Mesoscopic mapping of hemodynamic responses and neuronal activity during pharmacologically induced interictal spikes in awake and anesthetized mice.

Imaging hemodynamic responses to interictal spikes holds promise for presurgical epilepsy evaluations. Understanding the hemodynamic response function is crucial for accurate interpretation. Prior interictal neurovascular coupling data primarily come from anesthetized animals, impacting reliability. We simultaneously monitored calcium fluctuations in excitatory neurons, hemodynamics, and local field potentials (LFP) during bicuculline-induced interictal events in both isoflurane-anesthetized and awake mice. Isoflurane significantly affected LFP amplitude but had little impact on the amplitude and area of the calcium signal. Anesthesia also dramatically blunted the amplitude and latency of the hemodynamic response, although not its area of spread. Cerebral blood volume change provided the best spatial estimation of excitatory neuronal activity in both states. Targeted silencing of the thalamus in awake mice failed to recapitulate the impact of anesthesia on hemodynamic responses suggesting that isoflurane's interruption of the thalamocortical loop did not contribute either to the dissociation between the LFP and the calcium signal nor to the alterations in interictal neurovascular coupling. The blood volume increase associated with interictal spikes represents a promising mapping signal in both the awake and anesthetized states.

Excitatory-inhibitory mismatch shapes node recruitment in an epileptic network.

OBJECTIVE: Focal epilepsy is thought to be a network disease, in which epileptiform activity can spread noncontiguously through the brain via highly interconnected nodes, or hubs, within existing networks. Animal models confirming this hypothesis are scarce, and our understanding of how distant nodes are recruited is also lacking. Whether interictal spikes (IISs) also create and reverberate through a network is not well understood. METHODS: We injected bicuculline into the S1 barrel cortex and employed multisite local field potential and Thy-1 and parvalbumin (PV) cell mesoscopic calcium imaging during IISs to monitor excitatory and inhibitory cells in two monosynaptically connected nodes and one disynaptically connected node: ipsilateral secondary motor area (iM2), contralateral S1 (cS1), and contralateral secondary motor area (cM2). Node participation was analyzed with spike-triggered coactivity maps. Experiments were repeated with 4-aminopyridine as an epileptic agent. RESULTS: We found that each IIS reverberated throughout the network, differentially recruiting both excitatory and inhibitory cells in all connected nodes. The strongest response was found in iM2. Paradoxically, node cM2, which was connected disynaptically to the focus, was recruited more intensely than node cS1, which was connected monosynaptically. The explanation for this effect could be found in node-specific excitatory/inhibitory (E/I) balance, as cS1 demonstrated greater PV inhibitory cell activation compared with cM2, where Thy-1 excitatory cells were more heavily recruited. SIGNIFICANCE: Our data show that IISs spread noncontiguously by exploiting fiber pathways that connect nodes in a distributed network and that E/I balance plays a critical role in node recruitment. This multinodal IIS network model can be used to investigate cell-specific dynamics in the spatial propagation of epileptiform activity.

Seizure outcome-related factors in autoimmune encephalitis: A systematic review and meta-analysis.

Background: Identifying the predictors for seizure outcome in autoimmune encephalitis (AE) and investigating how to prevent persistent seizures would have major clinical benefits effectively. Thus, we aimed to perform a systematic review and meta-analysis to examine seizure outcome-related factors in AE patients. Methods: PubMed and EMBASE were systematically searched from inception to 10 June 2022 for studies investigating seizure outcome-related factors in AE. The pooled effect estimates, including standardized mean differences (SMDs) and odds ratios (ORs) with 95% confidence intervals (CIs), were calculated to estimate the effect of each included factor on the seizure outcome. Results: A total of 10 studies were included in the meta-analysis. Our pooled results of this meta-analysis showed that five factors were found to increase the risk of persistent seizures in AE patients, including onset with seizures (OR = 2.106, 95% CI = 1.262-3.514, p = 0.004), status epilepticus (OR = 3.017, 95% CI = 1.995-4.563, p < 0.001), EEG abnormalities (OR = 1.581, 95% CI = 1.016-2.46, p = 0.042), MRI abnormalities (OR = 1.554, 95% CI = 1.044-2.283, p = 0.03), and longer time from clinical onset to immunotherapy (SMD = 1.887, 95% CI = 0.598-3.156, p = 0.004). Conclusion: Our meta-analysis indicated that onset with seizures, status epilepticus, EEG abnormalities, MRI abnormalities, and longer time from clinical onset to immunotherapy were risk factors for persistent seizures in AE patients.

Mesoscopic Mapping of Ictal Neurovascular Coupling in Awake Behaving Mice Using Optical Spectroscopy and Genetically Encoded Calcium Indicators.

Unambiguously identifying an epileptic focus with high spatial resolution is a challenge, especially when no anatomic abnormality can be detected. Neurovascular coupling (NVC)-based brain mapping techniques are often applied in the clinic despite a poor understanding of ictal NVC mechanisms, derived primarily from recordings in anesthetized animals with limited spatial sampling of the ictal core. In this study, we used simultaneous wide-field mesoscopic imaging of GCamp6f and intrinsic optical signals (IOS) to record the neuronal and hemodynamic changes during acute ictal events in awake, behaving mice. Similar signals in isoflurane-anesthetized mice were compared to highlight the unique characteristics of the awake condition. In awake animals, seizures were more focal at the onset but more likely to propagate to the contralateral hemisphere. The HbT signal, derived from an increase in cerebral blood volume (CBV), was more intense in awake mice. As a result, the "epileptic dip" in hemoglobin oxygenation became inconsistent and unreliable as a mapping signal. Our data indicate that CBV-based imaging techniques should be more accurate than blood oxygen level dependent (BOLD)-based imaging techniques for seizure mapping in awake behaving animals.

Isoflurane-Induced Burst Suppression Is a Thalamus-Modulated, Focal-Onset Rhythm With Persistent Local Asynchrony and Variable Propagation Patterns in Rats.

Background: Inhalational anesthetic-induced burst suppression (BS) is classically considered a bilaterally synchronous rhythm. However, local asynchrony has been predicted in theoretical studies and reported in patients with pre-existing focal pathology. Method: We used high-speed widefield calcium imaging to study the spatiotemporal dynamics of isoflurane-induced BS in rats. Results: We found that isoflurane-induced BS is not a globally synchronous rhythm. In the neocortex, neural activity first emerged in a spatially shifting, variably localized focus. Subsequent propagation across the whole cortex was rapid, typically within <100 milliseconds, giving the superficial resemblance to global synchrony. Neural activity remained locally asynchronous during the bursts, forming complex recurrent propagating waves. Despite propagation variability, spatial sequences of burst propagation were largely preserved between the hemispheres, and neural activity was highly correlated between the homotopic areas. The critical role of the thalamus in cortical burst initiation was demonstrated by using unilateral thalamic tetrodotoxin injection. Conclusion: The classical impression that anesthetics-induced BS is a state of global brain synchrony is inaccurate. Bursts are a series of shifting local cortical events facilitated by thalamic projection that unfold as rapid, bilaterally asynchronous propagating waves.

Tumor necrosis factor-α in Guillain-Barré syndrome, friend or foe?

INTRODUCTION: Guillain-Barré syndrome (GBS) is an immune-mediated disorder in the peripheral nervous system (PNS), and experimental autoimmune neuritis (EAN) serves as an animal model of GBS. TNF-α plays an important role in the pathogenesis of GBS and is a potential therapeutic target of GBS. Areas covered: 'TNF-α' and 'Guillain-Barré syndrome' were the keywords used to search for related publications on Pubmed. By binding to different TNF receptors, TNF-α bears distinct immune properties. TNF-α gene polymorphisms are associated with the features of GBS. The major role of TNF-α in GBS/EAN is to aggravate inflammation; however, data from several studies indicated a protective role of TNF-α. Multiple lines of evidence point to TNF-α as a potential therapeutic target for GBS. However, such clinical trials are scarce in that GBS per se is a probable side effect of anti-TNF-α treatment. Expert opinion: TNF-α plays a dual role in GBS and EAN, and is a potential therapeutic target on GBS/EAN.