, interneuron excitability, and excitation/inhibition balance, thereby influencing the generation and synchronization of neural oscillations at specific frequency bands (e.g., gamma frequency band) critical for different cognitive, emotional, and perceptual processes in humans. The review highlights how polygenic influences and gene–circuit interactions underlie the neural oscillatory and connectivity abnormalities central to SZ pathophysiology, providing a framework for future research on common genetic-neural function interactions and on potential therapeutic interventions targeting local and global network-level neural dysfunction in SZ patients. As will be discussed, many of these genes affecting neural oscillations in SZ also affect other neurological disorders, ranging from autism to epilepsy. In time, it is hoped that future research will show why the same genetic anomaly leads to one illness in one person and to another illness in a different person. Full article

The serotonergic system, originating in the raphe nuclei, differentially modulates the dorsal and ventral hippocampus, which are implicated in cognition and emotion, respectively. Emerging evidence from rodent models (e.g., neonatal ventral hippocampal lesion, pharmacological NMDA receptor antagonist exposure) and human postmortem studies indicates dorsoventral serotonergic alterations in schizophrenia. These data include elevated 5-HT1A receptor expression in the dorsal hippocampus, linking serotonergic hypofunction to cognitive deficits, and hyperactive 5-HT2A/3 receptor signaling and denser serotonergic innervation in the ventral hippocampus driving local hyperexcitability associated with psychosis and stress responsivity. These dorsoventral serotonergic alterations are shown to disrupt the excitation–inhibition balance, impair synaptic plasticity, and disturb network oscillations, as established by in vivo electrophysiology and functional imaging. Synthesizing these multi-level findings, we propose a novel “dorsoventral serotonin imbalance” model of schizophrenia, in which ventral hyperactivation predominantly contributes to psychotic symptoms and dorsal hypoactivity underlies cognitive deficits. We further highlight promising preclinical evidence that selective targeting of region- and receptor-specific targeting, using both pharmacological agents and emerging delivery technologies, may offer novel therapeutic opportunities enabling symptom-specific strategies in schizophrenia. Full article

The balance between cortical excitation and inhibition (E/I balance) in the cerebral cortex is critical for cognitive processing and neuroplasticity. Modulation of this balance has been linked to a wide range of neuropsychiatric and neurodegenerative disorders. The human visual system has well-differentiated magnocellular (M) and parvocellular (P) pathways, which provide a useful model to study cortical excitability using non-invasive visual flicker stimulation. We present an Arduino-driven non-image forming system to deliver controlled flickering light stimuli at different frequencies and wavelengths. By triggering the critical flicker fusion (CFF) frequency, we attempt to modulate the M-pathway activity and attenuate P-pathway responses, in parallel with induced optical scattering. EEG recordings were used to monitor cortical excitability and oscillatory dynamics during visual stimulation. Visual stimulation in the CFF, combined with induced optical scattering, selectively enhanced magnocellular activity and suppressed parvocellular input. EEG analysis showed a modulation of cortical oscillations, especially in the high frequency beta and gamma range. Our results support the hypothesis that visual flicker in the CFF, in addition to spatial degradation, initiates detectable neuroplasticity and regulates cortical excitation and inhibition. These findings suggest new avenues for therapeutic manipulation through visual pathways in diseases such as Alzheimer’s disease, epilepsy, severe depression, and schizophrenia. Full article

Background and Objectives: Arthrogenic muscle inhibition (AMI) is a key neurophysiological barrier to effective rehabilitation in individuals with chronic ankle instability (CAI). The primary objective of this narrative review is to explore the role of arthrogenic muscle inhibition (AMI) in chronic ankle instability (CAI) and to critically appraise neurophysiological and rehabilitative strategies targeting its resolution. Although peripheral strengthening remains a cornerstone of treatment, the roles of spinal and cortical modulation are increasingly recognised. Materials and Methods: A narrative review was conducted to examine recent clinical trials targeting AMI in CAI populations. A structured search of MEDLINE, Web of Science, Scopus, Cochrane Central, and PEDro was performed. Five studies were included, encompassing peripheral, spinal, and cortical interventions. The outcomes were grouped and analysed according to neurophysiological and functional domains. Results: Manual therapy combined with exercise improved pain, strength, and functional mobility. Fibular reposition taping transiently enhanced spinal reflex excitability, while transcranial direct current stimulation (tDCS) over the primary motor cortex significantly modulated corticospinal excitability and voluntary muscle activation. Improvements in subjective stability, dynamic balance, and neuromuscular responsiveness were observed in the majority of the five included studies, although methodological heterogeneity and short-term follow-ups limit generalisability. Conclusions: Multimodal interventions targeting different levels of the neuromotor system appear to be more effective than isolated approaches. Integrating manual therapy, sensorimotor training, and neuromodulation may optimise outcomes in CAI rehabilitation. Future trials should focus on standardised outcome measures and long-term efficacy. Full article

A balanced excitatory/inhibitory (E/I) tone is crucial for proper brain function, and disruptions can lead to neurological disorders. This review explores the role of astrocytes in maintaining a balanced E/I tone in the brain, which is crucial for proper functioning. It highlights the potential for dysfunctional astrocyte metabolism to disrupt E/I balance, leading to neuronal dysfunction and potentially causing neurological disease pathogenesis. The review focuses on glucose, lactate shuttling, and glutamate metabolism. This review synthesizes findings from in vitro, in vivo, and human studies examining the interplay between astrocyte metabolism, neuronal activity, and E/I balance. Literature searches were conducted using keywords including “astrocyte metabolism”, “excitatory/inhibitory balance”, “glutamate”, “lactate shuttle”, “neurometabolic coupling”, and “neurological disorders” in databases such as PubMed and Web of Science. Disruptions in astrocyte glucose uptake or glycolysis can impair lactate production, reducing neuronal energy supply and affecting neuronal excitability. Impaired glutamate uptake and conversion to glutamine within astrocytes leads to elevated extracellular glutamate, promoting excitotoxicity. Altered glycogen metabolism and other metabolic impairments within astrocytes can also affect neuronal health and contribute to imbalances between excitation and inhibition. Dysfunctional astrocyte metabolism represents a significant contributor to E/I imbalance in the brain. Understanding the specific metabolic vulnerabilities of astrocytes and their impact on neuronal function provides potential therapeutic targets for neurological disorders characterized by E/I dysregulation. Targeting astrocyte metabolism may offer a novel approach to restoring E/I balance and improving neurological outcomes. Full article

Endocannabinoids, acting primarily through CB1 receptors, are critical modulators of neuronal activity, influencing cognitive functions and emotional processing. CB1 receptors are highly expressed in the hippocampus, primarily on GABAergic interneurons, modulating the excitation/inhibition balance. Previous evidence suggests the functional heterogeneity of CB1 receptors along the dorsoventral axis of the hippocampus. However, it is not known whether CB1 receptors differentially modulate basic aspects of the local neuronal network along the hippocampus. This study investigated how CB1 receptor activation modulates excitability, paired-pulse inhibition (PPI), and short-term neuronal dynamics (STND) in the dorsal and ventral CA1 hippocampus under physiologically relevant conditions. Using extracellular recordings from hippocampal slices of male Wistar rats, we compared the effects of two CB1 receptor agonists, ACEA and WIN55,212-2, on network activity in the dorsal and ventral hippocampus. We found that both agonists significantly increased excitability and reduced PPI in the dorsal, but not the ventral, hippocampus. Similarly, CB1 receptor activation modulated STND more prominently in the dorsal hippocampus, reducing facilitation at low frequencies and reversing depression at high frequencies, whereas effects on the ventral region were minimal. These dorsoventral differences in the actions of cannabinoid receptor agonists occurred despite similar CB1 receptor expression levels in both regions, suggesting that functional differences arise from downstream mechanisms rather than receptor density. Pre-application of the GIRK channel blocker Tertiapin-Q occluded the effects of WIN55,212-2 on STND, indicating a significant role of GIRK channel-mediated signaling in CB1 receptor actions. These findings demonstrate that CB1 receptors modulate hippocampal circuitry in a region-specific manner, with the dorsal hippocampus being more sensitive to cannabinoid signaling, likely through differential engagement of intracellular signaling pathways such as GIRK channel activation. These results provide novel insights into how endocannabinoid signaling differentially regulates neuronal dynamics along the dorsoventral axis of the hippocampus. They also have important implications for understanding the role of cannabinoids in hippocampus-dependent behaviors. Full article

Background/Objectives: Sensory perception is influenced by internal neuronal variability and external noise. Neuromodulators such as norepinephrine (NE) regulate this variability by modulating excitation–inhibition balance, oscillatory dynamics, and interlaminar connectivity. While NE is known to modulate cortical gain, it remains unclear how it shapes sensory processing under noisy conditions. This study investigates how adrenergic modulation affects signal-to-noise processing and perceptual decision-making in the primary visual cortex (V1) of mice exposed to varying levels of visual noise. Methods: We performed in vivo local field potential (LFP) recordings from layers 2/3 and 4 of V1 in sedated mice to assess the impact of visual noise and systemic administration of atomoxetine, a NE reuptake inhibitor, on cortical signal processing. In a separate group of freely moving mice, we used a two-alternative forced-choice to evaluate the behavioral effects of systemic and intracortical adrenergic manipulations on visual discrimination. Results: Moderate visual noise enhanced cortical signal processing and visual choices, consistent with stochastic resonance. High noise levels impaired both. Systemic atomoxetine administration flattened the cortical signal-to-noise ratio function, suggesting disrupted gain control. Behaviorally, clonidine impaired accuracy at moderate noise levels, while atomoxetine reduced discrimination performance and increased response variability. Intracortical NE infusions produced similar effects. Conclusions: Our findings demonstrate that NE regulates the balance between signal amplification and noise suppression in a noise- and context-dependent manner. These results extend existing models of neuromodulatory function by linking interlaminar communication and cortical variability to perceptual decision-making. Full article

The excitation/inhibition (E/I) balance is a critical feature of neural circuits, which is crucial for maintaining optimal brain function by ensuring network stability and preventing neural hyperexcitability. The hippocampus exhibits the particularly interesting characteristics of having different functions and E/I profiles between its dorsal and ventral segments. Furthermore, the hippocampus is particularly vulnerable to epilepsy and implicated in Fragile X Syndrome (FXS), disorders associated with heightened E/I balance and possible deficits in GABA-mediated inhibition. In epilepsy, the ventral hippocampus shows heightened susceptibility to seizures, while in FXS, recent evidence suggests differential alterations in excitability and inhibition between dorsal and ventral regions. This article explores the mechanisms underlying E/I balance regulation, focusing on the hippocampus in epilepsy and FXS, and emphasizing the possible mechanisms that may confer homeostatic flexibility to the ventral hippocampus in maintaining E/I balance. Notably, the ventral hippocampus in adult FXS models shows enhanced GABAergic inhibition, resistance to epileptiform activity, and physiological network pattern (sharp wave-ripples, SWRs), potentially representing a homeostatic adaptation. In contrast, the dorsal hippocampus in these FXS models is more vulnerable to aberrant discharges and displays altered SWRs. These findings highlight the complex, region-specific nature of E/I balance disruptions in neurological disorders and suggest that the ventral hippocampus may possess unique compensatory mechanisms. Specifically, it is proposed that the ventral hippocampus, the brain region most prone to hyperexcitability, may have unique adaptive capabilities at the cellular and network levels that maintain the E/I balance within a normal range to prevent the transition to hyperexcitability and preserve normal function. Investigating the mechanisms underlying these compensatory responses in the ventral hippocampus and their developmental trajectories may offer novel insights into strategies for mitigating E/I imbalances in epilepsy, FXS, and potentially other neuropsychiatric and neurodevelopmental disorders. Full article

Proteins involved in synaptic transmission in normal hearing, acoustic stimulation, and tinnitus were identified using protein–protein interaction (PPI) networks. The gene list for tinnitus was compiled from the GeneCards database using the keywords “synaptic transmission” AND “inferior colliculus” AND “tinnitus” (Tin). For comparison, two gene lists were built using the keywords “auditory perception” (AP) and “acoustic stimulation” (AS). The STRING and the Cytoscape data analyzer were used to identify the top two high-degree proteins (HDPs) and the corresponding high-score interaction proteins (HSIP). The top1 key proteins of the AP and AS processes are BDNF and the receptor NTRK2; the top2 key proteins in the AP process are PVALB, together with GAD1, CALB1, and CALB2, which are important for the balance of excitation and inhibition. In the AS process, the top2 key proteins are FOS, CREB1, EGR1, and MAPK1, reflecting an activated state. The top1 key proteins of the Tin process are BDNF, NTRK3, and NTF3; these proteins are associated with the proliferation and differentiation of neurons and indicate the remodeling of synaptic transmission in IC. The top2 key proteins are GFAP and S100B, indicating a role for astrocytes in the modulation of synaptic transmission. Full article

Interactions between excitatory and inhibitory neurons in the cerebral cortex give rise to different regimes of activity and modulate brain oscillations. A prominent regime in the cortex is the inhibition-stabilized network (ISN), defined by strong recurrent excitation balanced by inhibition. While theoretical models have captured the response of brain circuits in the ISN state, their connectivity is typically hard-wired, leaving unanswered how a network may self-organize to an ISN state and dynamically switch between ISN and non-ISN states to modulate oscillations. Here, we introduce a mean-rate model of coupled Wilson-Cowan equations, link ISN and non-ISN states to Kolmogorov-Sinai entropy, and demonstrate how homeostatic plasticity (HP) allows the network to express both states depending on its level of tonic activity. This mechanism enables the model to capture a broad range of experimental effects, including (i) a paradoxical decrease in inhibitory activity, (ii) a phase offset between excitation and inhibition, and (iii) damped gamma oscillations. Further, the model accounts for experimental work on asynchronous quenching, where an external input suppresses intrinsic oscillations. Together, findings show that oscillatory activity is modulated by the dynamical regime of the network under the control of HP, thus advancing a framework that bridges neural dynamics, entropy, oscillations, and synaptic plasticity. Full article

Focal cortical dysplasia (FCD) is a leading cause of drug-resistant epilepsy; however, the mechanisms underlying hyperexcitability in the affected cortical regions remain poorly understood. In this study, we employed a freeze-induced neocortical malformation model in rats to investigate the electrophysiological properties of pyramidal neurons surrounding the microgyrus and to evaluate changes in synaptic transmission. Using whole-cell patch-clamp recordings, we analyzed passive and active membrane properties, synaptic responses, and epileptiform activity in brain slices from rats with FCD and sham-operated controls. Our results revealed that while the intrinsic biophysical properties of neurons remained largely unchanged, the summation of excitatory and inhibitory inputs was significantly enhanced. Notably, the balance of inhibitory and excitatory synaptic currents was shifted toward excitation, making the perilesional cortex more susceptible to seizure generation. In a model of epileptiform activity induced by GABA_A receptor blockade and reduced Mg²⁺ concentration, we observed early ictal activity originating in the microgyrus and spreading to adjacent regions. These findings demonstrate that synaptic perturbations, rather than alterations in intrinsic neuronal properties, are the primary drivers of hyperexcitability in this model. Our study highlights the importance of synaptic dysregulation in FCD-related epilepsy and suggests that targeting synaptic transmission may offer a promising therapeutic strategy for controlling seizures in patients with cortical malformations. Full article

Cognitive impairment is a core feature of schizophrenia, playing a pivotal role in the pathogenesis and prognosis of this disorder. Cognitive impairment in schizophrenia encompasses a wide range of domains, including processing speed, episodic memory, working memory, and executive function. These deficits persist throughout the course of the illness and significantly impact functional outcomes and quality of life. Therefore, it is imperative to identify the biological basis of cognitive deficits in schizophrenia and develop effective treatments. The role of N-methyl-D-aspartate (NMDA) receptors in synaptic transmission and plasticity has long been recognized, making them potential targets for schizophrenia treatment. This review will focus on emerging pharmacology targeting NMDA receptors, offering strategies for the prevention and treatment of cognitive deficits in schizophrenia. Full article