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ABSTRACT: Approximately one-third of people with epilepsy receive insufficient benefit from currently available anticonvulsant medication, and some evidence suggests that this may be due to a lack of effective penetration into brain parenchyma. The current study investigated the ability of biodegradable polymer implants loaded with levetiracetam to ameliorate seizures following implantation above the motor cortex in the tetanus toxin model of temporal lobe epilepsy in rats. The implants led to significantly shorter seizures and a trend towards fewer seizures for up to 1week. The results of this study indicate that drug-eluting polymer implants represent a promising evolving treatment option for intractable epilepsy. Future research is warranted to investigate issues of device longevity and implantation site.
Journal of Clinical Neuroscience 10/2012; · 1.25 Impact Factor
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Dean R Freestone,
Levin Kuhlmann,
David B Grayden,
Anthony N Burkitt,
Alan Lai, Timothy S Nelson,
Simon Vogrin,
Michael Murphy,
Wendyl D'Souza,
Radwa Badawy,
Dragan Nesic,
Mark J Cook
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ABSTRACT: Standard methods for seizure prediction involve passive monitoring of intracranial electroencephalography (iEEG) in order to track the 'state' of the brain. This paper introduces a new method for measuring cortical excitability using an electrical probing stimulus. Electrical probing enables feature extraction in a more robust and controlled manner compared to passively tracking features of iEEG signals. The probing stimuli consist of 100 bi-phasic pulses, delivered every 10 min. Features representing neural excitability are estimated from the iEEG responses to the stimuli. These features include the amplitude of the electrically evoked potential, the mean phase variance (univariate), and the phase-locking value (bivariate). In one patient, it is shown how the features vary over time in relation to the sleep-wake cycle and an epileptic seizure. For a second patient, it is demonstrated how the features vary with the rate of interictal discharges. In addition, the spatial pattern of increases and decreases in phase synchrony is explored when comparing periods of low and high interictal discharge rates, or sleep and awake states. The results demonstrate a proof-of-principle for the method to be applied in a seizure anticipation framework. This article is part of a Supplemental Special Issue entitled The Future of Automated Seizure Detection and Prediction.
Epilepsy & Behavior 12/2011; 22 Suppl 1:S110-8. · 2.34 Impact Factor
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ABSTRACT: Epilepsy is a chronic neurological disorder characterized by recurrent seizures, and is highly resistant to medication with up to 40% of patients continuing to experience seizures whilst taking oral antiepileptic drugs. Recent research suggests that this may be due to abnormalities in the blood-brain barrier, which prevent the passage of therapeutic substances into the brain. We sought to develop a drug delivery material that could be implanted within the brain at the origin of the seizures to release antiepileptic drugs locally and avoid the blood brain barrier. We produced poly-lactide-co-glycolide drop-cast films and wet-spun fibers loaded with the novel antiepileptic drug Levetiracetam, and investigated their morphology, in vitro drug release characteristics, and brain biocompatibility in adult rats. The best performing structures released Levetiracetam constantly for at least 5 months in vitro, and were found to be highly brain biocompatible following month-long implantations in the motor cortex of adult rats. These results demonstrate the potential of polymer-based drug delivery devices in the treatment of epilepsy and warrant their investigation in animal models of focal epilepsy. © 2011 Wiley Periodicals, Inc. J Biomed Mater Res Part A:, 2011.
Journal of Biomedical Materials Research Part A 11/2011; · 2.63 Impact Factor
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Dean R Freestone,
Anthony N Burkitt,
Alan Lai, Timothy S Nelson,
David B Grayden,
Simon Vogrin,
Michael Murphy,
Wendyl D'Souza,
Radwa Badawy,
Levin Kuhlmann,
Mark J Cook
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ABSTRACT: This paper introduces a new method for measuring cortical excitability using an electrical probing stimulus via intracranial electroencephalography (iEEG). Stimuli consisted of 100 single bi-phasic pulses, delivered every 10 minutes. Neural excitability is estimated by extracting a feature from the iEEG responses to the stimuli, which we dub the mean phase variance (PV). We show that the mean PV increases with the rate of inter-ictal discharges in one patient. In another patient, we show that the mean PV changes with sleep and an epileptic seizure. The results demonstrate a proof-of-principal for the method to be applied in a seizure anticipation framework.
Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 08/2011; 2011:1644-7.
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ABSTRACT: A modified cortical stimulation model was used to investigate the effects of varying the synchronicity and periodicity of electrical stimuli delivered to multiple pairs of electrodes on seizure initiation. In this model, electrical stimulation of the motor cortex of rats, along four pairs of a microwire electrode array, results in an observable seizure with quantifiable electrographic duration and behavioural severity. Periodic stimuli had a constant inter-stimulus intervals across the two-second stimulus duration, whilst synchronous stimuli consisted of singular biphasic, bipolar pulses delivered to the four pairs of electrodes at precisely the same time for the entire two second stimulation period. In this way four combinations of stimulation were possible; periodic/synchronous (P/S), periodic/asynchronous (P/As), aperiodic/synchronous (Ap/S) and aperiodic/asynchronous (Ap/As). All stimulation types were designed with equal pulse width, current intensity and mean frequency of stimulation (60 Hz), standardizing net charge transfer. It was expected that the periodicity of the stimulus would be the primary determinant of seizure initiation and therefore severity and electrographic duration. However, the results showed that significant differences in both severity and duration only occurred when the synchronicity was altered. For periodic stimuli, synchronous delivery increased median seizure duration from 5 s to 13 s and increased median Racine severity from 1 to 3. In the aperiodic case, synchronous stimulus delivery increased median duration from 5.5 s to 11s and resulted in seizures of median severity 3 vs. 0 in the asynchronous case. These findings may have implications for the design of future neurostimulation waveform designs as higher numbers of electrodes and stimulator output channels become available in next generation implants.
Epilepsy research 07/2011; 96(3):267-75. · 2.48 Impact Factor
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ABSTRACT: A closed-loop system for the automated detection and control of epileptic seizures was created and tested in three Genetic Absence Epilepsy Rats from Strasbourg (GAERS) rats. In this preliminary study, a set of four EEG features were used to detect seizures and three different electrical stimulation strategies (standard (130 Hz), very high (500 Hz) and ultra high (1000 Hz)) were delivered to terminate seizures. Seizure durations were significantly shorter with all three stimulation strategies when compared to non-stimulated (control) seizures. We used mean seizure duration of epileptiform discharges persisting beyond the end of electrical stimulation as a measure of stimulus efficacy. When compared to the duration of seizures stimulated in the standard approach (7.0 s ± 10.1), both very high and ultra high frequency stimulation strategies were more effective at shortening seizure durations (1.3 ± 2.2 s and 3.5 ± 6.4 s respectively). Further studies are warranted to further understand the mechanisms by which this therapeutic effect may be conveyed, and which of the novel aspects of the very high and ultra high frequency stimulation strategies may have contributed to the improvement in seizure abatement performance when compared to standard electrical stimulation approaches.
International Journal of Neural Systems 04/2011; 21(2):163-73. · 4.28 Impact Factor
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ABSTRACT: The aim of this study was to determine the current intensities necessary to elicit three levels of varying EEG and behavioural phenomena with electrical stimulation, and also to determine the consistency of the EEG and behavioural components of the triggered seizures over time. Electrical stimulation of the primary motor/somatosensory cortex was performed in 16 adult rats with multichannel microwire electrode arrays. Stimulation was delivered at a frequency of 60 Hz (1 ms pulse width), for 2 s duration, as biphasic rectangular pulses over four of the eight available electrode pairs. Current intensity thresholds for interruption of normal behaviour, epileptiform afterdischarge (EAD) longer than 5 s and motor seizures with Racine severity greater than 3 were not correlated to time post-surgery. The Racine threshold was shown to be negatively correlated to the EAD duration and Racine severity of seizures elicited in the following sessions. Seizures were reliably generated in rats through cortical stimulation with microwire electrode arrays and these seizures were not shown to be subject to any kindling type effects up to 53 days post-implantation. Both the electrographic duration and behavioural severity of stimulated seizures remained, on average, constant during this experimental period. Approximately one-third of stimulations did not cause observable motor seizures and of those that did result in seizures, forelimb clonus was the most common manifestation and the mean EAD duration was 18.5 s. No damage beyond that caused by surgical implantation of electrodes was observed in the histological analyses of stimulated and non-stimulated tissue. The consistency, duration and severity of seizures within this timeframe make this cortical stimulation model suitable for investigations into novel therapeutic interventions for epilepsy that require a known seizure focus.
Epilepsy research 02/2010; 89(2-3):261-70. · 2.48 Impact Factor
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ABSTRACT: We investigate thalamocortical interactions in the tetanus toxin and the cortical stimulation rat models of epilepsy. Using local field potential recordings from the cortex and the thalamus of the rat, the nonlinear regression index is calculated to create the direction index in order to study neurodynamics during seizures. Coarse time-scale analysis reveals that the cortex drives the thalamus for the majority of the time during seizures. However, fine time-scale analysis provides evidence that epileptic spikes are driven from the thalamus. This new result has implications for understanding, diagnosing and using electrical stimulation to treat epileptic seizures.
Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 01/2009; 2009:1533-6.
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Dean R Freestone,
Anthony N Burkitt,
Alan Lai, Timothy S Nelson,
David B Grayden,
Simon Vogrin,
Michael Murphy,
Wendyl d'Souza,
Radwa Badawy,
Levin Kuhlmann,
Mark J Cook
[show abstract]
[hide abstract]
ABSTRACT: This paper introduces a new method for measuring cortical excitability using an electrical probing stimulus via intracranial electroencephalography (iEEG). Stimuli consisted of 100 single bi-phasic pulses, delivered every 10 minutes. Neural excitability is estimated by extracting a feature from the iEEG responses to the stimuli, which we dub the mean phase variance (PV). We show that the mean PV increases with the rate of inter-ictal discharges in one patient. In another patient, we show that the mean PV changes with sleep and an epileptic seizure. The results demonstrate a proof-of-principal for the method to be applied in a seizure anticipation framework.
2011:1644-1647.
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Dean R Freestone,
Levin Kuhlmann,
David B Grayden,
Anthony N Burkitt,
Alan Lai, Timothy S Nelson,
Simon Vogrin,
Michael Murphy,
Wendyl d'Souza,
Radwa Badawy,
Dragan Nesic,
Mark J Cook
[show abstract]
[hide abstract]
ABSTRACT: Standard methods for seizure prediction involve passive monitoring of intracranial electroencephalography (iEEG) in order to track the 'state' of the brain. This paper introduces a new method for measuring cortical excitability using an electrical probing stimulus. Electrical probing enables feature extraction in a more robust and controlled manner compared to passively tracking features of iEEG signals. The probing stimuli consist of 100 bi-phasic pulses, delivered every 10 min. Features representing neural excitability are estimated from the iEEG responses to the stimuli. These features include the amplitude of the electrically evoked potential, the mean phase variance (univariate), and the phase-locking value (bivariate). In one patient, it is shown how the features vary over time in relation to the sleep-wake cycle and an epileptic seizure. For a second patient, it is demonstrated how the features vary with the rate of interictal discharges. In addition, the spatial pattern of increases and decreases in phase synchrony is explored when comparing periods of low and high interictal discharge rates, or sleep and awake states. The results demonstrate a proof-of-principle for the method to be applied in a seizure anticipation framework. This article is part of a Supplemental Special Issue entitled The Future of Automated Seizure Detection and Prediction.
22 Suppl 1:S110-8.
