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It is increasingly understood that the epilepsies are characterized by network pathology that can span multiple spatial and temporal scales. Recent work indicates that infraslow (<0.2 Hz) envelope correlations may form a basis for distant spatial coupling in the brain. We speculated that infraslow correlation structure may be preserved even with some time lag between signals. To this end, we studied intracranial EEG (icEEG) data collected from 22 medically refractory epilepsy patients. For each patient, we selected hour-long background, awake icEEG epochs before and after antiseizure medication (ASM) taper. For each epoch, we selected 5,000 random electrode contact pairs and estimated magnitude-squared coherence (MSC) below 0.15 Hz of band power timeseries in the traditional EEG frequency bands. Using these same contact pairs, we shifted one signal of the pair by random durations in 15-s increments between 0 and 300 s. We aggregated these data across all patients to determine how infraslow MSC varies with duration of lag. We further examined the effect of ASM taper on infraslow correlation structure. We also used surrogate data to empirically characterize MSC estimator and to set optimal parameters for estimation specifically for the study of infraslow activity. Our empirical analysis of the MSC estimator showed that hour-long segments with MSC computed using 3-min windows with 50% overlap was sufficient to capture infraslow envelope correlations while minimizing estimator bias and variance. The mean MSC decreased monotonically with increasing time lag until 105 s of lag, then plateaued between 106 and 300 s. Significantly nonzero infraslow envelope MSC was preserved in all frequency bands until about 1 min of time lag, both pre- and post-ASM taper. We also saw a slight, but significant increase in infraslow MSC post-ASM taper, consistent with prior work. These results provide evidence for the feasibility of examining infraslow activity via its modulation of higherfrequency activity in the absence of DC-coupled recordings. The use of surrogate data also provides a general methodology for benchmarking measures used in network neuroscience studies. Finally, our study points to the clinical relevance of infraslow activity in assessing seizure risk. [ABSTRACT FROM AUTHOR]

Background: Millions of people struggle with alcohol use disorder (AUD). Abrupt abstinence after a period of chronic alcohol use can precipitate the alcohol withdrawal syndrome (AWS), which includes hyperexcitability and, potentially, seizures. We have shown that T‐type Ca2+ channels are novel, sensitive targets of alcohol, an effect that is dependent upon protein kinase C (PKC). The purpose of this study was to (1) understand midline thalamic neuronal hyperexcitability during alcohol withdrawal and its dependence on PKC; (2) characterize T channel functional changes using both current clamp and voltage clamp methods; and (3) determine which PKC isoform may be responsible for alcohol withdrawal (WD) effects. Methods: Whole‐cell patch clamp recordings were performed in midline thalamic neurons in brain slices prepared from C57bl/6 mice that underwent chronic intermittent alcohol exposure in a standard vapor chamber model. The recordings were compared to those from air‐exposed controls. T‐channel inactivation curves and burst responses were acquired through voltage‐clamp and current‐clamp recordings, respectively. Results: Whole‐cell voltage clamp recordings of native T‐type current exhibited a depolarizing shift in the voltage‐dependency of inactivation during alcohol withdrawal compared to air‐exposed controls. A PKCε translocation inhibitor peptide mitigated this change. Current clamp recordings demonstrated more spikes per burst during alcohol withdrawal. Consistent with voltage clamp findings, the PKCɛ translocation inhibitor peptide reduced the number of spikes per burst after WD. Conclusion: We found that alcohol WD produces T channel‐mediated hyperexcitability in the midline thalamus, produced in part by a shift in the inactivation curve consistent with greater availability of T current. WD effects on T current inactivation were reduced to control levels by blocking PKCε translocation. Our results demonstrate that PKCε translocation plays an important role in the regulation of alcohol withdrawal‐induced hyperexcitability in midline thalamic circuitry. [ABSTRACT FROM AUTHOR]

Rationale: Severe TBI (sTBI) is a devastating neurological injury that comprises a significant global trauma burden. Early comprehensive neurocritical care and rehabilitation improve outcomes for such patients, although better diagnostic and prognostic tools are necessary to guide personalized treatment plans. Methods: In this study, we explored the feasibility of conducting resting state magnetoencephalography (MEG) in a case series of sTBI patients acutely after injury (~7 days), and then about 1.5 and 8 months after injury. Synthetic aperture magnetometry (SAM) was utilized to localize source power in the canonical frequency bands of delta, theta, alpha, beta, and gamma, as well as DC-80 Hz. Results: At the first scan, SAM source maps revealed zones of hypofunction, islands of preserved activity, and hemispheric asymmetry across bandwidths, with markedly reduced power on the side of injury for each patient. GCS scores improved at scan 2 and by scan 3 the patients were ambulatory. The SAM maps for scans 2 and 3 varied, with most patients showing increasing power over time, especially in gamma, but a continued reduction in power in damaged areas and hemispheric asymmetry and/or relative diminishment in power at the site of injury. At the group level for scan 1, there was a large excess of neural generators operating within the delta band relative to control participants, while the number of neural generators for beta and gamma were significantly reduced. At scan 2 there was increased beta power relative to controls. At scan 3 there was increased group-wise delta power in comparison to controls. Conclusion: In summary, this pilot study shows that MEG can be safely used to monitor and track the recovery of brain function in patients with severe TBI as well as to identify patient-specific regions of decreased or altered brain function. Such MEG maps of brain function may be used in the future to tailor patient-specific rehabilitation plans to target regions of altered spectral power with neurostimulation and other treatments. [ABSTRACT FROM AUTHOR]

Background: Alcohol withdrawal syndrome (AWS) results from the sudden cessation of chronic alcohol use and is associated with high morbidity and mortality. Alcohol withdrawal‐induced central nervous system (CNS) hyperexcitability results from complex, compensatory changes in synaptic efficacy and intrinsic excitability. These changes in excitability counteract the depressing effects of chronic ethanol on neural transmission and underlie symptoms of AWS, which range from mild anxiety to seizures and death. The development of targeted pharmacotherapies for treating AWS has been slow, due in part to the lack of available animal models that capture the key features of human AWS. Using a unique optogenetic method of probing network excitability, we examined electrophysiologic correlates of hyperexcitability sensitive to early changes in CNS excitability. This method is sensitive to pharmacologic treatments that reduce excitability and may represent a platform for AWS drug development. Methods: We applied a newly developed method, the optogenetic population discharge threshold (oPDT), which uses light intensity response curves to measure network excitability in chronically implanted mice. Excitability was tracked using the oPDT before, during, and after the chronic intermittent exposure (CIE) model of alcohol withdrawal (WD). Results: Alcohol withdrawal produced a dose‐dependent leftward shift in the oPDT curve (denoting increased excitability), which was detectable in as few as three exposure cycles. This shift in excitability mirrored an increase in the number of spontaneous interictal spikes during withdrawal. In addition, Withdrawal lowered seizure thresholds and increased seizure severity in optogenetically kindled mice. Conclusion: We demonstrate that the oPDT provides a sensitive measure of alcohol withdrawal‐induced hyperexcitability. The ability to actively probe the progression of excitability without eliciting potentially confounding seizures promises to be a useful tool in the preclinical development of next‐generation pharmacotherapies for AWS. [ABSTRACT FROM AUTHOR]

Background: Severe alcohol withdrawal syndrome (SAWS) is highly morbid, costly, and common among hospitalized patients, yet minimal evidence exists to guide inpatient management. Research needs in this field are broad, spanning the translational science spectrum. Goals: This research statement aims to describe what is known about SAWS, identify knowledge gaps, and offer recommendations for research in each domain of the Institute of Medicine T0-T4 continuum to advance the care of hospitalized patients who experience SAWS. Methods: Clinicians and researchers with unique and complementary expertise in basic, clinical, and implementation research related to unhealthy alcohol consumption and alcohol withdrawal were invited to participate in a workshop at the American Thoracic Society 2019 International Conference. The committee was subdivided into four groups on the basis of interest and expertise: T0-T1 (basic science research with translation to humans), T2 (research translating to patients), T3 (research translating to clinical practice), and T4 (research translating to communities). A medical librarian conducted a pragmatic literature search to facilitate this work, and committee members reviewed and supplemented the resulting evidence, identifying key knowledge gaps. Results: The committee identified several investigative opportunities to advance the care of patients with SAWS in each domain of the translational science spectrum. Major themes included 1) the need to investigate non-γ-aminobutyric acid pathways for alcohol withdrawal syndrome treatment; 2) harnessing retrospective and electronic health record data to identify risk factors and create objective severity scoring systems, particularly for acutely ill patients with SAWS; 3) the need for more robust comparative-effectiveness data to identify optimal SAWS treatment strategies; and 4) recommendations to accelerate implementation of effective treatments into practice. Conclusions: The dearth of evidence supporting management decisions for hospitalized patients with SAWS, many of whom require critical care, represents both a call to action and an opportunity for the American Thoracic Society and larger scientific communities to improve care for a vulnerable patient population. This report highlights basic, clinical, and implementation research that diverse experts agree will have the greatest impact on improving care for hospitalized patients with SAWS. [ABSTRACT FROM AUTHOR]

Magnetoencephalography measures neuromagnetic activity with high temporal, and theoretically, high spatial resolution. We developed an experimental platform combining MEG-compatible optogenetic techniques in nonhuman primates for use as a functional brain-mapping platform. Here we show localization of optogenetically evoked signals to known sources in the superficial arcuate sulcus of cortex and in CA3 of hippocampus at a resolution of 750 µm3. We detect activation in subcortical, thalamic, and extended temporal structures, conforming to known anatomical and functional brain networks associated with the respective sites of stimulation. This demonstrates that high-resolution localization of experimentally produced deep sources is possible within an intact brain. This approach is suitable for exploring causal relationships between discrete brain regions through precise optogenetic control and simultaneous whole brain MEG recording with high-resolution magnetic source imaging (MSI). Identifying causal interactions between brain regions is important to understand its computations. Here the authors present optoMEG, a platform for combining optogenetic techniques with high-resolution magnetic source imaging in nonhuman primates to map network activation. [ABSTRACT FROM AUTHOR]

Purpose : A fundamental question for Alcohol use disorder (AUD) is how and when naïve brain networks are reorganized in response to alcohol consumption. The current study aimed to determine the progression of alcohol's effect on functional brain networks during transition from the naïve state to chronic consumption. Procedures : Resting-state brain networks of six female rhesus macaque (Macaca mulatta) monkeys were acquired using magnetoencephalography (MEG) prior to alcohol exposure and after free-access to alcohol using a well-established model of chronic heavy alcohol consumption. Functional brain network metrics were derived at each time point. Results : The average connection frequency (p < 0.024) and membership of the Rich Club (p < 0.022) changed significantly over time. Metrics describing network topology remained relatively stable from baseline to free-access drinking. The minimum degree of the Rich Club prior to alcohol exposure was significantly predictive of future free-access drinking (r = −0.88, p < 0.001). Conclusions : Results suggest naïve brain network characteristics may be used to predict future alcohol consumption, and that alcohol consumption alters functional brain networks, shifting hubs and Rich Club membership away from previous regions in a non-systematic manner. Further work to refine these relationships may lead to the identification of a high-risk drinking phenotype. [ABSTRACT FROM AUTHOR]

Objective: Determine how characteristics of deployment mild traumatic brain injury (TBI) and blast exposure influence the relationship between the functional brain connectome with cognitive outcomes and symptom severity. Participants and Methods: N = 181 Iraq and Afghanistan combat veterans completed structured clinical interviews, cognitive testing, self-report questionnaires, and magnetoencephalography (MEG). MEG data were acquired in the resting-state with eyes open. MEG data were beamformed to identify brain regions active at rest. Functional brain connectomes representing the unique network present for a given individual were created using active brain regions identified for each participant. Network metrics describing these connectomes were calculated at the participant level. Cognitive tests included the WAIS-IV, Trail Making Test Parts A&B, and the Controlled Oral Word Association test. Due to differences in normative data across tests, raw scores were used in analyses. Symptom measures included the PTSD Checklist - 5 (PCL-5), Patient Health Questionnaire (PHQ-9), Neurobehavioral Symptoms Inventory (NSI), Quality of Life After Brain Injury (QOLIBRI), Pittsburgh Sleep Quality Index (PsQi), the Distress Tolerance Scale (DTS), and the PROMIS Pain Interference Scale (PROMIS-PI). Results: Hierarchical linear regression analyses revealed that several network metrics were significantly related to both cognitive outcomes and symptom severity after adjusting for demographic covariates and clinical characteristics. The relationship between Global Efficiency (GE) and cognitive outcomes was moderated by deployment TBI on the WAIS-IV Full Scale Index (FSI), Perceptual Reasoning Index (PRI), and General Ability Index (GAI). In all cases, when deployment TBI was absent, greater GE was associated with poorer cognitive scores. The relationship between GE and symptom severity was moderated by the severity of blast exposure. Greater GE was associated with lower symptom severity at lower blast severities for the PHQ-9 and QOLIBRI A (thinking) and E (negative emotions). Moderation effects were also observed for the PSQI. In the absence of deployment TBI, greater GE was associated with better sleep quality; however, in the presence of deployment TBI, greater GE was associated with poorer sleep quality. Other connectome-outcome relationships were not consistently moderated by Deployment TBI or blast history Conclusions: Results demonstrated relationships between several aspects the functional connectome of the brain with both cognitive outcomes and symptom severity beyond effects of common demographic and clinical variables. Moderation analyses revealed that the relationship between GE of the connectome and outcomes is frequently disrupted by deployment TBI and blast. GE is a measure of the ease of information transfer through the network. These results identified consistent relationships between GE and outcomes in the absence of deployment TBI or blast, but these relationships disappear when deployment TBI or blast are present. Participants in this study were on average 11 years post-TBI or blast exposure, suggesting these are chronic rather than acute effects. GE was significantly correlated with most symptom severity measures as well as the WAIS-IV PRI, GAI, VCI, and FSI. Future efforts to normalize the relationship between GE and outcomes following TBI may improve rehabilitation outcomes and directly affect areas of concern commonly reported by service members following TBI or blast exposure. [ABSTRACT FROM AUTHOR]

Objective: Studies of infraslow amplitude modulations (<0.15 Hz) of band power time series suggest that these envelope correlations may form a basis for distant spatial coupling in the brain. In this study, we sought to determine how infraslow relationships are affected by antiepileptic drug (AED) taper, time of day, and seizure. Methods: We studied intracranial electroencephalographic (icEEG) data collected from 13 medically refractory adult epilepsy patients who underwent monitoring at Yale-New Haven Hospital. We estimated the magnitude-squared coherence (MSC) at <0.15 Hz of traditional EEG frequency band power time series for all electrode contact pairs to quantify infraslow envelope correlations between them. We studied, first, hour-long background icEEG epochs before and after AED taper to understand the effect of taper. Second, we analyzed the entire record for each patient to study the effect of time of day. Finally, for each patient, we reviewed the clinical record to find all seizures that were at least 6 hours removed from other seizures and analyzed infraslow envelope MSC before and after them. Results: Infraslow envelope MSC increased slightly, but significantly, after AED taper, and increased on average during the night and decreased during the day. It was also increased significantly in all frequency bands up to 3 hours preseizure and 1 hour postseizure as compared to background icEEG (61 seizures studied). These changes occurred for both daytime and nighttime seizures (28 daytime, 33 nighttime). Interestingly, there was significant spatial variability to these changes, with the seizure onset area peaking at 3 hours preseizure, then showing progressive desynchronization from 3 hours preseizure to 1 hour postseizure. Significance: Infraslow envelope analysis may be used to understand long-term changes over the course of icEEG monitoring, provide unique insight into interictal electrophysiological changes related to ictogenesis, and contribute to the development of novel seizure forecasting algorithms. [ABSTRACT FROM AUTHOR]

Aims We have previously demonstrated that blockade of T-type calcium channels by the non-selective antagonist, ethosuximide (ETX), is effective at reducing electrographical and behavioral correlates of alcohol-withdrawal (WD) seizure. Here, we investigated whether blockade of these calcium channels with the selective antagonist TTA-P2 also reduces alcohol-WD seizure. Short summary The non-specific T-type calcium channel antagonist, ETX, is protective against alcohol-WD seizure. However, the mechanism of this effect is unclear. Here, we provide evidence that further suggests selective blockade of T-type calcium channels are protective against alcohol-WD seizure and WD-related mortality. Methods We used an intermittent ethanol exposure model to produce WD-induced hyperexcitability in DBA/2 J mice. Seizure severity was intensified with the chemoconvulsant pentylenetetrazole (PTZ). Results TTA-P2 (10 mg/kg) reduced seizure severity in mice undergoing alcohol WD with concurrent PTZ treatment (20 mg/kg). Moreover, TTA-P2 (20 and 40 mg/kg) was also protective against PTZ-induced (40 mg/kg) seizure and mortality. Conclusions These results are consistent with prior results using ETX, and suggest that the protective effects of ETX and TTA-P2 against EtOH WD seizures are mediated by T-type calcium channels. [ABSTRACT FROM AUTHOR]

Magnetoencephalography (MEG) is a neurophysiological technique that detects the magnetic fields associated with brain activity. Synthetic aperture magnetometry (SAM), a MEG magnetic source imaging technique, can be used to construct both detailed maps of global brain activity as well as virtual electrode signals, which provide information that is similar to invasive electrode recordings. This innovative approach has demonstrated utility in both clinical and research settings. For individuals with epilepsy, MEG provides valuable, nonredundant information. MEG accurately localizes the irritative zone associated with interictal spikes, often detecting epileptiform activity other methods cannot, and may give localizing information when other methods fail. These capabilities potentially greatly increase the population eligible for epilepsy surgery and improve planning for those undergoing surgery. MEG methods can be readily adapted to research settings, allowing noninvasive assessment of whole brain neurophysiological activity, with a theoretical spatial range down to submillimeter voxels, and in both humans and nonhuman primates. The combination of clinical and research activities with MEG offers a unique opportunity to advance translational research from bench to bedside and back. [ABSTRACT FROM AUTHOR]

We recently demonstrated that T-type calcium channels are affected by alcohol abuse and withdrawal. Treatment with ethosuximide, an antiepileptic drug that blocks T-type calcium channels, reduces seizure activity induced by intermittent ethanol exposures and withdrawals. Here, we expand on these findings to test whether ethosuximide can reduce the sensitivity to pentylenetetrazole-induced seizures during ethanol withdrawal.~Aims~Objective~We used an intermittent ethanol exposure model to produce withdrawal-induced hyperexcitability in DBA/2J mice.~Methods~Methods~Ethosuximide (250 mg/kg) reduced seizure severity in mice undergoing ethanol withdrawal with concurrent PTZ treatment (20 mg/kg). Importantly, ethosuximide did not produce rebound excitability and protected against ethanol withdrawal-induced mortality produced by concurrent PTZ treatment (40 mg/kg).~Results~Results~These results, in addition to previous preclinical findings, suggest that ethosuximide should be further evaluated as a safe, effective alternative to benzodiazepines for the treatment of alcohol withdrawal.~Conclusion~Conclusions [ABSTRACT FROM AUTHOR]

Aims: We recently demonstrated that T-type calcium channels are affected by alcohol abuse and withdrawal. Treatment with ethosuximide, an antiepileptic drug that blocks T-type calcium channels, reduces seizure activity induced by intermittent ethanol exposures and withdrawals. Here, we expand on these findings to test whether ethosuximide can reduce the sensitivity to pentylenetetra-zole-induced seizures during ethanol withdrawal. Methods: We used an intermittent ethanol exposure model to produce withdrawal-induced hyper-excitability in DBA/2J mice. Results: Ethosuximide (250 mg/kg) reduced seizure severity in mice undergoing ethanol withdrawal with concurrent PTZ treatment (20 mg/kg). Importantly, ethosuximide did not produce rebound excitability and protected against ethanol withdrawal-induced mortality produced by concurrent PTZ treatment (40 mg/kg). Conclusion: These results, in addition to previous preclinical findings, suggest that ethosuximide should be further evaluated as a safe, effective alternative to benzodiazepines for the treatment of alcohol withdrawal. [ABSTRACT FROM AUTHOR]

Magnetoencephalography (MEG) provides useful and non-redundant information in the evaluation of patients with epilepsy, and in particular, during the pre-surgical evaluation of pharmaco-resistant epilepsy. Vagus nerve stimulation (VNS) is a common treatment for pharmaco-resistant epilepsy. However, interpretation of MEG recordings from patients with a VNS is challenging due to the severe magnetic artifacts produced by the VNS. We used synthetic aperture magnetometry (gg2) [SAM(gg2)], an adaptive beamformer that maps the excessive kurtosis, to map interictal spikes to the coregistered MRI image, despite the presence of contaminating VNS artifact.We present a series of eight patients with a VNS who underwent MEGrecording. Localization of interictal epileptiform activity by SAM(gg2) is compared to invasive electrophysiologic monitoring and other localizing approaches. While the raw MEG recordings were uninterpretable, analysis of the recordings with SAM(gg2) identified foci of peak kurtosis and source signal activity that was unaffected by the VNS artifact. SAM(g2) analysis of MEG recordings in patients with a VNS produces interpretable results and expands the use of MEG for the pre-surgical evaluation of epilepsy. [ABSTRACT FROM AUTHOR]

Background T-type calcium channels (T-channels) are widely distributed in the central and peripheral nervous system, where they mediate calcium entry and regulate the intrinsic excitability of neurons. T-channels are dysregulated in response to alcohol administration and withdrawal. We therefore investigated acute ethanol ( Et OH) effects and the underlying mechanism of action in human embryonic kidney ( HEK) 293 cell lines, as well as effects on native currents recorded from dorsal root ganglion ( DRG) neurons cultured from Long-Evans rats. Methods Whole-cell voltage-clamp recordings were performed at 32 to 34°C in both HEK cell lines and DRG neurons. The recordings were taken after a 10-minute application of Et OH or protein kinase C ( PKC) activator (phorbol 12-myristate 13-acetate [ PMA]). Results We recorded T-type Ca2+ currents (T-currents) from 3 channel isoforms ( Ca V3.1, Ca V3.2, and Ca V3.3) before and during administration of Et OH. We found that only 1 isoform, Ca V3.2, was significantly affected by EtOH. Et OH reduced current density as well as producing a hyperpolarizing shift in steady-state inactivation of both Ca V3.2 currents from HEK 293 cell lines and in native T-currents from DRG neurons that are known to be enriched in Ca V3.2. A myristoylated PKC peptide inhibitor ( MPI) blocked the major Et OH effects, in both the cell lines and the DRG neurons. However, PMA effects were more complex. Lower concentration PMA (100 nM) replicated the major effects of Et OH, while higher concentration PMA (1 μM) did not, suggesting that the Et OH effects operate through activation of PKC and were mimicked by lower concentration of PMA. Conclusions Et OH primarily affects the CaV3.2 isoform of T-type Ca2+ channels acting through PKC, highlighting a novel target and mechanism for Et OH effects on excitable membranes. [ABSTRACT FROM AUTHOR]

Background Chronic ethanol ( EtOH) leads to disruptions in resting electroencephalogram ( EEG) activity and in sleep patterns that can persist into the withdrawal period. These disruptions have been suggested to be predictors of relapse. The thalamus is a key structure involved in both normal brain oscillations, such as sleep-related oscillations, and abnormal rhythms found in disorders such as epilepsy and Parkinson's disease. Previously, we have shown progressive changes in mouse thalamic T-type Ca2+ channels during chronic intermittent EtOH exposures that occurred in parallel with alterations in theta (4 to 8 Hz) EEG patterns. Methods Two groups of 8-week-old male C57 BL/6 mice were implanted with wireless EEG/electromyogram ( EMG) telemetry and subjected to 4 weeks of chronic, intermittent EtOH vapor exposure and withdrawal. During the week after the final withdrawal, mice were administered ethosuximide ( ETX; 200 mg/kg) or saline. EEG data were analyzed via discrete Fourier transform, and sleep-scored for further analysis. Results Chronic intermittent EtOH exposure produced changes in the diurnal rhythms of the delta (0.5 to 4 Hz) and theta bands that persisted into a subsequent week of sustained withdrawal. These disruptions were restored with the T-channel blocker ETX. Repeated EtOH exposures preferentially increased the relative proportion of lower frequency power (delta and theta), whereas higher frequencies (8 to 24 Hz) were decreased. The EtOH-induced decreases in relative power for the higher frequencies continued into the sustained withdrawal week for both groups. Increases in absolute delta and theta power were observed in averaged nonrapid eye movement and rapid eye movement sleep spectral data during withdrawal in ETX-treated animals, suggesting increased sleep intensity. Conclusions These results suggest that persistent alterations in delta and theta EEG rhythms during withdrawal from chronic intermittent EtOH exposure can be ameliorated with ETX and that this treatment might also increase sleep intensity during withdrawal. [ABSTRACT FROM AUTHOR]

Mechanisms of plasticity are important to the astounding capacity of the brain to adapt and learn. Ion channels are significant contributors to neuronal plasticity, but their dysfunction has been implicated in several nervous system diseases from movement disorders to epilepsy. Although many inherited ion channel mutations have been associated with these disorders, it has been recently recognized that channelopathies can also include aberrant ion channel function that is acquired after an insult or injury to the brain. These acquired alterations are being investigated in animal models of temporal lobe epilepsy, where studies have shown functional changes in voltage-gated ion channels that lead to increases in excitability. Studies of these hyperexcitable neurons have included recordings in the hippocampus, entorhinal cortex, and thalamus and support the existence of an extended seizure network with several nodes of altered activity that are established during epileptogenesis. A better understanding of the key ion channels and brain regions that are responsible for the development of this hyperexcitability, along with the molecular mechanisms involved, may provide novel treatment strategies for epilepsy. [ABSTRACT FROM AUTHOR]

Some epilepsies are linked to inherited traits, but many appear to arise through acquired alterations in neuronal excitability. Status epilepticus (SE) is associated with numerous changes that promote spontaneous recurrent seizures (SRS), and studies have suggested that hippocampal T-type Ca2+ channels underlie increased bursts of activity integral to the generation of these seizures. The thalamus also contributes to epileptogenesis, but no studies have directly assessed channel alterations in the thalamus during SE or subsequent periods of SRS. We therefore investigated longitudinal changes in thalamic T-type channels in a mouse pilocarpine model of epilepsy. T-type channel gene expression was not affected during SE; however CaV3.2 mRNA was significantly upregulated at both 10 d post-SE (seizure-free period) and 31 d post-SE (SRS-period). Overall T-type current density increased during the SRS period, and the steady-state inactivation shifted from a more hyperpolarized membrane potential during the latent stage, to a more depolarized membrane potential during the SRS period. CaV3.2 functional involvement was verified with CaV3.2 inhibitors that reduced the native T-type current in mice 31 d post-SE, but not in controls. Burst discharges of thalamic neurons reflected the changes in whole-cell currents, and we used a computational model to relate changes observed during epileptogenesis to a decreased tendency to burst in the seizure-free period, or an increased tendency to burst during the period of SRS. We conclude that SE produces an acquired channelopathy by inducing long-term alterations in thalamic T-type channels that contribute to characteristic changes in excitability observed during epileptogenesis and SRS. [ABSTRACT FROM AUTHOR]

The thalamus relays sensory information to cortex, but this information may be influenced by excitatory feedback from cortical layer VI. The full importance of this feedback has only recently been explored, but among its possible functions are influences on the processing of sensory features, synchronization of thalamic firing, and transitions in response mode of thalamic relay cells. Uncontrolled, corticothalamic feedback has also been implicated in pathological thalamic rhythms associated with certain neurological disorders. We have found a form of presynaptic inhibition of corticothalamic synaptic transmission that is mediated by a Group II metabotropic glutamate receptor (mGluR) and activated by high-frequency corticothalamic activity. We tested putative retinogeniculate and corticogeniculate synapses for Group II mGluR modulation within the dorsal lateral geniculate nucleus of the ferret thalamus. Stimulation of optic-tract fibers elicited paired-pulse depression of excitatory postsynaptic currents (EPSCs), whereas stimulation of the optic radiations elicited paired-pulse facilitation. Pairedpulse responses were subsequently used to characterize the pathway of origin of stimulated synapses. Group II mGluR agonists (LY379268 and DCG-IV) applied to thalamic neurons under voltageclamp conditions reduced the amplitude of corticogeniculate EPSCs. Stimulation with high-frequency trains produced a facilitating response that was reduced by Group II mGluR agonists, but was enhanced by the selective antagonist LY341495, revealing a presynaptic, mGluR-mediated reduction of high-frequency corticogeniculate feedback. Agonist treatment did not affect EPSCs from stimulation of the optic tract. NAAG (reported to be selective for mGluR3) was ineffective at the corticogeniculate synapse, implicating mGluR2 in the observed effects. Our data are the first to show a synaptically elicited form of presynaptic inhibition of corticothalamic synaptic transmission that is mediated by presynaptic action of mGluR2. This presynaptic inhibition may partially mute sensory feedback and prevent reentrant excitation from initiating abnormal thalamic rhythms. [ABSTRACT FROM AUTHOR]