Continuous deep brain stimulation of the nucleus accumbens reduces food intake but does not affect body weight in mice fed a high-fat diet.

Obesity is an enormous health problem, and many patients do not respond to any of the available therapies. Deep brain stimulation (DBS) is currently investigated as a potential treatment for morbid obesity. In this study, we tested the hypothesis that high-frequency DBS targeting the nucleus accumbens (NAc) shell region reduces food intake and weight gain in mice fed a high-fat diet. We implanted male C57BL/6J mice with bilateral electrodes and a head-mounted microstimulator enabling continuous stimulation for up to 5 weeks. In successfully operated animals (n = 9 per group, high-frequency vs. sham stimulation), we investigated immediate and long-term stimulation effects on metabolic and behavioral phenotypes. Here we show that stimulation acutely induced a transient reduction in energy expenditure and locomotor activity but did not significantly affect spontaneous food intake, social interaction, anxiety or exploratory behaviors. In contrast, continuous stimulation over 5 weeks led to a decrease in food intake and thigmotaxis (the tendency to stay near walls in an open lit arena). However, chronic stimulation did not substantially change weight gain in mice fed a high-fat diet. Our results do not support the use of continuous high-frequency NAc shell DBS as a treatment for obesity. However, DBS can alter obesity-related parameters with differing short and long-term effects. Therefore, future research should employ time and context-sensitive experimental designs to assess the potential of DBS for clinical translation in this area.

Experimental deep brain stimulation in rodent models of movement disorders.

Deep brain stimulation (DBS) is the preferred treatment for therapy-resistant movement disorders such as dystonia and Parkinson's disease (PD), mostly in advanced disease stages. Although DBS is already in clinical use for ~30 years and has improved patients' quality of life dramatically, there is still limited understanding of the underlying mechanisms of action. Rodent models of PD and dystonia are essential tools to elucidate the mode of action of DBS on behavioral and multiscale neurobiological levels. Advances have been made in identifying DBS effects on the central motor network, neuroprotection and neuroinflammation in DBS studies of PD rodent models. The phenotypic dtsz mutant hamster and the transgenic DYT-TOR1A (ΔETorA) rat proved as valuable models of dystonia for preclinical DBS research. In addition, continuous refinements of rodent DBS technologies are ongoing and have contributed to improvement of experimental quality. We here review the currently existing literature on experimental DBS in PD and dystonia models regarding the choice of models, experimental design, neurobiological readouts, as well as methodological implications. Moreover, we provide an overview of the technical stage of existing DBS devices for use in rodent studies.

Development of an implantable microstimulation system for chronic DBS in rodents.

High frequency deep brain stimulation (DBS) of certain basal ganglia nuclei (e.g. subthalamic nucleus, STN) has emerged as a powerful neuromodulatory approach in the treatment of late stage Parkinson's disease patients. However, the underlying mechanisms of action are not fully understood. We have therefore established an implantable DBS device for small laboratory animals (e.g. rats) that allows the reliable and safe application of continuous DBS for at least 3 weeks. We could further show that miniaturized monopolar electrodes comprising activated iridium are suitable for continuous stimulation of small brain structures like the STN without inducing severe insertion or stimulation related injuries.

Continuous high-frequency stimulation in freely moving rats: development of an implantable microstimulation system.

High-frequency stimulation (HFS) of basal ganglia and thalamic nuclei is an established treatment for various movement disorders and has recently been extended to other neuro-psychiatric conditions. Numerous experimental studies in small laboratory animals provided important insights in the mode of action of HFS. However, the interpretation of the results is often limited by the use of short-term HFS, while patients receive continuous stimulation for many years. One reason is the lack of an established model for the application of long-term HFS in small animals. Therefore, we thought to develop an implantable microstimulation system for small laboratory animals and to establish a protocol for long-term HFS by defining non-damaging stimulus parameters with respect to brain integrity. For this purpose, we designed a miniaturized, microcontroller-based, and programmable microstimulator that allows the reliable application of continuous HFS for up to 5 weeks. Chronic HFS (total stimulation time: 3 weeks) of the subthalamic nucleus with up to 100 microA (5.2 nC/phase) through monopolar electrodes comprising activated iridium did not induce significant tissue damage as assessed by various histological techniques (Nissl's, hematoxylin and eosin, Klüver-Barrera, van Gieson's staining, NeuN and GFAP-immunoreactivity). In conclusion, chronic HFS with an implantable stimulator can be successfully applied in small animals.

A cold-response index for the assessment of Raynaud's phenomenon.

BACKGROUND: Quantification of Raynaud's phenomenon (RP) is a prerequisite in the evaluation of novel therapeutic strategies. Fingertip rewarming in response to local cold provocation has been used in many studies but not been systematically validated. We have previously described the time elapsed before 63% of pre-cooling temperature is reached as a RP activity index. OBJECTIVE: A comprehensive evaluation of fingertip rewarming in primary and scleroderma-associated RP. METHODS: We defined a cold-response index (CRI) as the log transformation of the 63% rewarming time upon cold challenge. RESULTS: The CRI shows high intra-individual reproducibility. The mean CRI values were (mean+/-S.D.): 2.4+/-0.3 in controls (n=53) versus 2.7+/-0.3 in RP (n=50, p<0.0001 versus controls), and 2.7+/-0.3 in scleroderma patients (n=46, p<0.0001). In addition, baseline fingertip temperature was also found to be significantly reduced both in primary as well as scleroderma-associated RP. Kinetic analysis of rewarming temperature curves demonstrates that the CRI is independent of individual rewarming patterns. Finally, the CRI decreases significantly upon a single low-level systemic hyperthermia treatment in scleroderma patients (2.68+/-0.28 before versus 2.45+/-0.33 after, p=0.0003), while the extent of cooling remained unchanged, thus demonstrating sensitivity to change. CONCLUSION: Our results provide a solid basis for using the cold-response assay as an endpoint in addition to clinical activity scores in RP treatment trials.