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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.

Dopaminergic medications ameliorate many of the motor impairments of Parkinson’s disease (PD). However, parkinsonism is often only partially reversed by these drugs, and they can have significant side effects. Therefore, a need remains for novel treatments of parkinsonism. Studies in rodents and preliminary clinical evidence have shown that T-type calcium channel (TTCC) antagonists have antiparkinsonian effects. However, most of the available studies utilized non-selective agents. We now evaluated whether systemic injections of the specific TTCC blocker ML218 have antiparkinsonian effects in MPTP-treated parkinsonian Rhesus monkeys. The animals were treated chronically with MPTP until they reached stable parkinsonism. In pharmacokinetic studies we found that ML218 reaches a peak CSF concentration 1–2 hrs after s.c. administration. In electrocardiographic studies, we found no effects of ML218 on cardiac rhythmicity. As expected, systemic injections of the dopamine precursor L-DOPA dose-dependently increased the movements in our parkinsonian animals. We then tested the behavioral effects of systemic injections of ML218 (1, 10 or 30 mg/kg) or its vehicle, but did not detect specific antiparkinsonian effects. ML218 (3 or 10 mg/kg) was also not synergistic with L-DOPA. Using recordings of electrocorticogram signals (in one animal), we found that ML218 increased sleep. We conclude that ML218 does not have antiparkinsonian effects in MPTP-treated parkinsonian monkeys, due at least in part, to the agent’s sedative effects.

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.

Analysis of the coupling between the phases and amplitudes of oscillations within the same continuously sampled signal has provided interesting insights into the physiology of memory and other brain process, and, more recently, the pathophysiology of parkinsonism and other movement disorders. Technical aspects of the analysis have a significant impact on the results. We present an empirical exploration of a variety of analysis design choices that need to be considered when measuring phase-amplitude coupling (PAC). We studied three alternative filtering approaches to the commonly used Kullback-Leibler distance-based method of PAC analysis, including one method that uses wavelets, one that uses constant filter settings, and one in which filtering of the data is optimized for individual frequency bands. Additionally, we introduce a time-dependent PAC analysis technique that takes advantage of the inherent temporality of wavelets. We examined how the duration of the sampled data, the stability of oscillations, or the presence of artifacts affect the value of the "modulation index", a commonly used parameter describing the degree of PAC. We also studied the computational costs associated with calculating modulation indices by the three techniques. We found that wavelet-based PAC performs better with similar or less computational cost than the two other methods while also allowing to examine temporal changes of PAC. We also show that the reliability of PAC measurements strongly depends on the duration and stability of PAC, and the presence (or absence) of artifacts. The best parameters to be used for PAC analyses of long samples of data may differ, depending on data characteristics and analysis objectives. Prior to settling on a specific PAC analysis approach for a given set of data, it may be useful to conduct an initial analysis of the time-dependence of PAC using our time-resolved PAC analysis.

Epilepsy is a network disorder and each type of seizure involves distinct cortical and subcortical network, differently implicated in the control and propagation of the ictal activity. The role of the basal ganglia has been revealed in several cases of focal and generalized seizures. Here, we review the data that shows the implication of the basal ganglia in absence, temporal lobe, and neocortical seizure in animal models (rodent, cat, and non-human primate) and in human. Based on these results and the advancement of deep brain stimulation for Parkinson’s disease, basal ganglia neuromodulation has been tested with some success that can be equally seen as promising or disappointing. The effect of deep brain stimulation can be considered promising with a 76% in seizures reduction in temporal lobe epilepsy patients, but also disappointing, since only few patients have become seizure free and the anti-epileptic effects have been highly variable among patients. This variability could probably be explained by the heterogeneity among the patients included in these clinical studies. To illustrate the importance of specific network identification, electrophysiological activity of the putamen and caudate nucleus has been recorded during penicillin-induced pre-frontal and motor seizures in one monkey. While an increase of the firing rate was found in putamen and caudate nucleus during pre-frontal seizures, only the activity of the putamen cells was increased during motor seizures. These preliminary results demonstrate the implication of the basal ganglia in two types of neocortical seizures and the necessity of studying the network in order to identify the important nodes implicated in the propagation and control of each type of seizure.

Parkinsonism is associated with changes in oscillatory activity patterns and increased synchronization of neurons in the basal ganglia and cortex in patients and animal models of Parkinson's disease, but the relationship between these changes and the severity of parkinsonian signs remains unclear. We examined this relationship by studying changes in local field potentials (LFPs) in the internal pallidal segment (GPi) and the subthalamic nucleus (STN), and in encephalographic signals (EEG) from the primary motor cortex (M1) in Rhesus monkeys which were rendered progressively parkinsonian by repeated systemic injections of small doses of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Observations during wakefulness and sleep (defined by EEG and video records) were analyzed separately. The severity of parkinsonism correlated with increases in spectral power at frequencies below 15.5 Hz in M1 and GPi and reductions in spectral power at frequencies above 15.6 Hz with little change in STN. The severity of parkinsonism also correlated with increases in the coherence between M1 EEG and basal ganglia LFPs in the low frequency band. Levodopa treatment reduced low-frequency activity and increased high-frequency activity in all three areas, but did not affect coherence. The state of arousal also affected LFP and EEG signals in all three structures, particularly in the STN. These results suggest that parkinsonism-associated changes in alpha and low-beta band oscillatory activity can be detected early in the parkinsonian state in M1 and GPi. Interestingly, oscillations detectable in STN LFP signals (including oscillations in the beta-band) do not appear to correlate strongly with the severity of mild-to-moderate parkinsonism in these animals. Levodopa-induced changes in oscillatory M1 EEG and basal ganglia LFP patterns do not necessarily represent a normalization of abnormalities caused by dopamine depletion.

Background and objective: Generating and characterizing primate models of epileptic seizures are important for understanding pathophysiology of diseases and establishing preclinical efficacy of novel therapies like Deep Brain Stimulation. A focal motor epilepsy model is described here. Method: Seizures were obtained after intracortical penicillin injection into the motor strip through a cannula in two awake monkeys and electrocorticograms were recorded by epidural screws. Seizures were analyzed and compared for number, average duration of each seizure and total duration of ictal activity. Pharmaco-resistance for antiepileptic drug was tested by administration of Diazepam during seizures. Results: A motor status with seizures mimicking those seen in Kojevnikov’s syndrome was easily generated several minutes after penicillin injection and lasted 24 h on an average. The model thus characterized appears stable and consistent. There is no significant variation between experiments in individual primate as well as between two specimens. Diazepam though reduced the total duration of seizures, failed to abolish behavioural seizures. Conclusion: This model represents a good alternative model for preclinical research aiming at testing novel therapies because seizures are obtained on demand, last up to 24 h after a single penicillin injection, are stable and resistant to Diazepam.

Focal motor seizures are characterized by transient motor behaviour that occurs simultaneously with paroxystic activity in the controlateral motor cortex. The implication of the basal ganglia has already been shown for generalized seizure but the propagation pathways from the motor cortex towards the basal ganglia during focal motor seizures are largely unknown. With a better knowledge of those pathways, a therapeutic modulation for reducing drug resistant motor epilepsy could be considered. Here, we recorded single-unit activities and local field potentials in the basal ganglia of two Macaca fascicularis in which acute focal motor seizures were induced by the injection of penicillin over the arm motor cortex territory. Each neuron was characterized using its mean firing rate and its type of firing pattern during interictal periods and seizures. Time-frequency analyses of local field potentials and electroencephalographic signals were used to assess dynamic changes occurring during seizure at a larger spatial level. The firing rate of neurons of input stages of basal ganglia (subthalamic nucleus and putamen) and those from the external part of the globus pallidus were significantly higher during seizures as compared to interictal periods. During seizures, the proportion of oscillatory neurons in subthalamic nucleus (71%), external globus pallidus (45%) and putamen (53%) significantly increased in comparison to interictal periods. Rhythmic activity was synchronized with ictal cortical spikes in external globus pallidus and subthalamic nucleus, but not in the putamen which oscillated faster than motor cortex. In contrast, no significant modification of the firing rate of the output stages of basal ganglia (internal part of the globus pallidus, substantia nigra pars reticulata) could be found during seizures. The local field potentials of subthalamic nucleus and external globus pallidus changed abruptly at the onset of the seizure, showing synchronization with the cortical activity throughout the seizure. In putamen, the synchronization appeared only by the end of seizures and for the two output structures, despite some increase of the oscillatory activity, the synchronization with the cortex was not significant. Our results suggest that the subthalamo-(external)-pallidal pathway is the main subcortical route involved during ictal motor seizures. Surprisingly, ictal activity did not propagate to the output structure of basal ganglia in that model. This finding may be important for clinical decisions of targeting when considering anti-epileptic neuromodulation in human beings suffering from disabling, drug resistant motor epilepsy. * Abbreviations : STN : subthalamic nucleus

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.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.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.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.

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.

Conventional anti-Parkinsonian dopamine replacement therapy is often complicated by side effects that limit the use of these medications. There is a continuing need to develop nondopaminergic approaches to treat Parkinsonism. One such approach is to use medications that normalize dopamine depletion-related firing abnormalities in the basal ganglia-thalamocortical circuitry. In this study, we assessed the potential of a specific T-type calcium channel blocker (ML218) to eliminate pathologic burst patterns of firing in the basal ganglia-receiving territory of the motor thalamus in Parkinsonian monkeys. We also carried out an anatomical study, demonstrating that the immunoreactivity for T-type calcium channels is strongly expressed in the motor thalamus in normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. At the electron microscopic level, dendrites accounted for >90% of all tissue elements that were immunoreactive for voltage-gated calcium channel, type 3.2-containing T-type calcium channels in normal and Parkinsonian monkeys. Subsequent in vivo electrophysiologic studies in awake MPTP-treated Parkinsonian monkeys demonstrated that intrathalamic microinjections of ML218 (0.5 μl of a 2.5-mM solution, injected at 0.1–0.2 μl/min) partially normalized the thalamic activity by reducing the proportion of rebound bursts and increasing the proportion of spikes in non-rebound bursts. The drug also attenuated oscillatory activity in the 3–13-Hz frequency range and increased gamma frequency oscillations. However, ML218 did not normalize Parkinsonism-related changes in firing rates and oscillatory activity in the beta frequency range. Whereas the described changes are promising, a more complete assessment of the cellular and behavioral effects of ML218 (or similar drugs) is needed for a full appraisal of their anti-Parkinsonian potential.

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.

In this study, modulation index (MI) features derived from local field potential (LFP) recordings in the sub-thalamic nucleus (STN) and electroencephalographic recordings (EEGs) from the primary motor cortex are shown to correlate with both the overall motor impairment and motor subscores in a monkey model of parkinsonism. The MI features used are measures of phase-amplitude cross frequency coupling (CFC) between frequency sub-bands. We used complex wavelet transforms to extract six spectral sub-bands within the 3-60 Hz range from LFP and EEG signals. Using the method of canonical correlation, we show that weighted combinations of the MI features in LFP or EEG signals correlate significantly with individual and composite scores on a scale for parkinsonian disability.

Electrophysiological studies of the effects of electrical brain stimulation have to contend with stimulus artifacts, which complicate both the maintenance of recorded neuron waveforms at recording time, and the post-hoc analysis of the data. The artifacts can be removed by digitally averaging some or all of the (stereotypic) artifact waveforms across artifacts, and then subtracting the resulting template from the recorded waveform at the time of artifact production. Available software-based approaches to this problem are effective but time consuming, and do not help with the problem of maintaining the recording quality at recording time. Alternative hardware-based methods are effective as well, but relatively inflexible and very expensive. We here provide a detailed description of a simple high-performance artifact removal device based on a multi-processor microcontroller as well as analog-to-digital and digital-to-analog converters. This device provides the benefits of self-adapting online-removal of stimulus artifacts for a fraction of the price of the commercially available devices. The device is fully customizable, and can be easily adjusted to various stimulation conditions, as well as AC line noise removal.