Distinct Roles of Rodent Thalamus and Corpus Callosum in Seizure Generalization.

OBJECTIVE: Bilateral synchronous cortical activity occurs during sleep, attention, and seizures. Canonical models place the thalamus at the center of bilateral cortical synchronization because it generates bilateral sleep spindle oscillations and primarily generalized absence seizures. However, classical studies suggest that the corpus callosum mediates bilateral cortical synchronization. METHODS: We mapped the spread of right frontal lobe-onset, focal to bilateral seizures in mice and modified it using chemo and optogenetic suppression of motor thalamic nucleus and corpus callosotomy. RESULTS: Seizures from the right cortex spread faster to the left cortex than to the left thalamus. The 2 thalami have minimal monosynaptic commissural connections compared to the massive commissure corpus callosum. Chemogenetic and closed-loop optogenetic inhibition of the right ventrolateral thalamic nucleus did not alter inter-hemispheric seizure spread. However, anterior callosotomy delayed bilateral seizure oscillations. INTERPRETATION: Thalamocortical oscillations amplify focal onset motor seizures, and corpus callosum spreads them bilaterally. ANN NEUROL 2022;91:682-696.

Activation of the basal ganglia and indirect pathway neurons during frontal lobe seizures.

There are no detailed descriptions of neuronal circuit active during frontal lobe motor seizures. Using activity reporter mice, local field potential recordings, tissue clearing, viral tracing, and super-resolution microscopy, we found neuronal activation after focal motor to bilateral tonic-clonic seizures in the striatum, globus pallidus externus, subthalamic nucleus, substantia nigra pars reticulata and neurons of the indirect pathway. Seizures preferentially activated dopamine D2 receptor-expressing neurons over D1 in the striatum, which have different projections. Furthermore, the D2 receptor agonist infused into the striatum exerted an anticonvulsant effect. Seizures activate structures via short and long latency loops, and anatomical connections of the seizure focus determine the seizure circuit. These studies, for the first time, show activation of neurons in the striatum, globus pallidus, subthalamic nucleus, and substantia nigra during frontal lobe motor seizures on the cellular level, revealing a complex neuronal activation circuit subject to modulation by the basal ganglia.

Limbic progesterone receptor activity enhances neuronal excitability and seizures.

OBJECTIVE: Emerging evidence raises the possibility that progesterone receptor (PR) signaling may contribute to the reproductive hormone fluctuation-linked seizure precipitation, called catamenial epilepsy. Therefore, we studied PR isoform expression in limbic regions involved in temporal lobe epilepsy and the effect of PR activation on neuronal activity and seizures. METHODS: We evaluated PR expression in the limbic regions, entorhinal cortex (EC), hippocampus, and amygdala in female rats using quantitative real-time polymerase chain reaction (qRT-PCR). A selective agonist, Nestorone (16-methylene-17 alpha-acetoxy-19-nor-pregn-4-ene-3,20-dione) activated PRs, and the effect on excitability and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated synaptic transmission of EC neurons was studied using electrophysiology. Finally, we assessed PR regulation of epileptic seizures and status epilepticus (SE) induced by lithium-pilocarpine in female rats with the global deletion of PRs (PR knockout; PRKO) using video electroencephalography (-EEG). RESULTS: Limbic regions EC, hippocampus, and amygdala robustly expressed PR messenger RNA (mRNA). Nestorone (16-methylene-17 alpha-acetoxy-19-nor-pregn-4-ene-3,20-dione) treatment reduced the action potential threshold of layer II/III EC neurons and increased the frequency of AMPA receptor-mediated synaptic currents of ovariectomized and estrogen-primed female rats. Female rats lacking PRs (PRKO) experienced a shorter duration, less intense, and less fatal SE than wild-type (WT) animals. Furthermore, Nestorone treatment caused seizure exacerbation in the WT epileptic animals, but not in the PRKO epileptic animals. SIGNIFICANCE: Activation of PRs expressed in the EC and hippocampus increased neuronal excitability and worsened seizures. These receptors may play a role in catamenial epilepsy.

Comparison of 1-year recurrence-free survival between sevoflurane and propofol use for general anesthesia management in primary breast cancer surgery.

PURPOSE: We evaluated the influence of anesthetic management with sevoflurane or propofol on recurrence in patients undergoing breast cancer surgery. METHODS: This single center, retrospective study, included patients who received either sevoflurane or propofol during primary breast cancer surgery between 2008 and 2012. Our primary outcome was recurrence-free survival (RFS) at 1 year. Recurrence was defined as locoregional recurrence and distal metastasis. Propensity scores were calculated using seven variables (age, sex, body mass index, cancer stage, tumor size, intrinsic subtype, and deviation from standard therapy), and Kaplan-Meier survival curves were constructed from the date of diagnosis of recurrence. Hazard ratios (HRs) were estimated using univariable Cox proportional hazard regression analysis. RESULTS: Two-hundred-twelve patients received sevoflurane and 814 patients received total intravenous anesthesia with propofol. The median follow-up was 59 (interquartile range, 44-75) months. Regional anesthetic techniques were not used. Recurrence occurred in 95 patients (9.26%), with 19 (8.96%) and 76 (9.33%) in the sevoflurane and propofol groups, respectively. The HR was 1.167 (95% confidence interval, 0.681-2.000, p = 0.574) for the use of sevoflurane over propofol. After 1:1 propensity-score matching, 318 patients were analyzed. The 1-year RFS rates were similar between the groups (sevoflurane group: 7.5% [n = 12], propofol group: 8.2% [n = 13]), yielding an HR of 1.002 (95% confidence interval 0.457-2.198, p = 0.995) associated with the use of sevoflurane over propofol. CONCLUSION: In patients undergoing primary breast cancer surgery, the use of either sevoflurane or propofol without regional anesthesia did not appear to affect the risk of recurrence after 1 year.

[Massive Air Inflow into the Left Ventricle Detected by Transesophageal Echocardiography during Rastelli Coduit Re-replacement].

We present a case of massive air inflow into the left ventricle from the right ventricle through a small intraventricular shunt detected by transesophageal echocardiography (TEE). This case suggests that TEE plays an important role in the right ventricle-pulmo- nary artery conduit re-replacement.

[Anesthetic Management of a Patient with Quasi-moyamoya Disease Undergoing Total Thyroidectomy for Graves' Disease].

Quasi-moyamoya disease defined as moyamoya disease combined with autoimmune diseases such as Graves' disease is rare. We report anesthetic management of a patient with quasi-moyamoya disease undergoing total thyroidectomy for Graves' disease resistant to medical therapy. This disease is characterized by the aggravation of cerebral ischemic symptoms with hyperthyroidism. We, therefore, applied steroid pulse therapy before the operation to induce temporal normalization of the thyroid function, and could perform safe anesthetic management of this patient with quasi-moyamoya disease.

Cortical parvalbumin neurons are responsible for homeostatic sleep rebound through CaMKII activation.

The homeostatic regulation of sleep is characterized by rebound sleep after prolonged wakefulness, but the molecular and cellular mechanisms underlying this regulation are still unknown. In this study, we show that Ca2+/calmodulin-dependent protein kinase II (CaMKII)-dependent activity control of parvalbumin (PV)-expressing cortical neurons is involved in homeostatic regulation of sleep in male mice. Prolonged wakefulness enhances cortical PV-neuron activity. Chemogenetic suppression or activation of cortical PV neurons inhibits or induces rebound sleep, implying that rebound sleep is dependent on increased activity of cortical PV neurons. Furthermore, we discovered that CaMKII kinase activity boosts the activity of cortical PV neurons, and that kinase activity is important for homeostatic sleep rebound. Here, we propose that CaMKII-dependent PV-neuron activity represents negative feedback inhibition of cortical neural excitability, which serves as the distributive cortical circuits for sleep homeostatic regulation.

Construction of Local Field Potential Microelectrodes for in vivo Recordings from Multiple Brain Structures Simultaneously.

Researchers often need to record local field potentials (LFPs) simultaneously from several brain structures. Recording from multiple desired brain regions requires different microelectrode designs, but commercially available microelectrode arrays often do not offer such flexibility. Here, the present protocol outlines the straightforward design of custom-made microelectrode arrays to record LFPs from multiple brain structures simultaneously at different depths. This work describes the construction of the bilateral cortical, striatal, ventrolateral thalamic, and nigral microelectrodes as an example. The outlined design principle offers flexibility, and the microelectrodes can be modified and customized to record LFPs from any structure by calculating stereotaxic coordinates and quickly changing the construction accordingly to target different brain regions in either freely moving or anesthetized mice. The microelectrode assembly requires standard tools and supplies. These custom microelectrode arrays allow investigators to easily design microelectrode arrays in any configuration to track neuronal activity, providing LFP recordings with millisecond resolution.

Progesterone receptor activation regulates seizure susceptibility.

OBJECTIVE: Progesterone is a potent neuromodulator that exerts effects on the brain through neurosteroids, progesterone receptors (PRs), and other molecules. Whether PR activation regulates seizures is not known. We determined whether PR activation increased seizure susceptibility. METHODS: Adult female rats that developed epilepsy following lithium-pilocarpine-induced status epilepticus (SE) were used. Seizures were recorded by continuous-video EEG and read by an individual blinded to the treatment of the animals. The animals were treated for a week with progesterone (50 mg/kg per day), and the effect of progesterone withdrawal on seizure frequency was assessed during the subsequent week. During the week of progesterone treatment, the animals were treated with PR antagonist RU-486 (10 mg/kg per day) or a vehicle control, which was administered 30 min before progesterone. In another set of animals, we determined the effect of the PR agonist Nestorone (3 mg/kg per day) on seizure frequency. The animals were treated with Nestorone or vehicle for a week, and seizure frequencies at baseline and during the treatment week were compared. RESULTS: Progesterone withdrawal induced twofold increase in seizures in 57% of animals (n = 14). RU-486 treatment in combination with progesterone, prevented this increase, and a smaller fraction of animals (17%) experienced withdrawal seizures (n = 13). The specific activation of PRs by Nestorone also increased the seizure frequency. Forty-six percent (n = 14) of Nestorone-treated animals experienced at least a 50% increase in seizures compared to only 9% of the vehicle-treated animals (n = 11). INTERPRETATION: PR activation increased seizure frequency in epileptic animals. Thus, PRs may be novel targets for treating catamenial epilepsy.