Thalamocortical circuits in generalized epilepsy: Pathophysiologic mechanisms and therapeutic targets

Neurobiology of Disease, Journal Year: 2023, Volume and Issue: 181, P. 106094 - 106094

Published: March 27, 2023

Generalized epilepsy affects 24 million people globally; at least 25% of cases remain medically refractory. The thalamus, with widespread connections throughout the brain, plays a critical role in generalized epilepsy. intrinsic properties thalamic neurons and synaptic between populations nucleus reticularis thalami thalamocortical relay nuclei help generate different firing patterns that influence brain states. In particular, transitions from tonic to highly synchronized burst mode can cause seizures rapidly generalize altered awareness unconsciousness. Here, we review most recent advances our understanding how activity is regulated discuss gaps mechanisms syndromes. Elucidating thalamus syndromes may lead new opportunities better treat pharmaco-resistant by modulation dietary therapy.

Language: Английский

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Alpha2-Adrenergic Receptors as a Pharmacological Target for Spike-Wave Epilepsy

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(2), P. 1477 - 1477

Published: Jan. 12, 2023

Spike-wave discharges are the hallmark of idiopathic generalized epilepsy. They caused by a disorder in thalamocortical network. Commercially available anti-epileptic drugs have pronounced side effects (i.e., sedation and gastroenterological concerns), which might result from low selectivity to molecular targets. We suggest specific subtype adrenergic receptors (ARs) as promising target. In rats with predisposition absence epilepsy, alpha2 ARs agonists provoke enhance spike-wave activity during transitions awake/sedation. A number studies together our own observations bring evidence that sedative proepileptic require different subtypes activation. Here we introduce new concept on target pharmacotherapy epilepsy via alpha2B presented almost exclusively thalamus. discuss HCN calcium channels most relevant cellular targets involved generation.

Language: Английский

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Low‐Frequency Stimulation at the Ventromedial Hypothalamus Exhibits Broad‐Spectrum Efficacy Across Models of Epilepsy

CNS Neuroscience & Therapeutics, Journal Year: 2025, Volume and Issue: 31(2)

Published: Feb. 1, 2025

The limited efficacy and very restricted antiseizure range of current deep brain stimulation (DBS) targets highlight the need to find an optimal target for managing various seizure types. Here, we aimed investigate DBS on ventromedial hypothalamus (VMH) in different types experimental epileptic seizures. was examined models, potential mechanisms were investigated by using vivo calcium signal recording optogenetics. c-fos expression significantly increased glutamatergic neurons VMH (VMHglu) following Then, 1-Hz low-frequency (LFS) at successfully attenuated severities across models epilepsy, including maximal electroshock, pentylenetetrazol, absence seizure, cortical or hippocampal kainic acid-induced acute hippocampal-kindling models. imaging recordings revealed that LFS could inhibit activities VMHglu. Optogenetic inhibition VMHglu mirrored LFS's impact. Further anterograde viral tracing confirmed extensive distributed projections VMHglu, which may compose circuitry basis broad-spectral LFS. These findings demonstrate VMH-LFS is a broad-spectrum treatment approach decreasing activity.

Language: Английский

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Respiratory alkalosis provokes spike-wave discharges in seizure-prone rats

eLife, Journal Year: 2022, Volume and Issue: 11

Published: Jan. 4, 2022

Hyperventilation reliably provokes seizures in patients diagnosed with absence epilepsy. Despite this predictable patient response, the mechanisms that enable hyperventilation to powerfully activate seizure-generating circuits remain entirely unknown. By utilizing gas exchange manipulations and optogenetics WAG/Rij rat, an established rodent model of epilepsy, we demonstrate are highly sensitive arterial carbon dioxide, suggesting pH. Moreover, consistently activated neurons within intralaminar nuclei thalamus, a structure implicated seizure generation. We show thalamus also contains pH-sensitive neurons. Collectively, these observations suggest activates provoke seizures.

Language: Английский

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The respiratory cycle modulates distinct dynamics of affective and perceptual decision-making

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: March 28, 2024

Abstract Respiratory rhythms play a critical role not only in homeostatic survival, but also modulating other non-interoceptive perceptual and affective processes. Recent evidence from both human rodent models indicates that neural behavioural oscillations are influenced by respiratory state as breathing cycles inspiration to expiration. To explore the mechanisms behind these effects, we carried out psychophysical experiment where 41 participants categorised dot motion facial emotion stimuli standardised discrimination task. When comparing behaviour across states, found accelerated responses domains. We applied hierarchical accumulation model determine which aspects of latent decision process best explained this acceleration. Computational modelling showed reduced evidential boundaries, such prioritised speed over accuracy In contrast, shifted starting point accumulation, inducing bias towards categorising expressions more positive. These findings provide novel computational account how modulate distinct decision-dynamics.

Language: Английский

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Respiratory modulations of cortical excitability and interictal spike timing in focal epilepsy: a case report

Communications Medicine, Journal Year: 2025, Volume and Issue: 5(1)

Published: April 10, 2025

Abstract Background Brain activity in focal epilepsy is marked by a pronounced excitation-inhibition (E:I) imbalance and interictal epileptiform discharges (IEDs) observed periods between recurrent seizures. As marker of E:I balance, aperiodic neural its underlying 1/f characteristic reflect the dynamic interplay excitatory inhibitory currents. Recent studies have independently assessed changes both context body-brain interactions neurotypical individuals where respiratory rhythm has emerged as potential modulator excitability states brain. Methods Here, we investigate respiration phase-locked modulations balance their involvement timing spike case report 25 year-old patient using magnetoencephalography (MEG). Results We show that i) differentially modulates compared to N = 40 controls ii) IED depends on states. Conclusions These findings overall suggest an intricate excitation consequential susceptibility for generation hope they will spark interest subsequent work coupling epilepsy.

Language: Английский

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In vitro and in-vivo exploration of physostigmine analogues to understand the mechanistic crosstalk between Klotho and targets for epilepsy

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: April 25, 2025

Epilepsy and seizures are characterized by neuronal hyperexcitability damage, influenced metabolic dysregulation, neuroinflammation, oxidative stress. Despite available treatments, many patients remain resistant to therapy, necessitating novel therapeutic strategies. Klotho, a neuroprotective, anti-inflammatory, antioxidative protein has emerged as potential modulator of epilepsy-related pathways. This study investigates the physostigmine analogues in regulating Klotho expression its downstream targets epilepsy. An integrative vitro vivo approach was employed PTZ-induced kindled mice. Behavioral assessments, including Morris Water Maze (MWM), Rota Rod, Black White Box, Tail Suspension tests were conducted. Biochemical analyses quantified serum glucose, lipid profiles, pro-inflammatory cytokines (TNF-α, FOXO1), apoptotic proteins (caspase-3). Quantitative real-time PCR (qRT-PCR) performed assess epilepsy-associated gene (STAT3, Bax, Bcl2). The synthesized exhibited varying inhibitory effects on transcriptional activators, with Compound C (1,8-bis(phenylsulfonyl)-1,8-dihydropyrrolo [2,3-b] indole) showing weakest inhibition (IC50 = 1.31 µM). In vivo, demonstrated anticonvulsant (p < 0.05), neuroprotective (5 mg/kg, p 0.05, 10 0.01, 20 mg/kg 0.0001), antidepressant anti-inflammatory 0.05) seizure models, improving motor function 0.001), cognitive performance 0.01), reducing neuroinflammatory/metabolic markers while modulating STAT3 BAX Bcl2 expression. 1,8-bis(phenylsulfonyl)-1,8-dihydropyrrolo indole epilepsy via modulation observed. Targeting metabolic, inflammatory, pathways presents promising strategy for management. Further research is required optimize clinical translation ensure long-term efficacy safety.

Language: Английский

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Respiratory brain impulse propagation in focal epilepsy

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: March 30, 2023

Abstract Respiratory brain pulsations pertaining to intra-axial hydrodynamic solute transport are markedly altered in focal epilepsy. We used optical flow analysis of ultra-fast functional magnetic resonance imaging (fMRI) data investigate the velocity characteristics respiratory impulse propagation patients with epilepsy treated antiseizure medication (ASM) (medicated epilepsy; ME, n = 23), drug-naïve at least one seizure (DN, 19) and matched healthy control subjects (HC, 75). detected two patient groups (ME DN) several significant alterations pulsation velocity, which showed a bidirectional change dominated by reduction speed. Furthermore, impulses moved more reversed or incoherent directions both vs. HC group. The speed reductions directionality changes occurred specific phases cycle. In conclusion, irrespective status, slower impulses, may contribute epileptic pathology hindering hydrodynamics.

Language: Английский

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Microglial activation and toll-like receptor 4-Dependent regulation of angiotensin II type I receptor-mu-opioid receptor 1 heterodimerization and hypertension in fructose-fed rats

European Journal of Pharmacology, Journal Year: 2023, Volume and Issue: 962, P. 176171 - 176171

Published: Nov. 22, 2023

Our previous study reported that the heterodimer of Angiotensin II Type I Receptor (AT1R) and Mu-Opioid 1 (MOR1) involves Nitric Oxide (NO) reduction which leads to elevation blood pressure. Secondly, we showed Toll-like 4 (TLR4) may be involved in heterodimerization AT1R MOR1 brainstem Nucleus Tractus Solitarii (NTS), regulates systemic pressure gastric nitric oxide through insulin pathway. Here, investigated role microglial activation TLR4 MOR1. Hypertensive rats were established after four weeks fructose consumption. SBP was measured using non-invasive method. PLA technique utilized determine protein-protein interaction nucleus tractus solitarii. Results level MOR-1 induced significantly group compared with control. signal potentially formed solitarii Meanwhile, innate immune cell CNS microglia observed biomarkers activated. inhibitor CLI-095, administered animals suppress neuroinflammation activation. CLI-095 treatment reduced formation restored production These findings imply TLR4-primed heterodimers increase

Language: Английский

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Attenuating midline thalamus bursting to mitigate absence epilepsy

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(28)

Published: July 5, 2024

Advancing the mechanistic understanding of absence epilepsy is crucial for developing new therapeutics, especially patients unresponsive to current treatments. Utilizing a recently developed mouse model carrying BK gain-of-function channelopathy D434G, here we report that attenuating burst firing midline thalamus (MLT) neurons effectively prevents seizures. We found enhanced channel activity in BK-D434G MLT promotes synchronized bursting during ictal phase Modulating through pharmacological reagents, optogenetic stimulation, or deep brain stimulation attenuates firing, leading reduced seizure frequency and increased vigilance. Additionally, enhancing vigilance by amphetamine, stimulant medication, physical perturbation also suppresses These findings suggest promising target clinical interventions. Our diverse approaches offer valuable insights next generation therapeutics treat epilepsy.

Language: Английский

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