The analysis of the central and the autonomic nervous systems (CNS, ANS) activities during general anesthesia (GA) provides fundamental information for the study of neural processes that support ...alterations of the consciousness level. In the present pilot study, we analyzed EEG signals and the heart rate (HR) variability (HRV) in a sample of 11 patients undergoing spinal surgery to investigate their CNS and ANS activities during GA obtained with propofol administration. Data were analyzed during different stages of GA: baseline, the first period of anesthetic induction, the period before the loss of consciousness, the first period after propofol discontinuation, and the period before the recovery of consciousness (ROC). In EEG spectral analysis, we found a decrease in posterior alpha and beta power in all cortical areas observed, except the occipital ones, and an increase in delta power, mainly during the induction phase. In EEG connectivity analysis, we found a significant increase of local efficiency index in alpha and delta bands between baseline and loss of consciousness as well as between baseline and ROC in delta band only and a significant reduction of the characteristic path length in alpha band between the baseline and ROC. Moreover, connectivity results showed that in the alpha band there was mainly a progressive increase in the number and in the strength of incoming connections in the frontal region, while in the beta band the parietal region showed mainly a significant increase in the number and in the strength of outcoming connections values. The HRV analysis showed that the induction of anesthesia with propofol was associated with a progressive decrease in complexity and a consequent increase in the regularity indexes and that the anesthetic procedure determined bradycardia which was accompanied by an increase in cardiac sympathetic modulation and a decrease in cardiac parasympathetic modulation during the induction. Overall, the results of this pilot study showed as propofol-induced anesthesia caused modifications on EEG signal, leading to a "rebalance" between long and short-range cortical connections, and had a direct effect on the cardiac system. Our data suggest interesting perspectives for the interactions between the central and autonomic nervous systems for the modulation of the consciousness level.
Abstract Unverricht–Lundborg disease (ULD) is the most common progressive myoclonic epilepsy. Its etiology has been identified in a defect of a protease inhibitor, cystatin B (CSTB), but the ...mechanism(s) by which this defect translates in the clinical manifestations of the disease are still obscure. We tested the hypothesis that ULD is accompanied by a loss of cortical GABA inhibition in a murine model (the CSTB knockout mouse) and in a human case. Cortical GABA signaling has been investigated measuring VGAT immunohistochemistry (a histological marker of the density of GABA terminals), GABA release from synaptosomes and paired-pulse stimulation. In CSTB knockout mice, a progressive decrease in neocortex thickness was found, associated with a prevalent loss of GABA interneurons. A marked reduction in VGAT labeling was found in the cortex of both CSTB knockout mice and an ULD patient. This implicates a reduction in GABA synaptic transmission, which was confirmed in the mouse model as reduction in GABA release from isolated nerve terminals and as loss of electrophysiologically measured GABA inhibition. The alterations in VGAT immunolabeling progressed in time, paralleling the worsening of myoclonus. These results provide direct evidence that loss of cortical GABA input occurs in a relevant animal model and in a case of human ULD, leading to a condition of latent hyperexcitability that favors myoclonus and seizures. These findings contribute to the understanding of the pathogenic mechanism of ULD and of the neurobiological basis of the effect of currently employed drugs.
To test the ability of different entropy measures to classify patients with different conditions of chronic disorder of consciousness, we applied the Lempel-Ziv complexity, the amplitude coalition ...entropy (ACE), and the synchrony coalition entropy (SCE) to the EEG signals recorded in 32 patients, clinically evaluated using the coma recovery scale revised (CRS-R). All the entropy measures indicated that differences found in the theta and alpha bands can distinguish patients in a minimal consciousness state (MCS) with respect to those in a vegetative state/unresponsive wakefulness state (VS/UWS). These differences were significant comparing the entropy measure performed on the anterior region of the left hemisphere and midline region. The values of theta-alpha entropy positively correlated with those of the CRS-R scores. Among the entropy measures, ACE most often highlighted significant differences. The higher values found in MCS were for the less impaired patients, according to their CRS-R, suggest that the preservation of signal entropy on the anterior region of the dominant hemisphere correlates with better preservation of consciousness, even in chronic conditions.
Synaptosomal-associated protein of 25 kDa (SNAP-25) is a SNARE protein that regulates neurotransmission by the formation of a complex with syntaxin 1 and synaptobrevin/VAMP2. SNAP-25 also reduces ...neuronal calcium responses to stimuli, but neither the functional relevance nor the molecular mechanisms of this modulation have been clarified. In this study, we demonstrate that hippocampal slices from Snap25⁺/⁻ mice display a significantly larger facilitation and that higher calcium peaks are reached after depolarization by Snap25⁻/⁻ and Snap25⁺/⁻ cultured neurons compared with wild type. We also show that SNAP-25b modulates calcium dynamics by inhibiting voltage-gated calcium channels (VGCCs) and that PKC phosphorylation of SNAP-25 at ser187 is essential for this process, as indicated by the use of phosphomimetic (S187E) or nonphosphorylated (S187A) mutants. Neuronal activity is the trigger that induces the transient phosphorylation of SNAP-25 at ser187. Indeed, enhancement of network activity increases the levels of phosphorylated SNAP-25, whereas network inhibition reduces the extent of protein phosphorylation. A transient peak of SNAP-25 phosphorylation also is detectable in rat hippocampus in vivo after i.p. injection with kainate to induce seizures. These findings demonstrate that differences in the expression levels of SNAP-25 impact on calcium dynamics and neuronal plasticity, and that SNAP-25 phosphorylation, by promoting inhibition of VGCCs, may mediate a negative feedback modulation of neuronal activity during intense activation.
Febrile seizures (FS) affect 5–12% of infants and children up to 6 years of age. There is now epidemiological evidence that FS are associated with subsequent afebrile and unprovoked seizures in ≈7% ...of patients, which is 10 times more than in the general population. Extensive genetic studies have demonstrated that various loci are responsible for familial FS, and the FEB3 autosomal-dominant locus has been identified on chromosome 2q23–24, where the SCN1A gene is mapped. However, gene mutations causing simple FS have not been found yet. Here we show that the M145T mutation of a well conserved amino acid in the first transmembrane segment of domain I of the human Na v 1.1 channel α-subunit cosegregates in all 12 individuals of a large Italian family affected by simple FS. Functional studies in mammalian cells demonstrate that the mutation causes a 60% reduction of current density and a 10-mV positive shift of the activation curve. Thus, M145T is a loss-of-function mutant. These results show that monogenic FS should also be considered a channelopathy. channelopathy FEB3 locus convulsions epilepsy neuronal excitability
Purpose. Periventricular nodular heterotopia (PNH) is among the most common malformations of cortical development, and affected patients are frequently characterized by focal drug‐resistant epilepsy. ...Here we analyzed clinical, MRI, and electrophysiologic findings in 54 PNH patients to reevaluate the classification of PNH, relate the anatomic features to epileptic outcome, and ascertain the contribution of PNH nodules to the onset of epileptic discharges.
Methods: The patients were followed up for a prolonged period at the Epilepsy Center of our Institute. In all cases, we related MRI findings to clinical and epileptic outcome and analyzed interictal and ictal EEG abnormalities. In one patient, EEG and stereo‐EEG (SEEG) recordings of seizures were compared.
Results: We included cases with periventricular nodules, also extending to white matter and cortex, provided that anatomic continuity was present between nodules and malformed cortex. Based on imaging and clinical data, patients were subdivided into five PNH groups: (a) bilateral and symmetrical; (b) bilateral single‐noduled; (c) bilateral and asymmetrical; (d) unilateral; and (e) unilateral with extension to neocortex. The latter three groups were characterized by worse epileptic outcome. No differences in outcome were found between unilateral PNH patients regardless the presence of cortical involvement. Interictal as well as ictal EEG abnormalities were always related to PNH location.
Conclusions: The distinctive clinical features and epileptic outcomes in each group of patients confirm the reliability of the proposed classification. Ictal EEG and SEEG recordings suggest that seizures are generated by abnormal anatomic circuitries including the heterotopic nodules and adjacent cortical areas.
Myoclonus classically presents as a brief (10–50 ms duration), non‐rhythmic jerk movement. The etiology could vary considerably ranging from self‐limited to chronic or even progressive disorders, the ...latter falling into encephalopathic pictures that need a prompt diagnosis. Beyond the etiological classification, others evaluate myoclonus' body distribution (i.e., clinical classification) or the location of the generator (i.e., neurophysiological classification); particularly, knowing the anatomical source of myoclonus gives inputs on the observable clinical patterns, such as EMG bursts duration or EEG correlate, and guides the therapeutic choices. Among all the chronic disorders, myoclonus often presents itself as a manifestation of epilepsy. In this context, myoclonus has many facets. Myoclonus occurs as one, or the only, seizure manifestation while it can also present as a peculiar type of movement disorder; moreover, its electroclinical features within specific genetically determined epileptic syndromes have seldom been investigated. In this review, following a meeting of recognized experts, we provide an up‐to‐date overview of the neurophysiology and nosology surrounding myoclonus. Through the dedicated exploration of epileptic syndromes, coupled with pragmatic guidance, we aim to furnish clinicians and researchers alike with practical advice for heightened diagnostic management and refined treatment strategies.
Plain Language Summary
In this work, we described myoclonus, a movement characterized by brief, shock‐like jerks. Myoclonus could be present in different diseases and its correct diagnosis helps treatment.
HCN channels are highly expressed and functionally relevant in neurons and increasing evidence demonstrates their involvement in the etiology of human epilepsies. Among HCN isoforms, HCN4 is ...important in cardiac tissue, where it underlies pacemaker activity. Despite being expressed also in deep structures of the brain, mutations of this channel functionally shown to be associated with epilepsy have not been reported yet. Using Next Generation Sequencing for the screening of patients with idiopathic epilepsy, we identified the p.Arg550Cys (c.1648C>T) heterozygous mutation on
in two brothers affected by benign myoclonic epilepsy of infancy. Functional characterization in heterologous expression system and in neurons showed that the mutation determines a loss of function of HCN4 contribution to activity and an increase of neuronal discharge, potentially predisposing to epilepsy. Expressed in cardiomyocytes, mutant channels activate at slightly more negative voltages than wild-type (WT), in accordance with borderline bradycardia. While HCN4 variants have been frequently associated with cardiac arrhythmias, these data represent the first experimental evidence that functional alteration of HCN4 can also be involved in human epilepsy through a loss-of-function effect and associated increased neuronal excitability. Since HCN4 appears to be highly expressed in deep brain structures only early during development, our data provide a potential explanation for a link between dysfunctional HCN4 and infantile epilepsy. These findings suggest that it may be useful to include
screening to extend the knowledge of the genetic causes of infantile epilepsies, potentially paving the way for the identification of innovative therapeutic strategies.
Aim The aim of this article was to describe the phenomenology and polymyographic features of paroxysmal non‐epileptic motor events (PNMEs) observed in a series of typically developing and children ...with neurological impairment.
Method We conducted a retrospective evaluation of 63 individuals (29 females; 34 males) affected by PNMEs at the National Neurological Institute ‘C. Besta’ between 2006 and 2008. Individuals were included in the study if they had PNMEs documented by a video‐electroencephalography–polymyographic study and were aged between 1 month and 18 years (mean age at the time of video‐electroencephalography–polymyography: 5y 10mo).
Results In 45 of the 63 participants (71%), PNMEs were associated with other neurological conditions (secondary) including epilepsy, whereas in 18 participants PNME was the only neurological symptom (primary). Clinical features allowed classification of the motor disturbance into usual movement disorder categories in 31 individuals (49%); in the remaining 32 (51%), the movement disorder was characterized on the basis of polymyographic pattern of ‘jerks’ or ‘sustained contraction’. The most frequent PNMEs were paroxysmal dyskinesias, followed by startle, stereotypies, shuddering, sleep myoclonus, psychogenic movement disorders, and benign myoclonus of early infancy; the last syndrome was also observed in children with neurological impairment. In eight participants, PNMEs remained unclassified.
Interpretation PNMEs may occur in both healthy and children with neurological impairment and are caused by a wide range of static and progressive conditions. In the majority of children with neurological impairment with associated epilepsy, the PNMEs do not fit into the usual movement disorders categories. A video‐electroencephalography–polymyography is therefore useful for characterizing them.
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