Contribution of the subthalamic nucleus to motor, cognitive and limbic processes: an electrophysiological and stimulation study in monkeys

Deep brain stimulation of the subthalamic nucleus (STN) has become the gold standard surgical treatment for Parkinson’s disease and is being investigated for obsessive compulsive disorders. Even if the role of the STN in the behavior is well documented, its organization and especially its division into several functional territories is still debated. A better characterization of these territories and a better knowledge of the impact of stimulation would address this issue. We aimed to find specific electrophysiological markers of motor, cognitive and limbic functions within the STN and to specifically modulate these components. Two healthy non-human primates (Macaca fascicularis) performed a behavioral task allowing the assessment of motor, cognitive and limbic reward-related behavioral components. During the task, four contacts in the STN allowed recordings and stimulations, using low frequency stimulation (LFS) and high frequency stimulation (HFS). Specific electrophysiological functional markers were found in the STN with beta band activity for the motor component of behavior, theta band activity for the cognitive component, and, gamma and theta activity bands for the limbic component. For both monkeys, dorsolateral HFS and LFS of the STN significantly modulated motor performances, whereas only ventromedial HFS modulated cognitive performances. Our results validated the functional overlap of dorsal motor and ventral cognitive subthalamic territories, and, provide information that tends toward a diffuse limbic territory sensitive to the reward within the STN

Cortical stimulation of the epileptogenic zone for the treatment of focal motor seizures: an experimental study in the nonhuman primate.

International audienceBACKGROUND: Cortical stimulation is under investigation in clinical trials of drug-resistant epilepsy. Results are heterogeneous; therefore, more evidence from animal studies is required. OBJECTIVE: To investigate the therapeutic effects of parameters of direct stimulation of the cortical focus in a Macaca fascicularis presenting focal motor epilepsy. METHODS: We developed a model of motor seizures after intracortical injection of penicillin G in the primary motor cortex of a Macaca fascicularis. We performed electric epidural cortical stimulation at low, medium, and high frequency using continuous or short-term stimulation. Short-term stimulation was triggered on seizure onset, either visually or automatically with a seizure detection algorithm connected to a programmable stimulator. RESULTS: Automated detection could detect 100% of the seizures, but ensuing cortical electric stimulation failed to abort seizures. CONCLUSION: This study demonstrates the inefficacy of the stimulation of the cortical focus to prevent seizures induced by local injection of penicillin G. Because this model may be too severe to allow comparison to human epilepsies, further work is required in other monkey models of focal epilepsy

Hyperbaric oxygen therapy promotes wound repair in ischemic and hyperglycemic conditions, increasing tissue perfusion and collagen deposition

The treatment of chronic wounds remains inconsistent and empirical. Hyperbaric oxygen therapy (HBOT) is a promising method to improve wound repair but there is still a lack of understanding of its mechanisms of action and its indications are not yet clearly defined. We studied the effects of HBOT in four different wound conditions by inflicting bilateral wounds on the dorsal aspect of the feet of nonischemic or ischemic limbs in normoglycemic or hyperglycemic rats. To create an ischemic condition, arterial resection was performed unilaterally. Forty-four animals received HBOT five times a week until complete wound closure. Wound repair was compared with 44 rats receiving standard dressing only. HBOT increased blood flow and accelerated wound closure in ischemic and hyperglycemic wounds, most significantly when the two conditions were combined. Wound contraction and reepithelialization were similarly stimulated by HBOT. The acceleration of wound contraction was not associated with increased myofibroblasts expression, nor fibroblast recruitment or higher cell count in the granulation tissue. Of note, we observed a significant increase in collagen deposition in early time points in ischemic wounds receiving HBOT. This data emphasizes that an early application of HBOT might be crucial to its efficacy. We concluded that wounds where ischemia and hyperglycemia are combined, as it is often the case in diabetic patients, have the best chance to benefit from HBOT

A putative generalized model of the effects and mechanism of action of high frequency electrical stimulation of the central nervous system.

International audienceHigh-frequency stimulation (HFS) of neural structures has been used since 1997 as an alternative to lesions in functional neurosurgery of movement disorders, and more recently, it has been applied to the treatment of epilepsies, obsessive-compulsive disorders, cluster headaches, and has other applications in experimental models, particularly for obesity. Although their clinical efficacy is not questioned, and that the effects most of the time parallel those of ablative techniques, leading to the concept of functional inhibition, the intimate mechanisms by which HFS induces excitation within fiber bundles and seems to inhibit cellular nuclei is still strongly debated. Principally due to the observation of long-term clinical effects over a period up to 15 years, it is clear that the mechanism is not due to a progressive lesion, as at every moment the interruption of stimulation reverses totally the effects. There is no current proof that long-term HFS is able to reset neural networks, or to induce profound modifications of the functional organization or of the synaptic connectivity. To understand what is responsible for the immediate, reversible and adaptable effects of HFS, several mechanisms must be considered, which might be involved simultaneously or in sequence: i) Jamming of neural transmission through stimulated nuclei is one possibility, based on the principle that the regular imposed activity might drive the neurons to fire in a regular pattern, making it impossible to transmit more subtle messages, either normal or abnormal. Although it is difficult to prove this type of mechanism, it might account for the reports of increased activity following HFS in various structures. ii) Direct inhibition of spike initiation at the level of the membrane could be due to activation of inhibitory terminals, particularly gaba-ergic, or by a blockade of the voltage gated ion channels. iii) Recent data show that HFS decreases the production and release of low molecular weight proteic neurotransmitters, which could account for the functional inhibition while the efferent axon is still excited by the electrical stimulus. iv) Retrograde activation of upstream neuronal structures, as reported in the external pallidum during stimulation of STN, might be responsible of additional jamming-like effects due to collisions with descending spikes

Monophasic but not biphasic pulses induce brain tissue damage during monopolar high-frequency deep brain stimulation.

International audienceOBJECTIVE: Electrical high-frequency stimulation (HFS) of deep brain structures has been successfully used as a treatment for patients with movement disorders. The mechanisms of HFS allowing therapeutic clinical effects remain unclear, which justifies experimental studies to address these questions. These experiments require an external stimulator, which may offer the possibility to deliver a current with monophasic or biphasic pulses. The aim of the present study was to quantify the evolution of a potentially deleterious effect of HFS according to the duration and/or intensity in monophasic and biphasic conditions. METHODS: In all rats, HFS was performed with monophasic pulses in deep brain structures of 1 hemisphere and with biphasic pulses symmetrically in the other hemisphere. The effect of HFS was tested, first for various durations of HFS at a constant intensity (100 microA) and, second, for measuring the effect of various current intensities of HFS at constant duration (10 minutes). At the end of each stimulation test, the volume of lesion was determined and analyzed. RESULTS: In all hemispheres in which stimulation using biphasic pulses was delivered, we never found any relevant lesions. Conversely, monophasic electrical stimulation always created a lesion: at 100 microA, a minimal duration of HFS of 5 minutes induced a tissue damage volume of 0.0055 +/- 0.0015 mm(3). For 10 minutes of HFS, a minimal intensity of 100 microA induced a tissue damage volume of 0.0062 +/- 0.0017 mm(3). Regression analysis showed that the extent of lesion increased linearly with the intensity and duration. CONCLUSION: In conclusion, this study proved that HFS using monophasic pulses systematically created tissue damage after 5 minutes of stimulation at 100 microA. HFS is safe when biphasic pulses are used for intensities as high as 2 mA and durations as long as 120 minutes. Monophasic pulses can be safely used only during short stimulation and at low intensities