Chronic Fragmentation of the Daily Sleep-Wake Rhythm Increases Amyloid-beta Levels and Neuroinflammation in the 3xTg-AD Mouse Model of Alzheimer's Disease.

Fragmentation of the daily sleep-wake rhythm with increased nighttime awakenings and more daytime naps is correlated with the risk of development of Alzheimer's disease (AD). To explore whether a causal relationship underlies this correlation, the present study tested the hypothesis that chronic fragmentation of the daily sleep-wake rhythm stimulates brain amyloid-beta (Aß) levels and neuroinflammation in the 3xTg-AD mouse model of AD. Female 3xTg-AD mice were allowed to sleep undisturbed or were subjected to chronic sleep fragmentation consisting of four daily sessions of enforced wakefulness (one hour each) evenly distributed during the light phase, five days a week for four weeks. Piezoelectric sleep recording revealed that sleep fragmentation altered the daily sleep-wake rhythm to resemble the pattern observed in AD. Levels of amyloid-beta (Aß40 and Aß42) determined by ELISA were higher in hippocampal tissue collected from sleep-fragmented mice than from undisturbed controls. In contrast, hippocampal levels of tau and phospho-tau differed minimally between sleep fragmented and undisturbed control mice. Sleep fragmentation also stimulated neuroinflammation as shown by increased expression of markers of microglial activation and proinflammatory cytokines measured by q-RT-PCR analysis of hippocampal samples. No significant effects of sleep fragmentation on Aß, tau, or neuroinflammation were observed in the cerebral cortex. These studies support the concept that improving sleep consolidation in individuals at risk for AD may be beneficial for slowing the onset or progression of this devastating neurodegenerative disease.

A novel approach to the study of hypoxia-ischemia-induced clinical and subclinical seizures in the neonatal rat.

Perinatal hypoxic-ischemic encephalopathy (HIE) is a major cause of acute mortality and chronic neurologic morbidity in infants and children. HIE is the most common cause of neonatal seizures, and seizure activity in neonates can be clinical, with both EEG and behavioral symptoms, subclinical with only EEG activity, or just behavioral. The accurate detection of these different seizure manifestations and the extent to which they differ in their effects on the neonatal brain continues to be a concern in neonatal medicine. Most experimental studies of the interaction between hypoxia-ischemia (HI) and seizures have utilized a chemical induction of seizures, which may be less clinically relevant. Here, we expanded our model of unilateral cerebral HI in the immature rat to include video EEG and electromyographic recording before, during and after HI in term-equivalent postnatal-day-12 rats. We observed that immature rats display both clinical and subclinical seizures during the period of HI, and that the total number of seizures and time to first seizure correlate with the extent of tissue damage. We also tested the feasibility of developing an automated seizure detection algorithm for the unbiased detection and characterization of the different types of seizure activity observed in this model.

Toward a quantitative multivariate analysis of the efficacy of antiseizure therapies.

Seizure frequency is the only variable used for assessing therapeutic efficacy. Advances in quantitative analyses allow measurement of intensity, duration, spread, and time between seizures (TBS). These variables are used here to investigate the efficacy of brain electrical stimulation in humans with pharmacoresistant seizures. The results of a trial of contingent high-frequency electrical stimulation (HFES) for abatement of clinical and subclinical seizures are examined using principal component analysis (PCA) and regression models. HFES significantly: (1) Decreased seizure severity in two of eight and increased TBS in one of eight subjects; (2) decreased seizure severity in the primary epileptogenic zone of one subject but increased it in the secondary zones; (3) had both a beneficial and detrimental effect on severity and/or TBS (increase). These effects were immediate and also outlasted the duration of stimulation ("carryover"). Contingent HFES has multifarious and complex effects, intra- and interindividually, on seizure severity and TBS. Two inferences, at once promising and sobering may be drawn from these results: one, that contingent electrical stimulation deserves a place in the armamentarium of therapies for pharmacoresistant seizures, and the other, that its apparently narrow therapeutic ratio calls for careful implementation and multivariate quantification of its effects.

Seizure modulation with applied electric fields in chronically implanted animals.

Low Frequency (<<100Hz) applied electric fields have been shown to modulate neuronal activity both In Vitro and in acute whole animal studies. We have been working to apply this technology for seizure control in chronically implanted animals. We have developed electronics for simultaneously recording neural activity while stimulating with low frequency fields. We have observed transient entrainment of spike and wave activity during spontaneous seizures with open loop sinusoidal stimulation with frequencies between 9-15 Hz. This is the first demonstration of low frequency field modulation of neural activity in chronically implanted mammalian brain.

Vagal and sciatic nerve stimulation have complex, time-dependent effects on chemically-induced seizures: a controlled study.

Previous studies of the effects of electrical vagus stimulation on experimental seizures were without suitable controls or statistical validation, and ignored the potential role of vagally-induced hemodynamic depression on seizure expression. This study addresses these limitations. The effects of periodic left vagus nerve stimulation (LVNS) on chemically-induced seizures in rats were compared with control groups receiving no stimulation (NoS), left sciatic nerve stimulation (LSNS) and LVNS after pretreatment with methyl atropine (MA-LVNS). Stimulation followed a 30 s on-120 s off cycle over 130 min. Seizures were scored visually and the temporal variation of their probability P(s) across the stimulation cycle was measured statistically. P(s) was significantly different (P<0.01) for all groups: LSNS had the highest and MA-LVNS the lowest seizure probability; LVNS and NoS had intermediate values. While LVNS blocked seizures, it also precipitated them, explaining why its anti-seizure effect was only slightly greater than NoS. Neither LVNS nor MA-LVNS induced changes in cortical rhythms ('activation') associated with decreased P(s), unlike LSNS which increased cortical rhythm synchrony and with it, P(s). LVNS alone induced marked bradycardia and moderate hypoxemia. In conclusion, cranial and peripheral nerve stimulation have complex, time-varying effects on cerebral excitability: low frequency LSNS facilitated seizures, while LVNS both suppressed and facilitated them. The anti-seizure effect of LVNS was small and may have, in part, been due to a hemodynamically-induced deficit in energy substrates. The effects of MA-LVNS on seizure duration and P(s) raise the possibility that, in the absence of hemodynamic depression, stimulation of this nerve does not have a strong anti-seizure effect.

Stochastic modeling and prediction of experimental seizures in Sprague-Dawley rats.

Most seizure prediction methods are based on nonlinear dynamic techniques, which are highly computationally expensive, thus limiting their clinical usefulness. The authors propose a different approach for prediction that uses a stochastic Markov chain model. Seizure (Ts) and interictal (Ti) durations were measured from 11 rats treated with 3-mercaptopropionic acid. The duration of a seizure Ts was used to predict the time (Ti2) to the next one. Ts and Ti were distributed bimodally into short (S) and long (L), generating four probable transitions: S --> S, S --> L, L --> S, and L --> L. The joint probability density f (Ts, Ti2) was modeled, and was used to predict Ti2 given Ts. An identical model predicted Ts given the duration Ti1 of the preceding interictal interval. The median prediction error was 3.0 +/- 3.5 seconds for Ts (given Ti1) and 6.5 +/- 2.0 seconds for Ti2 (given Ts). In comparison, ranges for observed values were 2.3 seconds < Ts < 120 seconds and 6.6 seconds < Ti < 782 seconds. These results suggest that stochastic models are potentially useful tools for the prediction of seizures. Further investigation of the probable temporal interdependence between the ictal and interictal states may provide valuable insight into the dynamics of the epileptic brain.

An introduction to contingent (closed-loop) brain electrical stimulation for seizure blockage, to ultra-short-term clinical trials, and to multidimensional statistical analysis of therapeutic efficacy.

Automated seizure blockage is a top research priority of the American Epilepsy Society. This delivery modality (referred to herein as contingent or closed loop) requires for implementation a seizure detection algorithm for control of delivery of therapy via a suitable device. The authors address the many potential advantages of this modality over conventional alternatives (periodic or continuous), and the challenges it poses in the design and analysis of trials to assess efficacy and safety-in the particular context of direct delivery of electrical stimulation to brain tissue. The experimental designs of closed-loop therapies are currently limited by ethical, technical, medical, and practical considerations. One type of design that has been used successfully in an in-hospital "closed-loop" trial using subjects undergoing epilepsy surgery evaluation as their own controls is discussed in detail. This design performs a two-way comparison of seizure intensity, duration, and extent of spread between the control (surgery evaluation) versus the experimental phase, and, within the experimental phase, between treated versus untreated seizures. The proposed statistical analysis is based on a linear model that accounts for possible circadian effects, changes in treatment protocols, and other important factors such as change in seizure probability. The analysis is illustrated using seizure intensity as one of several possible end points from one of the subjects who participated in this trial. In-hospital ultra-short-term trials to assess safety and efficacy of closed-loop delivery of electrical stimulation for seizure blockage are both feasible and valuable.

Hyponatraemia in the elderly.

A study of hyponatraemia in the in-patients of a Geriatric Department during a 10-month period showed that 77 patients (11.3%) had plasma sodium concentrations below 130 mmol/l. Thirty-one patients (4.5%) had severe hyponatraemia of less than 125 mmol/l. Seventy-three per cent of hyponatraemias were iatrogenic caused by diuretic or intravenous fluid therapy. Hydrochlorothiazide/amiloride combination has the greatest tendency to produce hyponatraemia compared to all other diuretics (P less than 0.01). Clinical features attributable to hyponatraemia were present in 61%. Nine patients needed hospital admission solely due to hyponatraemia. The mortality rate for hyponatraemia was twice the overall rate for the unit.

A clinical trial with glipizide - a relative new sulphonylurea.

Glipizide is a relatively new sulphonylurea- antidiabetic agent. 24 maturity-onset diabetics were studied to determine the dosage required to produce adequate control and the safety and tolerance of the drug. It was concluded that glipizide is a safe and potent anti-diabetic agent and a suitable alternative in those patients poorly-controlled on standard oral hypoglycaemic drugs.