Douglas A. Richards

Predictability analysis of absence seizures with permutation entropy

In this study, we investigate permutation entropy as a tool to predict the absence seizures of genetic absence epilepsy rats from Strasbourg (GAERS) by using EEG recordings. The results show that permutation entropy can track the dynamical changes of EEG data, so as to describe transient dynamics prior to the absence seizures. Experiments demonstrate that permutation entropy can successfully detect pre-seizure state in 169 out of 314 seizures from 28 rats and the average anticipation time of permutation entropy is around 4.9s. These findings could shed new light on the mechanism of absence seizure. In comparison with results of sample entropy, permutation entropy is better able to predict absence seizures.

Cortical-area specific block of genetically determined absence seizures by ethosuximide.

Absence epilepsy is characterised by a paroxysmal loss of consciousness, of abrupt onset and termination, and is associated with a bilateral synchronous spike and wave discharge (SWD) on the electroencephalogram. Absence seizures involve an interplay between thalamic and cortical structures, although most research has so far focussed on sensory thalamic nuclei and the reticular thalamic nucleus (RTN). Thus, microinfusion of ethosuximide (ETX), a first choice anti-absence drug, into either the ventrobasal thalamus or RTN of the genetic absence epilepsy rat from Strasbourg (GAERS), a validated rat model of absence epilepsy, does not produce immediate cessation of seizure activity, as is seen following systemic administration. As recent evidence indicates a seizure initiation site within the peri-oral region of the primary somatosensory cortex (S1po), we have now applied ETX into S1po as well as the somatosensory cortex forelimb region (S1FL) and the motor cortex (M1) of freely moving GAERS. Microinfusion of 10 or 20 nmol/side of ETX into S1po produced an immediate cessation of seizure activity. A less marked response was produced when even a higher dose (200 nmol/side) was infused into S1FL. No reduction of SWD was seen when ETX was infused into M1. Microinfusion of CGP 36742 (5 nmol/side), a GABA(B) antagonist, produced immediate cessation of seizure activity in both S1po and M1 and a delayed effect in S1FL. These data suggest that the ability of ETX to abolish genetically determined absence seizures is cortical-area specific and support the involvement of S1po in the initiation of SWDs.

Ordinal pattern based similarity analysis for EEG recordings.

OBJECTIVE Ordinal patterns analysis such as permutation entropy of the EEG series has been found to usefully track brain dynamics and has been applied to detect changes in the dynamics of EEG data. In order to further investigate hidden nonlinear dynamical characteristics in EEG data for differentiating brain states, this paper proposes a novel dissimilarity measure based on the ordinal pattern distributions of EEG series. METHODS Given a segment of EEG series, we first map this series into a phase space, then calculate the ordinal sequences and the distribution of these ordinal patterns. Finally, the dissimilarity between two EEG series can be qualified via a simple distance measure. A neural mass model was proposed to simulate EEG data and test the performance of the dissimilarity measure based on the ordinal patterns distribution. Furthermore, this measure was then applied to analyze EEG data from 24 Genetic Absence Epilepsy Rats from Strasbourg (GAERS), with the aim of distinguishing between interictal, preictal and ictal states. RESULTS The dissimilarity measure of a pair of EEG signals within the same group and across different groups was calculated, respectively. As expected, the dissimilarity measures during different brain states were higher than internal dissimilarity measures. When applied to the preictal detection of absence seizures, the proposed dissimilarity measure successfully detected the preictal state prior to their onset in 109 out of 168 seizures (64.9%). CONCLUSIONS Our results showed that dissimilarity measures between EEG segments during the same brain state were significant smaller that those during different states. This suggested that the dissimilarity measure, based on the ordinal patterns in the time series, could be used to detect changes in the dynamics of EEG data. Moreover, our results suggested that ordinal patterns in the EEG might be a potential characteristic of brain dynamics. SIGNIFICANCE This dissimilarity measure is a promising method to reveal dynamic changes in EEG, for example as occur in the transition of epileptic seizures. This method is simple and fast, so might be applied in designing an automated closed-loop seizure prevention system for absence epilepsy.

Using recurrence plot for determinism analysis of EEG recordings in genetic absence epilepsy rats

OBJECTIVE Understanding the transition of brain activity towards an absence seizure is a challenging task. In this paper, we use recurrence quantification analysis to indicate the deterministic dynamics of EEG series at the seizure-free, pre-seizure and seizure states in genetic absence epilepsy rats. METHODS The determinism measure, DET, based on recurrence plot, was applied to analyse these three EEG datasets, each dataset containing 300 single-channel EEG epochs of 5-s duration. Then, statistical analysis of the DET values in each dataset was carried out to determine whether their distributions over the three groups were significantly different. Furthermore, a surrogate technique was applied to calculate the significance level of determinism measures in EEG recordings. RESULTS The mean (+/-SD) DET of EEG was 0.177+/-0.045 in pre-seizure intervals. The DET values of pre-seizure EEG data are significantly higher than those of seizure-free intervals, 0.123+/-0.023, (P<0.01), but lower than those of seizure intervals, 0.392+/-0.110, (P<0.01). Using surrogate data methods, the significance of determinism in EEG epochs was present in 25 of 300 (8.3%), 181 of 300 (60.3%) and 289 of 300 (96.3%) in seizure-free, pre-seizure and seizure intervals, respectively. CONCLUSIONS Results provide some first indications that EEG epochs during pre-seizure intervals exhibit a higher degree of determinism than seizure-free EEG epochs, but lower than those in seizure EEG epochs in absence epilepsy. SIGNIFICANCE The proposed methods have the potential of detecting the transition between normal brain activity and the absence seizure state, thus opening up the possibility of intervention, whether electrical or pharmacological, to prevent the oncoming seizure.

Targeting thalamic nuclei is not sufficient for the full anti-absence action of ethosuximide in a rat model of absence epilepsy

Absence epilepsy is characterised by recurrent periods of physical and mental inactivity coupled to bilateral, synchronous spike and wave discharges (SWDs) on the electroencephalogram. The mechanism of action of ethosuximide (ETX), a drug specific for absence seizures, is believed to involve a reduction in the low threshold T-type Ca(2+) current in thalamocortical and nucleus reticularis thalami (NRT) neurones, although other electrophysiological data have questioned this. Here, we employed a genetic rat model of absence seizures to investigate the effects of directly administering ETX to the thalamus.SWDs were immediately and substantially reduced (approximately 90%) by systemic administration of ETX (177-709 micromol/kg), or by bilateral microinfusion into the thalamus of the GABA(B) antagonist, CGP 36742 (5-27 nmol per side). However, infusion of ETX (1-200 nmol per side) into the ventrobasal complex or the NRT resulted in a reduction of SWDs that was delayed (30-60 min) and less marked (approximately 50%). Administration of ETX (0.2 mM to 1M) to a greater volume of thalamus by reverse microdialysis also produced significant but delayed reduction of SWDs at concentrations >1mM. Only at 5mM were seizures significantly reduced (approximately 70%) within 30 min of administration. These results suggest that targeting of the thalamus alone may be insufficient for an immediate and full anti-absence action for ETX. Concomitant or exclusive actions in the cortex remain a possibility.

Extracellular glutamine to glutamate ratio may predict outcome in the injured brain: a clinical microdialysis study in children

The amino acid content of hourly microdialysis samples from nine severely head-injured children was examined. Of particular interest was the measurement of the excitatory amino acid glutamate, as high levels of this substance, which are associated with the excitotoxicity cascade, have been linked to high intracranial pressure and poor outcome in a similar study in adults. Interpretation of these data is complicated by many clinical and methodological factors and these are discussed in relation to the findings. Our findings from this pilot study in children confirm the associations between glutamate levels, intracranial pressure and outcome, but fail to corroborate the correlation between excitatory and structural amino acid levels seen in adult patients, that was interpreted as evidence of non-specific leakage of amino acids through damaged cell membranes. In addition, we have shown that the role of glutamine in glutamate homeostasis is an important consideration and that estimation of the extracellular glutamine/glutamate ratio may have some prognostic value in head trauma cases as there is evidence of links to clinical outcome.

Modification of GABAB1 and GABAB2 receptor subunits in the somatosensory cerebral cortex and thalamus of rats with absence seizures (GAERS)

In the present study, we have investigated GABA(B) receptor expression in somatosensory cortex (S1) and the ventrobasal (VB) and reticular (Rt) thalamic nuclei of Genetic Absence Epilepsy Rats from Strasbourg (GAERS), which represent an animal model for the human absence epilepsy. We focused our attention on the thalamocortical network because it has been demonstrated that absence seizures are generated in this specific circuit, which is under the control of several inhibitory, e.g. GABA, and excitatory systems. Autoradiography data obtained with the GABA(B) receptor antagonist [3H]CGP62349 did not show any differences in Kd or Bmax values between control rats and GAERS. In situ hybridisation (ISH) results showed a significant increase in messenger RNA for GABA(B1) in the S1 and a decrease in the VB thalamic nucleus but not in the Rt thalamic nucleus. By contrast the immunocytochemical data revealed an increased expression of both GABA(B1) and GABA(B2) receptor subunits in all the regions examined, somatosensory cerebral cortex, VB thalamus and Rt nucleus in GAERS compared to controls. The main finding was an up-regulation of GABA(B) receptor protein in the corticothalamic circuit in GAERS compared to controls.

Intrahepatic complement activation, sinusoidal endothelial injury, and lactic acidosis are associated with initial poor function of the liver after transplantation.

Background. Changes in glucose metabolism in the liver during transplantation have been recently described using microdialysis. Here, these findings are correlated with histopathologic, immunohistochemical, and ultrastructural changes in liver. Methods. Microdialysis catheters were inserted into 15 human livers, which were perfused with isotonic solution, and samples of perfusate were analyzed before harvest, after storage, and after reperfusion. At each stage Menghini needle biopsy samples were taken and each studied using light and electron microscopy. Results. Six livers showed serum biochemical evidence of initial poor function. These livers had significantly more staining for complement fragment 4d (C4d) of both lobular and periportal hepatocytes. C4d-positive hepatocytes were also found in the liver during cold storage (3 of 15). These periportal hepatocytes also showed evidence of necrosis and were found to have intracellular neutrophils. Hepatocyte rounding in zone III, necrosis, and C4d staining in recipient were also significantly correlated with the degree of lactic acidosis during this phase. Intrahepatic lactic acidosis at all time points was significantly associated with sinusoidal endothelial cell injury after reperfusion. There were no correlations between glucose, pyruvate, and glycerol levels and histopathologic changes in the liver. Discussion. In the patients studied, the degree of C4d staining correlated with initial poor function and was associated with intrahepatic lactic acidosis in the donor during cold storage and after reperfusion. Complement activity in the liver during cold storage may be after in situ activation. Intrahepatic lactic acidosis is associated with sinusoidal endothelial cell and hepatocyte injury. The role of intrahepatic neutrophils is uncertain and could possibly be in response to cell necrosis.

Comparison of energy metabolism in liver grafts from donors after circulatory death and donors after brain death during cold storage and reperfusion

Donation after circulatory death (DCD) liver grafts have supplemented the donor organ pool, but certain adverse outcomes have prevented exploration of the full potential of such organs. The aim of this study was to determine key differences in basic energy metabolism between DCD and donation after brainstem death (DBD) grafts.

Extracellular amino acid levels in the human liver during transplantation: a microdialysis study from donor to recipient

Summary.Using microdialysis, we have monitored extracellular levels of amino acids and related amines in the human liver at three stages of the transplantation procedure: donor retrieval, back table preparation and during 48 h post-implantation. By comparing the ratio of mean levels at the donor and back table stages, with the ratio between early (2–6 h) and late (43–48 h) post-reperfusion, these amines were classified into one of three groups. In one group, back table levels were markedly higher than during the donor stage, with levels declining over time post-reperfusion. A second group had much lower levels in the back table than during the donor phase, and post-reperfusion levels were either stable or increased over time. Concentrations of amino acids in the final group remained relatively constant at all stages. This study illustrates the value of microdialysis in providing organ-specific metabolic data that may indicate specific mechanisms of poor graft function.