A novel approach to investigate neuronal network activity patterns affected by deep brain stimulation in rats

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Abstract

The establishment of new therapeutic indications for deep brain stimulation (DBS) is ambitiously promoted though the underlying mechanisms remain contested. Here, we report that PET-imaging and subsequent c-Fos-immunostaining in rats constitute a new translational approach to further understand DBS-mechanisms and -effectiveness.

Introduction

In the clinical use, deep brain stimulation (DBS) is an approved or currently tested treatment for neurological or psychiatric disorders (Kuhn et al., 2009). In the preclinical use, DBS also serves as a tool to selectively affect neuronal function of brain regions and associated networks in order to depict (patho-)physiological circuitries (Winter et al., 2008). FDG-PET functional imaging provides an in vivo technique for analyzing consequences of DBS on brain activity patterns and as such has clinically been applied in various diseases. Clinical FDG-PET-studies, however, succumb to the bias entailed by uncontrolled study designs and exclusive investigations of diseased and pre-treated brains. Solely, comparative investigation in naïve, differentially diseased and pre-treated brains may accommodate for the multifactorial interaction of these variables and allow conclusions on distinct network activities altered by DBS and on DBS-mechanisms. To provide a basis for such endeavors, we applied FDG-PET to naïve rats and corroborated in vivo findings with post mortem c-Fos-immunostaining.

Section snippets

Methods and materials

Six male Wistar rats (275–325 g) were treated according to the European Communities Council Directive (86/609/EEC) and after approval of the local ethic committee at HGUGM. Animals were housed in a temperature and humidity controlled vivarium with a normal 12 h light–dark cycle; food (apart from a period of 6 h before PET-scans) and water were available ad libitum. Stereotaxic operations were carried out under sodium pentobarbital anesthesia (60 mg/kg i.p.). Concentric bipolar electrodes with

Results

Cresyl violet staining revealed correct placements of electrodes in all animals with no visible brain damage apart from the electrode tracks toward the STN (Fig. 1). SPM analysis of the FDG-PET study revealed increased metabolic activity in the brainstem, cingulate cortex ipsi- and contralateral as well as in the mediodorsal thalamus, the globus pallidus and the caudate ipsilateral to the stimulation site. Furthermore, we found decreased FDG-uptake in the amygdala, entorhinal and somatosensory

Discussion

The FDG-PET study revealed distinct changes in the naïve rat brain metabolic activity following unilateral STN-DBS. The pattern of altered activity reflects complex modifications of entire functional networks rather than isolated regions. The regional distribution of the altered activity patterns accords with i) network concepts of the STN in the healthy brain (i.e. for review: Joel and Weiner, 1997) as well as ii) clinical imaging studies on the effects of STN-DBS in the diseased brain. The

Role of funding source

Funding for this study was not provided and had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Contributors

CW designed the study, analyzed and interpreted the data and wrote the manuscript. JK performed experimental procedures, managed the literature searches and contributed to writing the manuscript. MS and JP contributed to designing the study, collected and analyzed PET data, contributed to literature searches and writing the manuscript (MS). LG contributed to literature searches and interpretation of the data. AK and MD contributed to designing the study and/or interpreting the data and/or

Conflict of interest

There is no conflict of interest, financial or otherwise, related directly or indirectly to the submitted work for all authors.

Acknowledgments

We thank R. Winter for excellent technical assistance.

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