Local Field Potential Recordings Research Articles

Altered Emotional Phenotypes in Chronic Kidney Disease Following 5/6 Nephrectomy.

Increased prevalence of chronic kidney disease (CKD) and neurological disorders including cerebrovascular disease, cognitive impairment, peripheral neuropathy, and dysfunction of central nervous system have been reported during the natural history of CKD. Psychological distress and depression are serious concerns in patients with CKD. However, the relevance of CKD due to decline in renal function and the pathophysiology of emotional deterioration is not clear. Male Sprague Dawley rats were divided into three groups: sham control, 5/6 nephrectomy at 4 weeks, and 5/6 nephrectomy at 10 weeks. Behavior tests, local field potentials, and histology and laboratory tests were conducted and investigated. We provided direct evidence showing that CKD rat models exhibited anxiogenic behaviors and depression-like phenotypes, along with altered hippocampal neural oscillations at 1–12 Hz. We generated CKD rat models by performing 5/6 nephrectomy, and identified higher level of serum creatinine and blood urea nitrogen (BUN) in CKD rats than in wild-type, depending on time. In addition, the level of α-smooth muscle actin (α-SMA) and collagen I for renal tissue was markedly elevated, with worsening fibrosis due to renal failures. The level of anxiety and depression-like behaviors increased in the 10-week CKD rat models compared with the 4-week rat models. In the recording of local field potentials, the power of delta (1–4 Hz), theta (4–7 Hz), and alpha rhythm (7–12 Hz) was significantly increased in the hippocampus of CKD rats compared with wild-type rats. Together, our findings indicated that anxiogenic behaviors and depression can be induced by CKD, and these abnormal symptoms can be worsened as the onset of CKD was prolonged. In conclusion, our results show that the hippocampus is vulnerable to uremia.

Dynamics of Neural Microstates in the VTA-Striatal-Prefrontal Loop during Novelty Exploration in the Rat.

Neural activity at the large-scale population level has been suggested to be consistent with a sequence of brief, quasistable spatial patterns. These "microstates" and their temporal dynamics have been linked to myriad cognitive functions and brain diseases. Most of this research has been performed using EEG, leaving many questions, such as the existence, dynamics, and behavioral relevance of microstates at the level of local field potentials (LFPs), unaddressed. Here, we adapted the standard EEG microstate analysis to triple-area LFP recordings from 192 electrodes in rats to investigate the mesoscopic dynamics of neural microstates within and across brain regions during novelty exploration. We performed simultaneous recordings from the prefrontal cortex, striatum, and ventral tegmental area in male rats during awake behavior (object novelty and exploration). We found that the LFP data can be accounted for by multiple, recurring microstates that were stable for ∼60-100 ms. The simultaneous microstate activity across brain regions revealed rhythmic patterns of coactivations, which we interpret as a novel indicator of inter-regional, mesoscale synchronization. Furthermore, these rhythmic coactivation patterns across microstates were modulated by behavioral states such as movement and exploration of a novel object. These results support the existence of a functional mesoscopic organization across multiple brain areas and present a possible link of the origin of macroscopic EEG microstates to zero-lag neuronal synchronization within and between brain areas, which is of particular interest to the human research community.SIGNIFICANCE STATEMENT The coordination of neural activity across the entire brain has remained elusive. Here we combine large-scale neural recordings at fine spatial resolution with the analysis of microstates (i.e., short-lived, recurring spatial patterns of neural activity). We demonstrate that the local activity in different brain areas can be accounted for by only a few microstates per region. These microstates exhibited temporal dynamics that were correlated across regions in rhythmic patterns. We demonstrate that these microstates are linked to behavior and exhibit different properties in the frequency domain during different behavioral states. In summary, LFP microstates provide an insightful approach to studying both mesoscopic and large-scale brain activation within and across regions.

Correlating Beta Oscillations from Intraoperative Microelectrode and Postoperative Implanted Electrode in Patients Undergoing Subthalamic Nucleus Deep Brain Stimulation for Parkinson Disease; A Feasibility Study

We sought to investigate the feasibility of intraoperative local field potential (LFP) recording from the microelectrode during deep brain stimulation surgery for patients with Parkinson disease. Sixteen subthalamic nucleus recordings from 10 Parkinson disease patients who underwent deep brain stimulation surgery were included in this study. Signals from microelectrodes were amplified and differently filtered to display real-time single-unit neuronal activity and LFP simultaneously during surgery. LFP recordings were also recorded postoperatively from the implanted macroelectrodes and, power spectral density and peak frequency of beta oscillation of LFP (beta LFP) between 2 conditions were compared. Stable intraoperative beta LFP were observed in 68.75% (11 of 16) cases. There was no significant difference of peak frequency between intraoperative and postoperative beta-LFP but significant difference of mean percentage of beta LFP was noted between 2 conditions. Despite low signal-to-noise ratio and susceptibility to noises from external sources, this study shows that intraoperative recording of beta LFP using microelectrode is feasible. And, given that no significant difference in peak frequency of beta LFP between intraoperative and postoperative LFP was found, we suggest that not only intraoperative beta LFP can be used as a reliable surrogate for postoperative beta LFP, but it can also provide us an information for estimating the location with maximal power of beta oscillation within the subthalamic nucleus.

Phenotypic analysis of catastrophic childhood epilepsy genes

Genetic engineering techniques have contributed to the now widespread use of zebrafish to investigate gene function, but zebrafish-based human disease studies, and particularly for neurological disorders, are limited. Here we used CRISPR-Cas9 to generate 40 single-gene mutant zebrafish lines representing catastrophic childhood epilepsies. We evaluated larval phenotypes using electrophysiological, behavioral, neuro-anatomical, survival and pharmacological assays. Local field potential recordings (LFP) were used to screen ∼3300 larvae. Phenotypes with unprovoked electrographic seizure activity (i.e., epilepsy) were identified in zebrafish lines for 8 genes; ARX, EEF1A, GABRB3, GRIN1, PNPO, SCN1A, STRADA and STXBP1. We also created an open-source database containing sequencing information, survival curves, behavioral profiles and representative electrophysiology data. We offer all zebrafish lines as a resource to the neuroscience community and envision them as a starting point for further functional analysis and/or identification of new therapies.

Concurrent electrophysiological recording and cognitive testing in a rodent touchscreen environment

Challenges in therapeutics development for neuropsychiatric disorders can be attributed, in part, to a paucity of translational models capable of capturing relevant phenotypes across clinical populations and laboratory animals. Touch-sensitive procedures are increasingly used to develop innovative animal models that better align with testing conditions used in human participants. In addition, advances in electrophysiological techniques have identified neurophysiological signatures associated with characteristics of neuropsychiatric illness. The present studies integrated these methodologies by developing a rat flanker task with electrophysiological recordings based on reverse-translated protocols used in human electroencephalogram (EEG) studies of cognitive control. Various touchscreen-based stimuli were evaluated for their ability to efficiently gain stimulus control and advance to flanker test sessions. Optimized stimuli were then examined for their elicitation of prototypical visual evoked potentials (VEPs) across local field potential (LFP) wires and EEG skull screws. Of the stimuli evaluated, purple and green photographic stimuli were associated with efficient training and expected flanker interference effects. Orderly stimulus-locked outcomes were also observed in VEPs across LFP and EEG recordings. These studies along with others verify the feasibility of concurrent electrophysiological recordings and rodent touchscreen-based cognitive testing and encourage future use of this integrated approach in therapeutics development.

Minocycline inhibits sleep deprivation-induced aberrant microglial activation and Keap1-Nrf2 expression in mouse hippocampus

Sleep deprivation (SD) is a hallmark of modern society and associated with many neuropsychiatric disorders, including depression and anxiety. However, the cellular and molecular mechanisms underlying SD-associated depression and anxiety remain elusive. Does the neuroinflammation play a role in mediating the effects of SD? In this study, we investigated SD-induced cellular and molecular alterations in the hippocampus and asked whether treatment with an anti-inflammatory drug, minocycline, could attenuate these alterations. We found that SD animals exhibit activated microglia and decreased levels of Keap1 and Nrf2 (antioxidant and anti-inflammatory factors) in the hippocampus. In vivo local field potential recordings show decreased theta and beta oscillations, but increased high gamma oscillations, as a result of SD. Behavioral analysis revealed increased immobility time in the forced swim and tail suspension tests, and decreased sucrose intake in SD mice, all indicative of depressive-like behavior. Moreover, open field test and elevated plus maze test results indicated that SD increases anxiety-like behavior. Interestingly, treatment with the microglial modulator minocycline prevented SD-induced microglial activation, restored Keap1 and Nrf2 levels, normalized neuronal oscillations, and alleviated depressive-like and anxiety-like behavior. The present study reveals that microglial activation and Keap1-Nrf2 signaling play a crucial role in SD-induced behavioral alteration, and that minocycline treatment has a protective effect on these alterations.

In vivo calcium imaging reveals disordered interictal network dynamics in epileptic stxbp1b zebrafish

SummarySTXBP1 mutations are associated with encephalopathy, developmental delay, intellectual disability, and epilepsy. While neural networks are known to operate at a critical state in the healthy brain, network behavior during pathological epileptic states remains unclear. Examining activity during periods between well-characterized ictal-like events (i.e., interictal period) could provide a valuable step toward understanding epileptic networks. To study these networks in the context of STXBP1 mutations, we combine a larval zebrafish model with in vivo fast confocal calcium imaging and extracellular local field potential recordings. Stxbp1b mutants display transient periods of elevated activity among local clusters of interacting neurons. These network “cascade” events were significantly larger in size and duration in mutants. At mesoscale resolution, cascades exhibit neurodevelopmental abnormalities. At single-cell scale, we describe spontaneous hyper-synchronized neuronal ensembles. That calcium imaging reveals uniquely disordered brain states during periods between pathological ictal-like seizure events is striking and represents a potential interictal biomarker.

D-Amphetamine Rapidly Reverses Dexmedetomidine-Induced Unconsciousness in Rats.

D-amphetamine induces emergence from sevoflurane and propofol anesthesia in rats. Dexmedetomidine is an α2-adrenoreceptor agonist that is commonly used for procedural sedation, whereas ketamine is an anesthetic that acts primarily by inhibiting NMDA-type glutamate receptors. These drugs have different molecular mechanisms of action from propofol and volatile anesthetics that enhance inhibitory neurotransmission mediated by GABAA receptors. In this study, we tested the hypothesis that d-amphetamine accelerates recovery of consciousness after dexmedetomidine and ketamine. Sixteen rats (Eight males, eight females) were used in a randomized, blinded, crossover experimental design and all drugs were administered intravenously. Six additional rats with pre-implanted electrodes in the prefrontal cortex (PFC) were used to analyze changes in neurophysiology. After dexmedetomidine, d-amphetamine dramatically decreased mean time to emergence compared to saline (saline:112.8 ± 37.2 min; d-amphetamine:1.8 ± 0.6 min, p < 0.0001). This arousal effect was abolished by pre-administration of the D1/D5 dopamine receptor antagonist, SCH-23390. After ketamine, d-amphetamine did not significantly accelerate time to emergence compared to saline (saline:19.7 ± 18.0 min; d-amphetamine:20.3 ± 16.5 min, p = 1.00). Prefrontal cortex local field potential recordings revealed that d-amphetamine broadly decreased spectral power at frequencies <25 Hz and restored an awake-like pattern after dexmedetomidine. However, d-amphetamine did not produce significant spectral changes after ketamine. The duration of unconsciousness was significantly longer in females for both dexmedetomidine and ketamine. In conclusion, d-amphetamine rapidly restores consciousness following dexmedetomidine, but not ketamine. Dexmedetomidine reversal by d-amphetamine is inhibited by SCH-23390, suggesting that the arousal effect is mediated by D1 and/or D5 receptors. These findings suggest that d-amphetamine may be clinically useful as a reversal agent for dexmedetomidine.

Longitudinal analysis of local field potentials recorded from directional deep brain stimulation lead implants in the subthalamic nucleus

Objective. The electrode–tissue interface surrounding a deep brain stimulation (DBS) lead is known to be highly dynamic following implantation, which may have implications on the interpretation of intraoperatively recorded local field potentials (LFPs). We characterized beta-band LFP dynamics following implantation of a directional DBS lead in the sensorimotor subthalamic nucleus (STN), which is a primary target for treating Parkinson’s disease. Approach. Directional STN-DBS leads were implanted in four healthy, non-human primates. LFPs were recorded over two weeks and again 1–4 months after implantation. Impedance was measured for two weeks post-implant without stimulation to compare the reactive tissue response to changes in LFP oscillations. Beta-band (12–30 Hz) peak power was calculated from the LFP power spectra using both common average referencing (CAR) and intra-row bipolar referencing (IRBR). Results. Resting-state LFPs in two of four subjects revealed a steady increase of beta power over the initial two weeks post-implant whereas the other two subjects showed variable changes over time. Beta power variance across days was significantly larger in the first two weeks compared to 1–4 months post-implant in all three long-term subjects. Further, spatial maps of beta power several hours after implantation did not correlate with those measured two weeks or 1–4 months post-implant. CAR and IRBR beta power correlated across short- and long-term time points. However, depending on the time period, subjects showed a significant bias towards larger beta power using one referencing scheme over the other. Lastly, electrode–tissue impedance increased over the two weeks post-implant but showed no significant correlation to beta power. Significance. These results suggest that beta power in the STN may undergo significant changes following DBS lead implantation. DBS lead diameter and electrode recording configurations can affect the post-implant interpretation of oscillatory features. Such insights will be important for extrapolating results from intraoperative and externalized LFP recordings.

Is there a single beta oscillation band interfering with movement in Parkinson's disease?

Beta oscillations in basal ganglia are considered to contribute to motor dysfunction in Parkinson's disease (PD). However, there is a high variety in frequency borders for beta oscillations between studies, which complicates the comparison and interpretation of results. Here we aimed to study the homogeneity of oscillations in the broad "beta" range (8-30Hz) and their implication to motor functioning in PD. For this purpose, we recorded local field potentials (LFP) in the subthalamic nucleus (STN) during 34 deep brain stimulation surgeries. We identified spectral features of LFP recordings in the range 8-30Hz to search for candidate sub-regions of stable oscillations and assessed their association with clinical scores on the contralateral side of the body and sensitivity to motor tests. Lower frequency oscillations (8-16Hz) had a significant positive association with bradykinesia score. During voluntary movements, we observed a significant increase in LFP power in the 12-16Hz range and a decrease in the 18-26Hz range. We may conclude that the 8-30Hz oscillation range includes oscillations with different functional features-sensitivity and responsiveness to movement, and clinical symptoms, which should be taken into account in further studies of beta oscillations association with PD pathophysiology. These data assume the coexistence of several frequency domains within beta range that are modulated in different ways under dopaminergic regulation and motor processing in human STN.

Risk of Infection after Deep Brain Stimulation Surgery with Externalization and Local-Field Potential Recordings: Twelve-Year Experience from a Single Institution

Introduction: Deep brain stimulation (DBS) has been an established surgical procedure in the field of functional neurosurgery for many years. The experimental electrophysiological method of local field potential (LFP) recordings in postsurgically externalized patients has made substantial contributions to the better understanding of pathophysiologies underlying movement disorders. As interest in LFP recordings for the development of improved stimulation strategies increases, this study’s aim was to provide evidence concerning safety of this research method, in a major DBS center. Methods: We retrospectively analyzed incidence and infection characteristics in adult patients who underwent two-staged DBS surgery with temporary externalization of leads in our center between January 2008 and November 2019. We focused on whether patients had participated in LFP recordings, and evaluated incidence of infections at 3 months and 1 year after the surgery based on medical records. Infection rates were compared to major DBS studies and reports focusing on the risk of infection due to externalization of DBS leads. Results were visualized using descriptive statistics. Results: Between January 2008 and November 2019, DBS surgery was performed in 528 patients (389/139 patients in the LFP/non-LFP group), mainly for movement disorders such as Parkinson’s disease (308), dystonia (93), and essential tremor (86). Of the patients, 72.9% participated in LFP recordings. The incidence of infections in the acute postsurgical phase (3 months) was 2.46% and did not differ significantly between the LFP group (1.8%) and the non-LFP group (4.32%). The overall incidence after 1 year amounted to 3.6% (19 patients) with no difference between LFP/non-LFP groups. Incidence rates reported in the literature show a large variety (2.6–10%), and the incidence reported here is within the lower range of reported incidences. Discussion/Conclusion: This study demonstrates that DBS is a surgical procedure with a low risk of infection in a large patient cohort. Importantly, it shows that LFP recordings do not have a significant effect on the incidence of infections in patients with externalization. With a representative cohort of more than 380 patients participating in LFP-recordings, this underlines LFP as a safe method in research and supports further use of this method, for example, for the development of adaptive stimulation protocols.

Frequency selective neuronal modulation triggers spreading depolarizations in the rat endothelin-1 model of stroke

Ischemia is one of the most common causes of acquired brain injury. Central to its noxious sequelae are spreading depolarizations (SDs), waves of persistent depolarizations which start at the location of the flow obstruction and expand outwards leading to excitotoxic damage. The majority of acute stage of stroke studies to date have focused on the phenomenology of SDs and their association with brain damage. In the current work, we investigated the role of peri-injection zone pyramidal neurons in triggering SDs by optogenetic stimulation in an endothelin-1 rat model of focal ischemia. Our concurrent two photon fluorescence microscopy data and local field potential recordings indicated that a ≥ 60% drop in cortical arteriolar red blood cell velocity was associated with SDs at the ET-1 injection site. SDs were also observed in the peri-injection zone, which subsequently exhibited elevated neuronal activity in the low-frequency bands. Critically, SDs were triggered by low- but not high-frequency optogenetic stimulation of peri-injection zone pyramidal neurons. Our findings depict a complex etiology of SDs post focal ischemia and reveal that effects of neuronal modulation exhibit spectral and spatial selectivity.

Altered theta and beta oscillatory synchrony in a genetic mouse model of pathological anxiety.

While the neural circuits mediating normal, adaptive defensive behaviors have been extensively studied, substantially less is currently known about the network mechanisms by which aberrant, pathological anxiety is encoded in the brain. Here we investigate in mice how deletion of Neuroligin-2 (Nlgn2), an inhibitory synapse-specific adhesion protein that has been associated with pathological anxiety and other psychiatric disorders, alters the communication between key brain regions involved in mediating defensive behaviors. To this end, we performed multi-site simultaneous local field potential (LFP) recordings from the basolateral amygdala (BLA), centromedial amygdala (CeM), bed nucleus of the stria terminalis (BNST), prefrontal cortex (mPFC) and ventral hippocampus (vHPC) in an open field paradigm. We found that LFP power in the vHPC was profoundly increased and was accompanied by an abnormal modulation of the synchrony of theta frequency oscillations particularly in the vHPC-mPFC-BLA circuit. Moreover, deletion of Nlgn2 increased beta and gamma frequency synchrony across the network, and this increase was associated with increased center avoidance. Local deletion of Nlgn2 in the vHPC and BLA revealed that they encode distinct aspects of this avoidance phenotype, with vHPC linked to immobility and BLA linked to a reduction in exploratory activity. Together, our data demonstrate that alterations in long-range functional connectivity link synaptic inhibition to abnormal defensive behaviors, and that both exaggerated activation of normal defensive circuits and recruitment of fundamentally distinct mechanisms contribute to this phenotype. Nlgn2 knockout mice therefore represent a highly relevant model to study the role of inhibitory synaptic transmission in the circuits underlying anxiety disorders.

Aging-Related Neural Disruption Might Predispose to Postoperative Cognitive Impairment Following Surgical Trauma

Accumulating evidence has demonstrated that aging is associated with an exaggerated response to surgical trauma together with cognitive impairments. This has significant implications for the development of clinical phenotype such as perioperative neurocognitive disorders (PND), which is a common complication following surgery, especially for the elderly. However, the mechanism by which aging brain is vulnerable to surgical trauma remains to be elucidated. To test whether age-related alterations in hippocampal network activities contribute to increased risk of PND following surgery. Thirty-two adult and seventy-two aged male C57BL/6 mice undergone sevoflurane anesthesia and exploratory laparotomy were used to mimic human abdominal surgery. For the interventional study, mice were treated with minocycline. Behavioral tests were performed post-surgery with open field, novel object recognition and fear conditioning tests, respectively. The brain tissues were then harvested and subjected to biochemistry studies. Local field potential (LFP) recording was performed in another separate experiment. Aged mice displayed signs of neuroinflammation, as reflected by significantly increased proinflammatory mediators in the hippocampus. Also, aged mice displayed persistently decreased oscillation activities under different conditions, both before and after surgery. Further correlation analysis suggested that theta power was positively associated with time with novel object, while γ oscillation activity was positively associated with freezing time to context. Of note, downregulation of neuroinflammation by microglia inhibitor minocycline reversed some of these abnormities. Our study highlights that age-related hippocampal oscillation dysregulation increases the risk of PND incidence, which might provide diagnostic/prognostic biomarkers for PND and possible other neurodegenerative diseases.

Multimodal neural recordings with Neuro-FITM uncover diverse patterns of cortical-hippocampal interactions.

Many cognitive processes require communication between the neocortex and the hippocampus. However, coordination between large-scale cortical dynamics and hippocampal activity is not well understood, partially due to the difficulty in simultaneously recording from those regions. In the present study, we developed a flexible, insertable and transparent microelectrode array (Neuro-FITM) that enables investigation of cortical-hippocampal coordinations during hippocampal sharp-wave ripples (SWRs). Flexibility and transparency of Neuro-FITM allow simultaneous recordings of local field potentials and neural spiking from the hippocampus during wide-field calcium imaging. These experiments revealed that diverse cortical activity patterns accompanied SWRs and, in most cases, cortical activation preceded hippocampal SWRs. We demonstrated that, during SWRs, different hippocampal neural population activity was associated with distinct cortical activity patterns. These results suggest that hippocampus and large-scale cortical activity interact in a selective and diverse manner during SWRs underlying various cognitive functions. Our technology can be broadly applied to comprehensive investigations of interactions between the cortex and other subcortical structures.

Electrophysiological Correlates of Rodent Default-Mode Network Suppression Revealed by Large-Scale Local Field Potential Recordings.

Here we show that alpha/beta frequency oscillations in rats show key features of DMN activity, including intrinsic correlations between DMN brain regions, task-related suppression, and interference with attention/decision-making. We found similar task-related suppression at alpha/low beta-frequencies of DMN activity in humans.

Adaptive changes in local field potential oscillation associated with morphine conditioned place preference in mice

Neural adaptation associated with formation of morphine conditioned place preference remained largely unexplored. This study monitored longitudinal changes in neural signaling during pre-conditioning, conditioning and post-conditioning periods of morphine conditioned place preference (CPP) paradigm for investigation of adaptive mechanisms of opiate addiction. Male Swiss albino mice implanted with intracranial electrodes into the nucleus accumbens (NAc), striatum (STr) and hippocampus (HC) were used for recording of local field potentials (LFPs). Animals received a 10-day schedule for associative learning to pair the specific compartment of the chamber with morphine effects. Exploratory behavior and LFP signals were recorded during pre-conditioning (baseline level), conditioning (day 1, 5 and 10) and post-conditioning (day 1, 4 and 7) periods. Repeated measures one-way ANOVA followed by Tukey test revealed significant increases in number of visit and time spent in morphine compartment during post-conditioning days. Frequency analysis of LFP highlighted the increases in alpha activity (12 – 18 Hz) in the NAc from post-conditioning day 1 until day 7. Moreover, significantly increased coherent activities between the pair of NAc-HC were developed within gamma frequency range (35 – 42 Hz) on morphine conditioning day 10 and disappeared during post-conditioning days. Taken together, these findings emphasized NAc LFP signaling and neural connectivities between the NAc and HC associated with morphine CPP. These adaptive changes might underlie the formation of morphine conditioned place preference and behavioral consequences such as craving and relapse.

Defining the latent period of epileptogenesis and epileptogenic zone in a focal cortical dysplasia type II (FCDII) rat model.

SummaryObjectivesFocal cortical dysplasia type II (FCDII) is one of the most common underlying pathologies in patients with drug‐resistant epilepsy. However, mechanistic understanding of FCDII fails to keep pace with genetic discoveries, primarily due to the significant challenge in developing a clinically relevant animal model. Conceptually and clinically important questions, such as the unknown latent period of epileptogenesis and the controversial epileptogenic zone, remain unknown in all experimental FCDII animal models, making it even more challenging to investigate the underlying epileptogenic mechanisms.MethodsIn this study, we used continuous video‐electroencephalography (EEG) monitoring to detect the earliest interictal and ictal events in a clustered regularly interspaced short palindromic repeats (CRISPR)‐in utero electroporation (IUE) FCDII rat model that shares genetic, pathological, and electroclinical signatures with those observed in humans. We then took advantage of in vivo local field potential (LFP) recordings to localize the epileptogenic zone in these animals.ResultsTo the best of our knowledge, we showed for the first time that epileptiform discharges emerged during the third postnatal week, and that the first seizure occurred as early as during the fourth postnatal week. We also showed that both interictal and ictal discharges are localized within the dysplastic cortex, concordant with human clinical data.SignificanceTogether, our work identified the temporal and spatial frame of epileptogenesis in a highly clinically relevant FCDII animal model, paving the way for mechanistic studies at molecular, cellular, and circuitry levels.

Network and synaptic mechanisms underlying high frequency oscillations in the rat and cat olfactory bulb under ketamine-xylazine anesthesia

Wake-related ketamine-dependent high frequency oscillations (HFO) can be recorded in local field potentials (LFP) from cortical and subcortical regions in rodents. The mechanisms underlying their generation and occurrence in higher mammals are unclear. Unfortunately, anesthetic doses of pure ketamine attenuate HFO, which has precluded their investigation under anesthesia. Here, we show ketamine-xylazine (KX) anesthesia is associated with a prominent 80–130 Hz rhythm in the olfactory bulb (OB) of rats, whereas 30–65 Hz gamma power is diminished. Simultaneous LFP and thermocouple recordings revealed the 80–130 Hz rhythm was dependent on nasal respiration. This rhythm persisted despite surgical excision of the piriform cortex. Silicon probes spanning the dorsoventral aspect of the OB revealed this rhythm was strongest in ventral areas and associated with microcurrent sources about the mitral layer. Pharmacological microinfusion studies revealed dependency on excitatory-inhibitory synaptic activity, but not gap junctions. Finally, a similar rhythm occurred in the OB of KX-anesthetized cats, which shared key features with our rodent studies. We conclude that the activity we report here is driven by nasal airflow, local excitatory-inhibitory interactions, and conserved in higher mammals. Additionally, KX anesthesia is a convenient model to investigate further the mechanisms underlying wake-related ketamine-dependent HFO.

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.