Hippocampal EEG Research Articles

The protective effect of DMI on hippocampus EEG, behavioral and biochemical parameters in hypoxia-induced seizure on neonatal period.

Hypoxia-Induced Neonatal Seizure (HINS) is a prevalent type of seizure in infants caused by hypoxic conditions, which can lead to an increased risk of epilepsy, learning disabilities, and cognitive impairments later in life. This study focuses on examining the effects of dimethyl itaconate (DMI) on cognition, motor coordination, and anxiety-like behavior in male rats that have experienced HINS. 42 male Wistar newborn rats (PND10) were randomly divided into six groups (n = 7). 1) Control (Vehicle only); received DMI solvent (0.1ml) without applying hypoxia. 2-3) DMI; receiving (20 and 50 mg/kg; i.p). 4) HINS; they were placed in a hypoxia chamber with 7% oxygen and 93% nitrogen concentration for 15 minutes. 5-6) DMI+HINS; received DMI (20 and 50 mg/kg; i.p) 24h before hypoxia. Behavioral tests including; Novel object recognition test, Rotarod, Parallel bar, Open field and elevated plus maze (EPM); started at age 45 after birth. After behavioral tests, the hippocampal CA1 region local EEG was recorded in all groups. Then the brain hippocampus tissue was isolated and the amount of MDA, SOD, NO, and Thiol was measured by ELISA method. Data showed that the administration of DMI improved motor symptoms, anxiety-like behaviors, and cognition in HINS rats (p<0.05). EEG power in the HINS group decreased significantly compared to other experimental groups (p<0.05). Biochemical observations showed that DMI significantly reduced oxidative stress and inflammation in the hippocampal tissue of HINS rats (p<0.05). Increased hippocampal oxidative stress and inflammation can be effective in the occurrence of behavioral disorders observed in HINS rats. While DMI improved these behavioral impairments by reducing oxidative stress and inflammation.

Temporal development of seizure threshold and spontaneous seizures after neonatal asphyxia and the effect of prophylactic treatment with midazolam in rats

Birth asphyxia (BA) and subsequent hypoxic-ischemic encephalopathy (HIE) is one of the most serious birth complications affecting full-term infants and can result in severe disabilities including mental retardation, cerebral palsy, and epilepsy. Animal models of BA and HIE are important to characterize the functional and behavioral correlates of injury , explore cellular and molecular mechanisms, and assess the potential of novel therapeutic strategies. Here we used a non-invasive, physiologically validated rat model of BA and acute neonatal seizures that mimics many features of BA and HIE in human infants to study (i) the temporal development of epilepsy with spontaneous recurrent seizures (SRS) in the weeks and months after the initial brain injury, (ii) alterations in seizure threshold and hippocampal EEG that may precede the onset of SRS, and (iii) the effect of prophylactic treatment with midazolam. For this purpose, a total of 89 rat pups underwent asphyxia or sham asphyxia at postnatal day 11 and were examined over 8–10.5 months. In vehicle-treated animals, the incidence of electroclinical SRS progressively increased from 0 % at 2.5 months to 50 % at 6.5 months, 75 % at 8.5 months, and > 80 % at 10.5 months after asphyxia. Unexpectedly, post-asphyxial rats did not differ from sham-exposed rats in seizure threshold or interictal epileptiform discharges in the EEG. Treatment with midazolam (1 mg/kg i.p.) after asphyxia, which suppressed acute symptomatic neonatal seizures in about 60 % of the rat pups, significantly reduced the incidence of SRS regardless of its effect on neonatal seizures. This antiepileptogenic effect of midazolam adds to the recently reported prophylactic effects of this drug on BA-induced neuroinflammation, brain damage, behavioral alterations, and cognitive impairment in the rat asphyxia model of HIE.

A simple, automated method of seizure detection in mouse models of temporal lobe epilepsy

The lack of preventive and disease modifying therapies for temporal lobe epilepsy (TLE) is a major unmet medical need. Search for such therapies utilize mouse models and require detection of seizures in electroencephalography (EEG) recordings. The labor-intensive nature of reviewing EEGs spanning many weeks underscores the need for a method of automated detection. Here we report a simple automated method of detecting seizures in long term EEG recordings from electrodes implanted in the hippocampus in animal models of TLE. We utilize a 2-pronged approach that relies on the increase in power within the gamma band range (20–50hz) during the seizure followed by suppression of activity following the seizure (post-ictal suppression [PIS]). We demonstrate the utility of this method for detecting seizures in hippocampal and amygdala EEG recordings from multiple models of TLE.

Low-frequency amplitude modulation of hippocampal theta rhythm in rats during treadmill running

The hippocampus is the main structure involved in the generation of the theta rhythm (4–12 Hz), which is among the most regular neural oscillations in electroencephalography (EEG) signals recorded during locomotion. However, whether changes in hippocampal theta rhythm amplitude provide any information remains unclear, primarily because traditional analytical methods cannot directly quantify such changes. ObjectiveThis study was conducted to (1) examine the characteristics of signal addition or multiplication through Holo-Hilbert spectral analysis (HHSA), (2) determine whether hippocampal EEG signals recorded in rats during locomotion provide high-dimensional information, and (3) investigate the physiological importance of high-dimensional information obtained from hippocampal EEG recordings. MethodsWe conducted HHSA to analyze hippocampal EEG signals recorded in rats. HHSA enabled us to determine carrier frequency and amplitude modulation (AM) characteristics. ResultsHHSA revealed that hippocampal EEG signals recorded before and after treadmill running were concentrated in the delta band and were characterized by AM at 0.5–1 Hz (P < 0.05). Throughout the treadmill exercise, the hippocampal EEG signals were concentrated in the theta band and were characterized by AM at 0.5–4 Hz (P < 0.05). ConclusionHippocampal theta signals recorded in the rats during treadmill running exhibited low-frequency AM. The hippocampal theta rhythm can provide insights into functional brain connectivity. SignificanceHHSA could be used to obtain high-dimensional EEG information; moreover, EEG signals recorded in rats during treadmill running exhibited low-frequency AM.

Exploring New Electroencephalogram Parameters in Electroconvulsive Therapy.

This pilot study aims to evaluate a novel metric based on the power spectrum of the EEG recordings from ECT-induced seizures-its association to volume changes in the hippocampus after ECT and improvement in depression rating scores. Depressed patients treated with ECT underwent brain magnetic resonance imaging before and after treatment and the EEG from each seizure was recorded (N = 29). Hippocampal volume changes and EEG parameters were recorded in addition to clinician-rated and self-reported measures of depressive symptoms. The slope of the power law in the power spectral density of the EEG was calculated. Multivariate linear models relating seizure parameters to volume change or clinical outcome were systematically and successively simplified. The best models were selected according to Akaike information criterion. The slope of the power law was steeper in the right than the left hemisphere (P < 0.001). Electroencephalogram measures were included in the best models of volume change for both hippocampi as well as in the models explaining clinical outcome ( P = 0.014, P = 0.004). In this pilot study, novel EEG measures were explored and contributed in models explaining the variation in volume change in the hippocampus and in clinical outcome after ECT.

Functional Neurophysiological Biomarkers of Early‐Stage Alzheimer’s Disease: An Experimental Perspective of Network Hyperexcitability in Disease Progression and Pharmacological Interventions

AbstractBackgroundNeuronal network hyperexcitability and related alterations in the excitation‐inhibition balance hold promise as early functional biomarkers of network dysfunction and as prodromal indicators of Alzheimer’s disease (AD) pathogenesis. However, the translational validity of hyperexcitability as found in some AD pathology animal models seems restricted by their limited capacity to encompass the complexity of clinical AD.MethodA comparison was made between different AD pathology mouse models with respect to the development of neuronal network hyperexcitability (LFPs) and epileptiform EEG. To this end, amyloid APP‐KI and APP/PS1 mice were assessed with and without hippocampal seeding of (human‐derived) pathological tau conformers at different ages (3‐6 months) and post‐seeding periods (1‐5 months) concerning alterations in amyloid and tau pathology in relation to hyperexcitability‐related, vigilance‐controlled neurophysiological changes.ResultsAnimals from both AD models progressively developed AT8‐tau pathology that is amplified by the presence of amyloid pathology, but that only in APP/PS1 is further intensified by the starting amount of amyloid pathology. Alterations in EEG gamma oscillations appears to be associated with the development of amyloid and tau pathology, and may be an indicator of neuropathology, of neuronal network dysfunction, and of a potential disposition to future deposition of pathogenic amyloids. Immediate localized alterations in hippocampal EEG power spectra associated with tau seeding were found, while a lack of longitudinal changes in neuronal hypersynchrony was noted: hyperexcitability as indicated by increased broadband power spectra was noted in APP/PS1 but not APP‐KI animals at baseline. These differential findings between AD models exemplify the difficulty and complexity associated with identifying physiologically relevant and translatable early biomarkers of AD dysfunction.ConclusionFunctional neurophysiological biomarkers based on early alterations in neuronal circuits, including hyperexcitability, in combination with dysfunctional (GABA‐ergic) inhibitory control of cortical pyramidal neurons should be assessed and validated in the complex context of neurodegeneration, specific amyloid/tau pathology, as well as neuroinflammation and disturbed sleep‐related processes like glymphatic clearance. This complexity constitutes both an additional challenge and a novel opportunity to AD pathology rodent models, in which such an integrative approach is feasible, but whose translational validity is still to be determined in the development of neuroprotective and neurorestorative therapeutic strategies.

Hippocampal recording via the RNS system reveals marked ipsilateral activation of epileptiform activity during Wada testing

Wada testing remains an important component of pre-surgical testing to assess the feasibility of temporal lobectomy for patients with intractable epilepsy. In this procedure, an anesthetic is injected into either internal carotid artery while memory and language testing is performed, simulating the effect of temporal lobe resection. The mechanism remains poorly understood because the hippocampal vasculature is predominantly via the posterior circulation. We recorded hippocampal EEG during bilateral methohexital Wada testing in three patients who had previously been implanted with a responsive neurostimulation system (RNS) to determine the effect of the injections on hippocampal activity. In all six injections from three patients, methohexital caused immediate, transient increases in hippocampal spikes. With at least two of these injections, the electrographic changes were consistent with electrographic seizures. In all cases, the epileptiform activity was not apparent on scalp EEG and was without obvious clinical correlate other than the negative findings expected from the anesthetic. The results demonstrate the utility of intracranial EEG during Wada testing and suggest that the elicitation of seizures or continuous spiking might contribute to dysfunction of the hippocampus during the Wada test. We hypothesize that this effect is due to disconnection and disinhibition of medial temporal structures.

Intravenous kainic acid induces status epilepticus and late onset seizures in mice

We set out to establish a novel model of temporal lobe epilepsy (TLE) in a mouse. We sought to induce TLE through the injection of kainic acid (KA) into the tail vein with subsequent development of status epilepticus (SE). Using C57BL/6 mice, we implanted hippocampal EEG recording electrodes before or after injection of KA or phosphate buffered saline (PBS). Video and EEG analysis were conducted to evaluate for SE and development of recurrent seizures, the hallmark of TLE. All mice injected with KA developed SE while those who were injected with PBS did not. Of the animals injected with KA monitored for recurrent seizures following SE, 33% developed spontaneous recurrent seizures while those injected with PBS did not. Injection of KA through the tail vein of a mouse reliably and rapidly induces SE which remits spontaneously and leads to the development of TLE in a subset of mice.

Potentiating Hemorrhage in a Periadolescent Rat Model of Closed-Head Traumatic Brain Injury Worsens Hyperexcitability but Not Behavioral Deficits.

Post-traumatic epilepsy (PTE) and neurocognitive deficits are devastating sequelae of head injuries that are common in adolescents. Investigating desperately needed treatments is hindered by the difficulties in inducing PTE in rodents and the lack of established immature rat models of pediatric PTE. Hemorrhage is a significant risk factor for PTE, but compared to humans, rats are less prone to bleeding because of their rapid blood coagulation system. In this study, we promoted bleeding in the controlled cortical impact (CCI) closed-head injury model with a 20 min pre-impact 600 IU/kg intraperitoneal heparin injection in postnatal day 35 (P35) periadolescent rats, given the preponderance of such injuries in this age group. Temporo-parietal CCI was performed post-heparin (HTBI group) or post-saline (TBI group). Controls were subjected to sham procedures following heparin or saline administration. Continuous long-term EEG monitoring was performed for 3 months post-CCI. Sensorimotor testing, the Morris water maze, and a modified active avoidance test were conducted between P80 and P100. Glial fibrillary acidic protein (GFAP) levels and neuronal damage were also assessed. Compared to TBI rats, HTBI rats had persistently higher EEG spiking and increased hippocampal GFAP levels (p < 0.05). No sensorimotor deficits were detected in any group. Compared to controls, both HTBI and TBI groups had a long-term hippocampal neuronal loss (p < 0.05), as well as contextual and visuospatial learning deficits (p < 0.05). The hippocampal astrogliosis and EEG spiking detected in all rats subjected to our hemorrhage-promoting procedure suggest the emergence of hyperexcitable networks and pave the way to a periadolescent PTE rat model.

A hydrogen sulfide donor suppresses pentylenetetrazol-induced seizures in rats via PKC signaling

Epilepsy is a serious neurological disorder. Available antiepileptic drugs are still lacking. Hydrogen sulfide (H2S), a neuron-protective endogenous gasotransmitter, is reported to have effect on epilepsy. But it remains to be determined for its mechanism. In the present study, we found that a novel carbazole-based H2S donor could effectively suppress pentylenetetrazol-induced seizures in rats. The H2S donor could alleviate not only the epileptic behavior of animals but also the hippocampal EEG activity of seizures. The H2S donor down-regulated the expression of aquaporin 4 in the hippocampus of epilepsy rats. The H2S donor also decreased the seizure-induced release of inflammatory cytokines including IL-1β, IL-6 and TNF-α. In addition, the H2S donor increased protein kinase C (PKC) expression in the hippocampus of epilepsy rats. These effects of the H2S donor on epilepsy rats were attenuated after blockade of PKC signaling by Go6983, suggesting that PKC signaling participated in the antiepileptic process of H2S donor. Taken together, the H2S donor has a beneficial effect on epilepsy control in a PKC-dependent manner.

Calea zacatechichi Schltdl. (Compositae) produces anxiolytic- and antidepressant-like effects, and increases the hippocampal activity during REM sleep in rodents

Ethnopharmacological relevanceCalea zacatechichi is a plant with an extensive popular and ritual use in Mexico. In healthy volunteers, it induces well-being and tranquility senses, and facilitates superficial stages of sleep. However, anxiolytic, and antidepressant-like effects and changes on the sleep-waking stages have not been explored. AimTo determine anxiolytic and antidepressant-like effects of an aqueous extract of C. zacatechichi (CZ) in rodents and to analyze their effects on hippocampal activity in the rat sleep-waking cycle. Material and methodsCZ anxiolytic- and antidepressant-like effects were evaluated in several mice and rat behavioral paradigms. CZ effects on temporal distribution of sleep were described, and hippocampus EEG frequency patterns were analyzed during the sleep-waking cycle; absolute and relative powers were analyzed during Rapid Eye Movements (REM) and non-REM sleep stages. CZ chemical analysis was performed by UPLC-ESI-MS. ResultsCZ produced specific and robust anxiolytic- and antidepressant-like effects in mice and rats, similar to those of prototypical drugs, at doses ranging from 0.5 to 50 mg/kg. CZ at 100 mg/kg produced visible mild sedative effects in rats, associated with a significant increase in Slow Wave Sleep episodes during a 6 h recording, and enhanced fast frequencies of hippocampus (gamma-band:31–50 Hz) during REM sleep. ConclusionResults could support the well-being and tranquility senses reported by healthy consumers, and to explain the oneiric content during dreams and some improvements in cognitive processes described by consumers. Anxiolytic- and antidepressant-like effects of this species, reported for first time in this study could improve some aspects of mental health.

Molecular, physiological and behavioral characterization of the heterozygous Df[h15q13]/+ mouse model associated with the human 15q13.3 microdeletion syndrome

The human 15q13.3 microdeletion syndrome (DS) is caused by a heterozygous microdeletion (MD) affecting six genes: FAN1; MTMR10; TRPM1; KLF13; OTUD7A; and CHRNA7. Carriers are at risk for intellectual disability, epilepsy, autism spectrum disorder, and schizophrenia. Here we used the Df[h15q13]/+ mouse model with an orthologous deletion to further characterize molecular, neurophysiological, and behavioral parameters that are relevant to the 15q13.3 DS. First, we verified the expression and distribution of the α7 nicotinic acetylcholine receptor (nAChR), a gene product of the CHRNA7, in cortical and subcortical areas. Results revealed similar mRNA distribution pattern in wildtype (WT) and heterozygous (Het) mice, with about half the number of α7 nAChR binding sites in mutants. Hippocampal recordings showed similar input/output responses of field excitatory post-synaptic potentials and theta-burst induced long-term potentiation in WT and Het mice. Het males exhibited impaired spatial learning acquisition in the Barnes Maze. Indicative of increased seizure susceptibility, Het mice developed secondary seizures after 6-Hz corneal stimulation, and had significantly increased sensitivity to the chemoconvulsant pentylenetetrazol resulting in increased spiking in hippocampal EEG recordings. Basal mRNA expression of brain derived neurotrophic factor and activity regulated immediate early genes (c-fos, Arc, Erg-1 and Npas4) during adolescence, a critical period of brain maturation, was unaffected by genotype. Thus, the MD did not show gross neuroanatomical, molecular, and neurophysiological abnormalities despite deficits in spatial learning and increased susceptibility to seizures. Altogether, our results verify the phenotypic profile of the heterozygous Df[h15q13]/+ mouse model and underscore its translational relevance for human 15q13.3 DS.

Identification of vagus nerve stimulation parameters affecting rat hippocampal electrophysiology without temperature effects

BackgroundRecent experiments in rats have demonstrated significant effects of VNS on hippocampal excitability but were partially attributed to hypothermia, induced by the applied VNS parameters. ObjectiveTo allow meaningful preclinical research on the mechanisms of VNS and translation of rodent results to clinical VNS trials, we aimed to identify non-hypothermia inducing VNS parameters that significantly affect hippocampal excitability. MethodsVNS was administered in cycles of 30 s including either 0.1, 0.16, 0.25, 0.5, 1.5, 3 or 7 s of VNS ON time (biphasic pulses, 250μs/phase, 1 mA, 30 Hz) and the effect of different VNS ON times on brain temperature was evaluated. VNS paradigms with and without hypothermia were compared for their effects on hippocampal neurophysiology in freely moving rats. ResultsUsing VNS parameters with an ON time/OFF time of up to 0.5 s/30 s did not cause hypothermia, while clear hypothermia was detected with ON times of 1.5, 3 and 7 s/30 s. Relative to SHAM VNS, the normothermic 0.5 s VNS condition significantly decreased hippocampal EEG power and changed dentate gyrus evoked potentials with an increased field excitatory postsynaptic potential slope and a decreased population spike amplitude. ConclusionVNS can be administered in freely moving rats without causing hypothermia, while profoundly affecting hippocampal neurophysiology suggestive of reduced excitability of hippocampal neurons despite increased synaptic transmission efficiency.

Chronic DREADD Isn't As Bad As It Sounds.

Long-Term Chemogenetic Suppression of Spontaneous Seizures in a Mouse Model for Temporal Lobe Epilepsy Desloovere J, Boon P, Larsen LE, et al. Epilepsia. 2019;60(11):2314-2324. doi:10.1111/epi.16368.Objective:More than one-third of patients with temporal lobe epilepsy (TLE) continue to have seizures despite treatment with antiepileptic drugs, and many experience severe drug-related side effects, illustrating the need for novel therapies. Selective expression of inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) allows cell-type-specific reduction of neuronal excitability. In this study, we evaluated the effect of chemogenetic suppression of excitatory pyramidal and granule cell neurons of the sclerotic hippocampus in the intrahippocampal mouse model (IHKA) for TLE.Methods:Intrahippocampal IHKA mice were injected with an adeno-associated viral vector carrying the genes for an inhibitory DREADD hM4Di in the sclerotic hippocampus or control vector. Next, animals were treated systemically with different single doses of clozapine-N-oxide (CNO; 1, 3, and 10 mg/kg) and clozapine (0.03 and 0.1 mg/kg), and the effect on spontaneous hippocampal seizures, hippocampal electroencephalography (EEG) power, fast ripples (FRs), and behavior in the open field test was evaluated. Finally, animals received prolonged treatment with clozapine for 3 days, and the effect on seizures was monitored.Results:Treatment with both CNO and clozapine resulted in a robust suppression of hippocampal seizures for at least 15 hours only in DREADD-expressing animals. Moreover, total EEG power and the number of FRs were significantly reduced. Clozapine-N-oxide and/or clozapine had no effects on interictal hippocampal EEG, seizures, or locomotion/anxiety in the open field test in non-DREADD epileptic IHKA mice. Repeated clozapine treatment every 8 hours for 3 days resulted in almost complete seizure suppression in DREADD animals.Significance:This study shows the potency of chemogenetics to robustly and sustainably suppress spontaneous epileptic seizures and pave the way for an epilepsy therapy in which a systemically administered exogenous drug selectively modulates specific cell types in a seizure network, leading to a potent seizure suppression devoid of the typical drug-related side effects.

Dynamic functional connectivity and graph theory metrics in a rat model of temporal lobe epilepsy reveal a preference for brain states with a lower functional connectivity, segregation and integration

Epilepsy is a neurological disorder characterized by recurrent epileptic seizures. The involvement of abnormal functional brain networks in the development of epilepsy and its comorbidities has been demonstrated by electrophysiological and neuroimaging studies in patients with epilepsy. This longitudinal study investigated changes in dynamic functional connectivity (dFC) and network topology during the development of epilepsy using the intraperitoneal kainic acid (IPKA) rat model of temporal lobe epilepsy (TLE). Resting state functional magnetic resonance images (rsfMRI) of 20 IPKA animals and 7 healthy control animals were acquired before and 1, 3, 6, 10 and 16 weeks after status epilepticus (SE) under medetomidine anaesthesia using a 7 T MRI system. Starting from 17 weeks post-SE, hippocampal EEG was recorded to determine the mean daily seizure frequency of each animal. Dynamic FC was assessed by calculating the correlation matrices between fMRI time series of predefined regions of interest within a sliding window of 50 s using a step length of 2 s. The matrices were classified into 6 FC states, each characterized by a correlation matrix, using k-means clustering. In addition, several time-variable graph theoretical network metrics were calculated from the time-varying correlation matrices and classified into 6 states of functional network topology, each characterized by a combination of network metrics. Our results showed that FC states with a lower mean functional connectivity, lower segregation and integration occurred more often in IPKA animals compared to control animals. Functional connectivity also became less variable during epileptogenesis. In addition, average daily seizure frequency was positively correlated with percentage dwell time (i.e. how often a state occurs) in states with high mean functional connectivity, high segregation and integration, and with the number of transitions between states, while negatively correlated with percentage dwell time in states with a low mean functional connectivity, low segregation and low integration. This indicates that animals that dwell in states of higher functional connectivity, higher segregation and higher integration, and that switch more often between states, have more seizures.

Long-term chemogenetic suppression of spontaneous seizures in a mouse model for temporal lobe epilepsy.

More than one-third of patients with temporal lobe epilepsy (TLE) continue to have seizures despite treatment with antiepileptic drugs, and many experience severe drug-related side effects, illustrating the need for novel therapies. Selective expression of inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) allows cell-type-specific reduction of neuronal excitability. In this study, we evaluated the effect of chemogenetic suppression of excitatory pyramidal and granule cell neurons of the sclerotic hippocampus in the intrahippocampal mouse model (IHKA) for temporal lobe epilepsy. IntrahippocampalIHKA mice were injected with an adeno-associated viral vector carrying the genes for an inhibitory DREADD hM4Di in the sclerotic hippocampus or control vector. Next, animals were treated systemically with different single doses of clozapine-N-oxide (CNO) (1, 3, and 10mg/kg) and clozapine (0.03 and 0.1mg/kg) and the effect on spontaneous hippocampal seizures, hippocampal electroencephalography (EEG) power, fast ripples (FRs) and behavior in the open field test was evaluated. Finally, animals received prolonged treatment with clozapine for 3 days and the effect on seizures was monitored. Treatment with both CNO and clozapine resulted in a robust suppression of hippocampal seizures for at least 15hours only in DREADD-expressing animals. Moreover, total EEG power and the number of FRs were significantly reduced. CNO and/or clozapine had no effects on interictal hippocampal EEG, seizures, or locomotion/anxiety in the open field test in non-DREADD epileptic IHKA mice. Repeated clozapine treatment every 8 hours for 3 days resulted in almost complete seizure suppression in DREADD animals. This study shows the potency of chemogenetics to robustly and sustainably suppress spontaneous epileptic seizures and pave the way for an epilepsy therapy in which a systemically administered exogenous drug selectively modulates specific cell types in a seizure network, leading to a potent seizure suppression devoid of the typical drug-related side effects.

Five Decades of Hippocampal Place Cells and EEG Rhythms in Behaving Rats.

Over the last 50 years, much has been learned about the physiology and functions of the hippocampus from studies in freely behaving rats. Two relatively early works in the field provided major insights that remain relevant today. Here, I revisit these studies and discuss how our understanding of the hippocampus has evolved over the last several decades.

Neonatal Monosodium Glutamate Administration Disrupts Place Learning and Alters Hippocampal–Prefrontal Learning-Related Theta Activity in the Adult Rat

Neonatal treatment with monosodium glutamate causes profound deficits in place learning and memory in adult rats evaluated in the Morris maze. Theta activity has been related to hippocampal learning, and increased high-frequency theta activity occurs through efficient place learning training in the Morris maze. We wondered whether the place learning deficits observed in adult rats that had been neonatally treated with monosodium glutamate (MSG), were related to altered theta patterns in the hippocampus and prelimbic cortex, which were recorded during place learning training in the Morris maze. The MSG-treated group had a profound deficit in place learning ability, with a marginal reduction in escape latencies during the final days of training. Learning-related changes were observed in the relative power distribution in control and MSG-treated groups in the hippocampal EEG, but not in the prelimbic cortex. Increased prefrontal and reduced hippocampal absolute power that appeared principally during the final days of training, and reduced coherence between regions throughout the training (4–12 Hz), were observed in the MSG-treated rats, thereby suggesting a misfunction of the circuits rather than a hyperexcitable general state. In conclusion, neonatal administration of MSG, which caused a profound deficit in place learning at the adult age, also altered the theta pattern both in the hippocampus and prelimbic cortex.

Chaotic Analysis of Hippocampal and Cortical Sleep EEG during Various Vigilance States.

In this paper, we investigate the hippocampal and cortical sleep EEG of adult rats at different sleep stages by employing Lyapunov exponent and third-order cumulant measures to quantify and compare the chaotic and nonlinear behavior of EEG obtained during vigilance states of quiet- waking, slow-wave sleep, and rapid eye movement (REM) sleep. Lyapunov exponent was computed to characterize the EEG for chaos and third-order cumulant was used to measure the deviations from Gaussianity of the signal. Our results show positive Lyapunov exponents for all EEG states indicating a Iow- dimensional chaos for both REM and non-REM system. Furthermore, REM sleep EEG exhibits the largest Lyapunov exponent in both hippocampal and cortical EEG amongst other vigilance states. We also identified non-zero third-order cumulant for all the vigilance states which suggests their non- Gaussian behavior.

Small sharp spikes as EEG markers of mesiotemporal lobe epilepsy

ObjectiveMesial temporal lobe epilepsy (mTLE) is the most common type of focal epilepsy, but often lacks scalp EEG correlates. We ask if hippocampal epileptiform discharges that are characteristic of mTLE are associated with small sharp spikes (SSS) recorded on scalp EEG. SSS are considered benign waveforms, so are not currently used as markers of epilepsy. MethodsTo determine if there is a relationship between SSS and hippocampal discharges, simultaneous scalp and hippocampal depth electrode EEGs were recorded from 27 patients being evaluated for possible mTLE. Scalp EEG waveforms were assessed at the time of hippocampal discharges identified on intracranial hippocampal depth electrodes. Results15 of 27 patients had SSS on scalp EEG that were time locked to hippocampal epileptiform discharges measured intracranially. These hippocampal spikes tended to have overlying high frequency oscillations and to co-localize with a seizure onset zone, suggesting that they were pathological discharges. ConclusionsThere is a tight coupling between a subset of pathological hippocampal discharges and SSS. SignificanceSSS can be scalp EEG markers of mTLE rather than normal EEG variants.