Deep brain stimulation for obesity in the normal non human primate: A preclinical approach.
Identifieur interne : 000873 ( Hal/Checkpoint ); précédent : 000872; suivant : 000874Deep brain stimulation for obesity in the normal non human primate: A preclinical approach.
Auteurs : Napoleon Torres [France]Source :
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Abstract
Abstract Object: Deep brain stimulation (DBS) has become an effective therapy in a variety of brain disorders. Recently, Hypothalamic DBS in cases of chronic intractable cluster headache has revived the interest in this region, which is also well-known to be involved in food intake and energy balance regulation. In the other hand, risks and problems related with implantation in this area has raised several questions regarding the safety of this approach. In this study, the authors proposed an Intraventricular “floating” electrode inserted in the third ventricle adjacent to the ventromedial hypothalamus (VMH) in freely moving Macaca fascicularis to modulate food intake and weight and as a potential treatment of morbid obesity. Methods: Five adults Macaca fascicularis (4 subjects and 1 sham) monkeys were implanted stereotactically in the third ventricle contiguous to the VMH with chronic indwelling 3389 and 3388 Medtronic electrodes used for Deep Brain Stimulation (DBS). The study was divided in two phases: acute tests and chronic 8-weeks trials. In the acute tests, the meal size, eating time and locomotor activity were recorded after short periods of electrical stimulation (ES) in 24 hrs fasting animals at different frequencies and intensities of stimulation, in order to obtain the most effective sets of ES parameters able to reduced food intake (FI) and consequently weight and fat during chronic stimulation. In the chronic trials, three cycles of continuous ES of 8 weeks each were performed at the most effective frequency reducing FI in the acute test (or 80Hz), at 130Hz (considered High Frequency ES and used in Parkinson Disease DBS) , and 30Hz (considered Low frequency ES and used in Pain DBS). Body Mass Index, weight, fat content, subcutaneous skinfolds and hormones were measured during baseline and at the end of each 8 week stimulation trials. Results: Results: During Acute 24 hrs-fasting trials, there was a decrease in FI in all subjects at 80 Hz, (mean 15 ±4.4%). During Chronic 8 weeks stimulation trials, a decrease in weight and BMI was observed in three out four monkeys at 80 HZ (mean 8% ± 4.4%), and slight increase at 130HZ (mean 2% ± 2.5) and at 30HZ (mean 5%±2,93). Fat mass decreased at the end of 80 Hz trials to ratio 0.82±0.08. (18% reduction).Subcutaneous skinfolds were reduced in all four subjects at 80 Hz and slightly increased at 130 Hz. Sham monkey remained stable. FI increased during off stimulation period (washout) following effective weight loss. Glucose also increased during hyperphagic period. Hormones and Leptin did not show significative variations in relation to different frequencies stimulation. No major adverse effects were recorded. Conclusion: We conclude that stimulating the VMH region throughout an Intraventricular approach might modulate acutely food ingestion and induce a sustained decrease in weight and in fat content in normal non obese human primates.
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<front><div type="abstract" xml:lang="en">Abstract Object: Deep brain stimulation (DBS) has become an effective therapy in a variety of brain disorders. Recently, Hypothalamic DBS in cases of chronic intractable cluster headache has revived the interest in this region, which is also well-known to be involved in food intake and energy balance regulation. In the other hand, risks and problems related with implantation in this area has raised several questions regarding the safety of this approach. In this study, the authors proposed an Intraventricular “floating” electrode inserted in the third ventricle adjacent to the ventromedial hypothalamus (VMH) in freely moving Macaca fascicularis to modulate food intake and weight and as a potential treatment of morbid obesity. Methods: Five adults Macaca fascicularis (4 subjects and 1 sham) monkeys were implanted stereotactically in the third ventricle contiguous to the VMH with chronic indwelling 3389 and 3388 Medtronic electrodes used for Deep Brain Stimulation (DBS). The study was divided in two phases: acute tests and chronic 8-weeks trials. In the acute tests, the meal size, eating time and locomotor activity were recorded after short periods of electrical stimulation (ES) in 24 hrs fasting animals at different frequencies and intensities of stimulation, in order to obtain the most effective sets of ES parameters able to reduced food intake (FI) and consequently weight and fat during chronic stimulation. In the chronic trials, three cycles of continuous ES of 8 weeks each were performed at the most effective frequency reducing FI in the acute test (or 80Hz), at 130Hz (considered High Frequency ES and used in Parkinson Disease DBS) , and 30Hz (considered Low frequency ES and used in Pain DBS). Body Mass Index, weight, fat content, subcutaneous skinfolds and hormones were measured during baseline and at the end of each 8 week stimulation trials. Results: Results: During Acute 24 hrs-fasting trials, there was a decrease in FI in all subjects at 80 Hz, (mean 15 ±4.4%). During Chronic 8 weeks stimulation trials, a decrease in weight and BMI was observed in three out four monkeys at 80 HZ (mean 8% ± 4.4%), and slight increase at 130HZ (mean 2% ± 2.5) and at 30HZ (mean 5%±2,93). Fat mass decreased at the end of 80 Hz trials to ratio 0.82±0.08. (18% reduction).Subcutaneous skinfolds were reduced in all four subjects at 80 Hz and slightly increased at 130 Hz. Sham monkey remained stable. FI increased during off stimulation period (washout) following effective weight loss. Glucose also increased during hyperphagic period. Hormones and Leptin did not show significative variations in relation to different frequencies stimulation. No major adverse effects were recorded. Conclusion: We conclude that stimulating the VMH region throughout an Intraventricular approach might modulate acutely food ingestion and induce a sustained decrease in weight and in fat content in normal non obese human primates.</div>
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<abstract xml:lang="en">Abstract Object: Deep brain stimulation (DBS) has become an effective therapy in a variety of brain disorders. Recently, Hypothalamic DBS in cases of chronic intractable cluster headache has revived the interest in this region, which is also well-known to be involved in food intake and energy balance regulation. In the other hand, risks and problems related with implantation in this area has raised several questions regarding the safety of this approach. In this study, the authors proposed an Intraventricular “floating” electrode inserted in the third ventricle adjacent to the ventromedial hypothalamus (VMH) in freely moving Macaca fascicularis to modulate food intake and weight and as a potential treatment of morbid obesity. Methods: Five adults Macaca fascicularis (4 subjects and 1 sham) monkeys were implanted stereotactically in the third ventricle contiguous to the VMH with chronic indwelling 3389 and 3388 Medtronic electrodes used for Deep Brain Stimulation (DBS). The study was divided in two phases: acute tests and chronic 8-weeks trials. In the acute tests, the meal size, eating time and locomotor activity were recorded after short periods of electrical stimulation (ES) in 24 hrs fasting animals at different frequencies and intensities of stimulation, in order to obtain the most effective sets of ES parameters able to reduced food intake (FI) and consequently weight and fat during chronic stimulation. In the chronic trials, three cycles of continuous ES of 8 weeks each were performed at the most effective frequency reducing FI in the acute test (or 80Hz), at 130Hz (considered High Frequency ES and used in Parkinson Disease DBS) , and 30Hz (considered Low frequency ES and used in Pain DBS). Body Mass Index, weight, fat content, subcutaneous skinfolds and hormones were measured during baseline and at the end of each 8 week stimulation trials. Results: Results: During Acute 24 hrs-fasting trials, there was a decrease in FI in all subjects at 80 Hz, (mean 15 ±4.4%). During Chronic 8 weeks stimulation trials, a decrease in weight and BMI was observed in three out four monkeys at 80 HZ (mean 8% ± 4.4%), and slight increase at 130HZ (mean 2% ± 2.5) and at 30HZ (mean 5%±2,93). Fat mass decreased at the end of 80 Hz trials to ratio 0.82±0.08. (18% reduction).Subcutaneous skinfolds were reduced in all four subjects at 80 Hz and slightly increased at 130 Hz. Sham monkey remained stable. FI increased during off stimulation period (washout) following effective weight loss. Glucose also increased during hyperphagic period. Hormones and Leptin did not show significative variations in relation to different frequencies stimulation. No major adverse effects were recorded. Conclusion: We conclude that stimulating the VMH region throughout an Intraventricular approach might modulate acutely food ingestion and induce a sustained decrease in weight and in fat content in normal non obese human primates.</abstract>
<abstract xml:lang="fr">Résume Objet: La stimulation cérébrale profonde (SCP) est devenue une thérapie efficace dans une série de maladies cérébrales. Récemment, dans les cas des algies vasculaires de la face résistantes au traitement (intraitables), chroniques, la SCP hypothalamique a suscité un nouvel intérêt pour cette région, également bien connue pour son implication dans la régulation de la prise alimentaire et de la balance énergétique. Cependant, les risques et les problèmes connexes liés à l'implantation dans cette aire cérébrale ont soulevé plusieurs questions concernant la sûreté de cette technique chirurgicale. Dans cette étude, les auteurs ont proposé l'implantation d'une électrode intraventriculaire insérée dans le troisième ventricule au niveau de l'hypothalamus ventromedial (VMH) chez des singes macaca fascicularis non obèses dans le but de moduler la prise alimentaire et le masse corporelle des sujets. Cette méthode de SCP pourrait s'avérer être un traitement potentiel de l'obésité morbide. Méthodes: Cinq singes de macaca fascicularis adultes (4 sujets et 1 contrôle ou sham) ont été implantés de façon stéréotaxique dans le troisième ventricule. Une électrode chronique Medtronic®, habituellement utilisée dans le cadre de la SCP chez les patients atteints de la maladie de Parkinson, a été positionnées dans l'espace intraventriculaire adossée à la paroi de ce dernier au niveau du VMH. Dans la première phase de l'étude, le comportement alimentaire de chaque animal (durée du repas, quantité de nourriture avalée) et son activité motrice ont été enregistrés et analysés en fonction différents paramètres de stimulation (fréquence et intensité) après une période de jeun de 24 heures. Dans la seconde phase du protocole, trois cycles de stimulation intraventriculaire de 8 semaines chacun ont été réalisés à 130Hz, à 80Hz et à 30Hz, suivi des périodes de « washout » de 4 semaines entre les périodes« on - stimulation ». L'index de masse corporelle, le poids (masse corporelle), la « teneur « en graisse, l'épaisseur cutanée et les concentrations hormonales ont été mesurés au début de l'étude pour établir une ligne de base et après chaque session de stimulation. Résultats: Lors de la première phase du protocole réalisée sur des animaux a jeun depuis 24 heures, nous avons remarqué une diminution de la prise alimentaire comprise entre 11 et 19% chez tous les sujets stimulés à une fréquence 80 hertz. A partie de ces résultats, , une diminution de la masse corporelle et du BMI (body mass index indice de masse corporelle) ont été observés chez trois de quatre singes lors des phases de stimulation chronique à une fréquence de 80 hertz : la moyenne de perte pondérale était de 8± 4.4%. Une augmentation de 2-6 ± 2.5% et de 5 ±2,93 %de la masse corporelle a été observée respectivement chez les animaux stimulés à une fréquence de 130Hzet de 30Hz. Une diminution importante des épaisseurs sous-cutanées ( )a été observée pour chacun des quatre sujets à une fréquence de 80 hertz et dans une moindre mesure, une augmentation de cette variable ( ) a été remarquée une fréquence de 130 Hz. Tout au long de l'étude, les variables relevées sur le singe Sham sont restées stables. Sur la durée de l'étude, aucun effet potentielle ment délétère n'a été remarqués sur les animaux. Conclusion: La stimulation de la région de VMH par voie intraventriculaire pourrait s'avérer efficace pour moduler le comportement alimentaire et induire une diminution soutenue de la masse corporelle caractérisée par réduction de la masse graisseuse chez les primates non humains non obèses.</abstract>
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