Understanding Epileptiform After-Discharges as Rhythmic Oscillatory Transients

Electro-cortical activity in patients with epilepsy may show abnormal rhythmic transients in response to stimulation. Even when using the same stimulation parameters in the same patient, wide variability in the duration of transient response has been reported. These transients have long been considered important for the mapping of the excitability levels in the epileptic brain but their dynamic mechanism is still not well understood. To understand the occurrence of abnormal transients dynamically, we use a thalamo-cortical neural population model of epileptic spike-wave activity and study the interaction between slow and fast subsystems. In a reduced version of the thalamo-cortical model, slow wave oscillations arise from a fold of cycles (FoC) bifurcation. This marks the onset of a region of bistability between a high amplitude oscillatory rhythm and the background state. In vicinity of the bistability in parameter space, the model has excitable dynamics, showing prolonged rhythmic transients in response to suprathreshold pulse stimulation. We analyse the state space geometry of the bistable and excitable states, and find that the rhythmic transient arises when the impending FoC bifurcation deforms the state space and creates an area of locally reduced attraction to the fixed point. This area essentially allows trajectories to dwell there before escaping to the stable steady state, thus creating rhythmic transients. In the full thalamo-cortical model, we find a similar FoC bifurcation structure. Based on the analysis, we propose an explanation of why stimulation induced epileptiform activity may vary between trials, and predict how the variability could be related to ongoing oscillatory background activity.Comment: http://journal.frontiersin.org/article/10.3389/fncom.2017.00025/ful

Clozapine-induced paroxysmal discharges

PhD ThesisThe atypical antipsychotic clozapine is a widely prescribed and effective treatment for the positive and negative symptoms of schizophrenia, but reports of side effects are common. In one study EEG abnormalities were observed in 53% of patients treated with clozapine, and the absence or presence of EEG abnormalities correlated with the plasma clozapine concentration. Here, epileptiform activity was present in conventional EEG recordings from a 32 year old male patient with psychiatric illness taking clozapine for 3 weeks. Brief (ca.100ms), transient epileptiform spikes occurred at a frequency of approximately 2 per h and originated primarily in parietal cortex. One month after withdrawal of clozapine, epileptiform spikes were no longer present. An in vitro model was developed using the equivalent region of association cortex, namely 2⁰ somatosensory cortex, in normal rat brain slices to probe such activity with increased spatial and temporal resolution, and to investigate mechanisms underlying its generation. Wide band in vitro recordings revealed that clozapine (10-20µM) induced regular, frequent very fast oscillations (VFO, > 70Hz) in this region. These VFO comprised short transient high frequency discharges and were maximal in patches along layer V. The atypical antipsychotic olanzapine, but not the classical antipsychotic haloperidol, also induced prominent VFO in this region. Sharp electrode intracellular recordings revealed that there was almost no correlation between the somatic activity of layer V regular spiking (RS) pyramidal cells and field VFO, but layer V intrinsically bursting (IB) cells did correlate to some extent with the local field. Interestingly, IB cell spikelets were also weakly correlated with field VFO suggesting a role for axonal hyperexcitability in this cell type in the mechanism. Clozapine-induced VFO persisted following blockade of AMPA, NMDA, and GABAA chemical synaptic receptors, and the gap junction blockers carbenoxolone and quinine also failed to significantly attenuate the power of this activity. Although octanol abolished clozapine-induced VFO, it was not clear that this effect resulted from blockade of gap junctions as this drug also blocks spikes. In addition to VFO events, clozapine (10-20µM) also induced occasional, spontaneous transient paroxysmal discharges, similar to the EEG phenomena, in 33% (11/33 slices) of slices in vitro. Sharp electrode intracellular recordings revealed that clozapine- induced full paroxysmal discharges were associated with spikes, EPSPs and IPSPs in layer V RS and IB cells, suggesting that these events were mediated via chemical synaptic transmission in both of these cell types. Multi-electrode array recordings of local field potentials and units suggested that clozapine-induced paroxysmal events started superficially in association cortex, moved deeper and then propagated horizontally along these deep layers. The onset of clozapine-induced VFO was accompanied by a significant elevation in parvalbumin immunoreactivity, particularly in layer II-IV, where there was a greater than twofold increase in the signal, and this may be relevant to the therapeutic action of the drug

Somatic Depdc5 deletion recapitulates electroclinical features of human focal cortical dysplasia type IIA

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/145530/1/ana25272_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/145530/2/ana25272.pd

Spatio-temporal modelling and analysis of epileptiform EEG

In this thesis we investigate the mechanisms underlying the generation of abnormal EEG rhythms in epilepsy, which is a crucial step towards better treatment of this disorder in the future. To this end, macroscopic scale mathematical models of the interactions between neuronal populations are examined. In particular, the role of interactions between neural masses that are spatially distributed in cortical networks are explored. In addition, two other important aspects of the modelling process are addressed, namely the conversion of macroscopic model variables into EEG output and the comparison of multivariate, spatio-temporal data. For the latter, we adopt a vectorisation of the correlation matrix of windowed data and subsequent comparison of data by vector distance measures. Our modelling studies indicate that excitatory connectivity between neural masses facilitates self-organised dynamics. In particular, we report for the first time the production of complex rhythmic transients and the generation of intermittent periods of 'abnormal' rhythmic activity in two different models of epileptogenic tissue. These models therefore provide novel accounts of the spontaneous, intermittent transition between normal and pathological rhythms in primarily generalised epilepsies and the evocation of complex, self-terminating, spatio-temporal dynamics by brief stimulation in focal epilepsies. Two key properties of these models are excitability at the macroscopic level and the presence of spatial heterogeneities. The identification of neural mass excitability as an important processes in spatially extended brain networks is a step towards uncovering the multi-scale nature of the pathological mechanisms of epilepsy. A direct consequence of this work is therefore that novel experimental investigations are proposed, which in itself is a validation of our modelling approach. In addition, new considerations regarding the nature of dynamical systems as applied to problems of transitions between rhythmic states are proposed and will prompt future investigations of complex transients in spatio-temporal excitable systems.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Ion homeostasis in rhythmogenesis : the interplay between neurons and astroglia

Proper function of all excitable cells depends on ion homeostasis. Nowhere is this more critical than in the brain where the extracellular concentration of some ions determines neurons' firing pattern and ability to encode information. Several neuronal functions depend on the ability of neurons to change their firing pattern to a rhythmic bursting pattern, whereas, in some circuits, rhythmic firing is, on the contrary, associated to pathologies like epilepsy or Parkinson's disease. In this review, we focus on the four main ions known to fluctuate during rhythmic firing: calcium, potassium, sodium, and chloride. We discuss the synergistic interactions between these elements to promote an oscillatory activity. We also review evidence supporting an important role for astrocytes in the homeostasis of each of these ions and describe mechanisms by which astrocytes may regulate neuronal firing by altering their extracellular concentrations. A particular emphasis is put on the mechanisms underlying rhythmogenesis in the circuit forming the central pattern generator (CPG) for mastication and other CPG systems. Finally, we discuss how an impairment in the ability of glial cells to maintain such homeostasis may result in pathologies like epilepsy and Parkinson's disease

Cellular Mechanisms of Temporal Lobe Epilepsy: In Vitro studies in Animal Models

To summarize our key findings, (i). Prolonged incubation in high [K+]o condition leads to the development of gamma bursts in CA1 which characteristically consists of spike discharges at 30-40Hz. (ii). Anatomical and pharmacological isolation of CA1 increased the frequency at which gamma bursts occurred, thus showing the independent and highly rhythmic nature of these bursts. (iii). Gamma bursts are primarily GABA-ergic in nature and are strongly attenuated by GABAA receptor blocker BMI. (iv). Similar to BMI, application of oxytocin and bumetanide strongly attenuate the gamma bursts. These results suggest that a compromised Cl- homeostasis could possibly underlie gamma bursts generation. FUTURE SCOPE OF THE STUDY: The primary finding of this dissertation is the generation of gamma bursts in CA1. We have described the properties of these bursts and the putative mechanisms that underlie CA1 gamma bursts. However, this study has its limitations. In our study, we have not included the EC in our slice preparation and therefore the effect of EC inputs on CA1 gamma bursts has not been studied. The direct projection from EC to CA1 via the TA pathway and the projections from CA1 back to EC are believed to form a short reverberating loop which aggravate seizures generated by EC (28). Moreover, Ang et al have shown a 10 fold increase in the strength of TA projections in temporal lobe epilepsy (10). Epileptiform activity in this loop is controlled by interictal discharges from CA3 (95). Loss of CA3 inputs on CA1 might therefore expose CA1 directly to EC generated seizures and can also lead to the development of seizures in CA1(37). Thus future studies should be aimed at studying the effect of direct projections of EC on CA1 gamma bursts. Additionally, we have studied the gamma bursts using extracellular field recordings. Precise identification and characterization of individual CA1 neurons that participate in gamma burst generation might help us understand this phenomenon better. This would also allow us to study the effect of oxytocin on gamma bursts precisely and may also shed light on the putative mechanisms through which these effects are exerted

Epileptiform bursting in the disinhibited neonatal cerebral cortex

The cerebral cortex, which include the neocortex and hippocampus, is an elaborate neuronal network communicating mainly through glutamate and gamma-aminobutyric acid (GABA). Glutamate, operating via AMPA, kainate, and NMDA receptors excites neurons, and operating via metabotropic glutamate receptors can either increase or decrease the excitation in the neuronal network. GABA, operating through GABAA and GABAB receptors, inhibits the mature neuronal network, and GABAA receptor blockade in the adult cerebral cortex leads to epileptiform bursts. In contrast, in the neonatal cerebral cortex, GABAA has been proposed to function as an excitatory neurotransmitter, and glutamatergic synapses are claimed to be underdeveloped. It is important to understand the mechanisms underlying epileptiform activity in the neonate, because epileptiform activity in the neonate can potentially damage the developing cerebral cortex. In this dissertation I explore the role of GABA in controlling epileptiform activity in the neonatal cerebral cortex. Bath application of GABAA receptor antagonists induced spontaneous generation of large-amplitude population discharges resembling interictal bursts, a form of epileptiform activity; activation of GABAA receptors reduced the amplitude of interictal bursts. Interictal bursts were mediated by glutamatergic neurotransmission, demonstrating that glutamate synapses are functional in the neonate. We conclude that GABA is inhibitory in the neonatal cerebral cortex because it serves to suppress excitatory synchronous activity. Interictal bursts in the neonatal hippocampus were generated in a temporally precise rhythm. The rhythmicity of interictal bursts was not modulated by GABAB receptors, calcium activated potassium conductances, or internally released calcium, butmanipulations that facilitate or suppress the hyperpolarization-activated cation current, Ih, increased or decreased, respectively, the frequency of the bursts. We conclude Ih plays a major role in pacing neonatal interictal bursts. Immunocytochemistry illustrated that Ih channel subunits in neonatal pyramidal neurons were distributed predominately in somata, while in the juvenile and mature hippocampus and neocortex the subunits were mostly found in GABAergic terminals and in the membrane of apical dendrites of pyramidal neurons, with diminished or no expression inside the somata. We conclude that the unique expression of Ih channel subunits in the neonatal hippocampus could contribute to the increased temporal precision of interictal bursts at this developmental stage

Improvements in Neonatal Brain Monitoring after Perinatal Asphyxia

Perinatal hypoxic ischemic encephalopathy (HIE) is a major cause of morbidity and mortality world-wide. Common sequelae in survivors include cerebral palsy (CP), epilepsy and sensory as well as cognitive problems. The consequences of HIE impose significant long-term personal and financial burden on the affected families and the society. The most cost-effective approach to reducing neonatal mortality world-wide would be to improve access to antenatal care4. However, even in developed countries, the exact factors triggering perinatal asphyxia as well as the time of onset of brain injury are often difficult to determine, and it remains a major clinical problem. Seizures commonly occur in the neonate with HIE and are often the only sign of serious underlying brain dysfunction6. Animal studies have shown that neonatal seizures in the context of HIE may cause additional brain injury and that their pharmacological suppression may improve outcome9. Monitoring of brain function using the electroencephalogram (EEG), continuously or by serial EEGs is well-suited to give insight into brain function and its dynamic changes in neonatal HIE and helps to guide treatment as well as prognostication. A good understanding of the pathophysiology of HIE is needed not only in the selection of suitable diagnostic tests and treatment methods, but also to develop new therapeutic strategies