Body fat and body weight reduction following hypothalamic deep brain stimulation in monkeys: an intraventricular approach.

OBJECTIVE: The authors proposed an intraventricular 'floating' electrode inserted in the third ventricle (V3) adjacent to the ventromedian hypothalamus (VMH) in a freely moving Macaca fascicularis to modulate food intake (FI), body fat (BF), body weight (BW) and body mass index (BMI), as a potential treatment of obesity. METHODS: Five adult Macaca fascicularis monkeys were implanted stereotactically in the V3 contiguous to the VMH with one deep brain stimulation (DBS) electrode. The study was divided in two phases: (a) acute 24 h-fasting trials: different electrical stimulation parameters were applied to a fasting primate to determine the best combination in reducing FI; and (b) chronic 8-week stimulation trials: three cycles of intraventricular-VMH DBS lasting 8-10 weeks were performed at 130 Hz, 80 Hz (most effective frequency reducing FI) and 30 Hz, respectively. BMI, BW, BF content, skinfolds and hormones were measured during baseline and at the end of each session of stimulation. RESULTS: Acute 24 h-fasting trials: there was a decrease in FI in all subjects at 80 Hz, (11-19%, mean 15%). Chronic 8-week stimulation trials: a significant decrease in BW and BMI was observed in three out of four monkeys at 80 Hz (mean 8 ± 4.4%). Subcutaneous skinfolds were reduced in all four subjects at 80 Hz and slightly increased at 130 Hz. The sham monkey remained stable. No significant adverse effects were recorded. CONCLUSION: The stimulation of the VMH region through an intraventricular approach might acutely modulate FI and induce a sustained decrease in BW and fat mass in normal non-human primate.

Sleep fragmentation and decreased REM sleep in a primate model of diurnal cortical seizures.

Many people with epilepsy suffer from comorbid sleep disorders and sleep fragmentation. While the disruptive nature of seizures on sleep is well documented, it is unclear how diurnal seizures impact sleep quality and for how long these changes persist during the following nights. To better understand this relationship, the sleep architecture of two rhesus macaques were studied before and several nights after penicillin-induced diurnal seizures. These focal seizures stopped naturally, and none occurred at night. We scored sleep-stage during the nights immediately following the seizures, as well as several nights after seizure induction. We noted a significant increase in movement along with a decrease in sleep efficiency, both limited to the night of seizure induction. For both animals, we observed a significant decrease in the number of REM periods that manifested as a decrease in total REM sleep duration, and this phenomenon persisted up to 2 nights after the seizures. We also found a significant increase in the probability to transition from stage N2 to stage N1 on the night of the seizures. This study shows for the first time that the NHP model of penicillin-induced cortical seizures exhibits significant changes in sleep architecture, including an increase in nocturnal movement, change in sleep architecture and a prolonged decrease in REM activity. The prolonged decrease in REM periods compared to the temporary enhanced movement and reduction of sleep efficiency suggest that these seizures may affect two neural circuits, one controlling REM sleep entry and the other controlling nocturnal wakefulness.

Head mounted telemetry system for seizures monitoring and sleep scoring on non-human primate.

Radio telemetry systems are a useful way to continuously monitor broad electrical neuronal activity in behaving animals. It can also be used to study sleep disturbances or monitor seizure activity. Many different telemeter styles are available, but the more versatile and cost-efficient ones are the head mounted systems. They permit long-term recordings and allow more flexibility in the recordings. However, there are currently no such system available for non-human primate (NHP). In fact, the choices for NHP telemetry solutions are very limited. Here, we present a chronically implantable 3D printed chamber specifically designed to accommodate a rodent head-mounted system (RodentPACK) onto a NHP's head. We recorded EEG signal for more than a year, confirmed quality of the signal, and the ability to use the data to monitor sleep activity. We also used two of our epileptic animals to validate the embedded alarm system for real time seizure monitoring. While initially not designed for NHP, but with a minimum number of adaptions, this telemeter is in fact perfectly suitable for NHP experiments. Since early medical intervention during seizures is critical to avoid status epilepticus and to save the animal's life, real time seizures monitoring is becoming a safety requirement in many NHP studies. This method refines the current seizure monitoring methods for NHP and creates a flexible telemetry solution.

[Animal models to develop surgery of focal epilepsies?]. / Des modèles animaux pour développer la chirurgie des épilepsies focales ?

A model is a simplified preparation that reproduces only the most critical features of a disease. To be considered as a validated animal model, such an experimental preparation must fulfill three criteria: isomorphism or similarities of the symptoms; predictivity or identical pharmacological reactivity; homology or etiological similarity. In epilepsy, the use of animal models helps our understanding of physiological and pathological networks involved in the genesis, maintenance, and propagation of seizures. The animal models of epilepsy are also useful in designing and testing new surgical therapeutical strategies, in particular using deconnection or neuromodulation in drug-resistant focal epilepsies. Here we describe three animal models of focal epilepsy, adapted to addressing experimental surgery issues. Kindling consists in the regular liminar stimulation of a given brain structure in the rodent to develop a focal discharge that is secondarily generalized. The local application of epileptogenic agents such as cobalt, iron, or penicillin leads to focal discharges that do not generalize in the rodent or the primate. It is a model of focal neocortical epilepsy without secondary generalization. The focal application of kainate, an excitotoxic glutamate agonist, in the dorsal hippocampus of the adult mouse results, after a latent period, in spontaneous and recurrent focal discharges, behavioral interictal troubles, drug resistance, and histological anomalies reminiscent of hippocampal sclerosis. This constitutes a model of mesial-temporal epilepsy. Better knowledge, in these models, of the neural networks generating, propagating, and/or controlling the seizures should make it possible to design innovative surgical approaches for the treatment of drug-resistant epilepsies.

Effect of subthalamic nucleus stimulation on penicillin induced focal motor seizures in primate.

BACKGROUND: Drug-resistant motor epilepsies are particularly incapacitating for the patients. In a primate model of focal motor seizures induced by intracortical injection of penicillin, we recently showed that seizures propagated from the motor cortex towards the basal ganglia. OBJECTIVE: Using the same animal model here, we hypothesized that disruption of subthalamic nucleus (STN) activity by chronic high frequency stimulation (HFS) could modify pathological excessive cortical synchronisation occurring during focal motor seizures, and therefore could reduce seizure activity. METHODS: Two monkeys were chronically implanted with one electrode positioned into the STN. In each experiment, seizures were induced during 6 hours by injecting penicillin into the motor cortex. During stimulation sessions, HFS-STN was applied at the beginning of penicillin injection. RESULTS: Our results indicate that HFS-STN improved focal motor seizures by delaying the occurrence of the first seizure, by decreasing the number of seizures by 47% and therefore the total time spent seizing by 53% compared to control. These results argue for a therapeutic use of HFS-STN in motor seizures because they were obtained in a very severe primate model of motor status similar to that seen in human. Furthermore, HFS-STN was much more efficient than direct cortical HFS of the epileptic focus, which we already tested in the same primate model. CONCLUSIONS: The present study suggests that HFS-STN could be used as an experimental therapy when other therapeutic strategies are not possible or have failed in humans suffering from motor epilepsy but the present study still warrants controlled studies in humans.