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Animal Models and Animal Experimentation in the Development of Deep Brain Stimulation: From a Specific Controversy to a Multidimensional Debate.

ABSTRACT: In this article, we explore a specific controversy about animal experimentation and animal models in the recent history of deep brain stimulation (DBS), and we question its ramifications. DBS development intertwines clinical practice with fundamental research and stands at the crossroads of multiple legacies. We take up the various issues and controversies embedded in this rarely addressed dispute, from a standpoint that combines socio-anthropological and legal aspects. Our starting point is a debate on the role of animal experimentation in the development of DBS between Jarrod Bailey, a researcher promoting the abolition of animal experimentation, and Alim Louis Benabid, Marwan Hariz, and Mahlon DeLong, three key figures in the area of DBS and neuroscience. By clarifying the positions of the different protagonists and retracing the issues raised in these discussions, our objective is to show how this specific debate has extended from its initial space and how it provides an object of study with heuristic scope. We first present this partially polemic discussion about the history of DBS, and its link with a more general debate on the validity and use of animal models and the need for animal experiments. Then, we raise the issue of the relations and interactions between experiments on animals and on humans in the logics of biomedical innovation. The third step is to situate the discussion within the wider framework of opposition towards animal experimentation and the promotion of animal' rights. Finally, combining these interweaved issues, possible implications emerge regarding the future of DBS. We show that behind these several controversies lie the question of translational research and the model of medicine upheld by DBS. We describe how the technology contributes to blurring the lines between research (fundamental, preclinical and clinical research) and care, as well as between humans and animals as substrates and objects of knowledge. The dynamics of DBS future development might then become a point of convergence for neuroscientists and animal rights defenders' interests.

SUBMITTER: Desmoulin-Canselier S

PROVIDER: S-EPMC6548025 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Animal Models and Animal Experimentation in the Development of Deep Brain Stimulation: From a Specific Controversy to a Multidimensional Debate.

Desmoulin-Canselier Sonia S Moutaud Baptiste B

Frontiers in neuroanatomy 20190528

In this article, we explore a specific controversy about animal experimentation and animal models in the recent history of deep brain stimulation (DBS), and we question its ramifications. DBS development intertwines clinical practice with fundamental research and stands at the crossroads of multiple legacies. We take up the various issues and controversies embedded in this rarely addressed dispute, from a standpoint that combines socio-anthropological and legal aspects. Our starting point is a d ...[more]

PMID: 31191261

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Project description:Medical imaging has played a major role in defining the general anatomical targets for deep brain stimulation (DBS) therapies. However, specifics on the underlying brain circuitry that is directly modulated by DBS electric fields remain relatively undefined. Detailed biophysical modeling of DBS provides an approach to quantify the theoretical responses to stimulation at the cellular level, and has established a key role for axonal activation in the therapeutic mechanisms of DBS. Estimates of DBS-induced axonal activation can then be coupled with advances in defining the structural connectome of the human brain to provide insight into the modulated brain circuitry and possible correlations with clinical outcomes. These pathway-activation models (PAMs) represent powerful tools for DBS research, but the theoretical predictions are highly dependent upon the underlying assumptions of the particular modeling strategy used to create the PAM. In general, three types of PAMs are used to estimate activation: 1) field-cable (FC) models, 2) driving force (DF) models, and 3) volume of tissue activated (VTA) models. FC models represent the "gold standard" for analysis but at the cost of extreme technical demands and computational resources. Consequently, DF and VTA PAMs, derived from simplified FC models, are typically used in clinical research studies, but the relative accuracy of these implementations is unknown. Therefore, we performed a head-to-head comparison of the different PAMs, specifically evaluating DBS of three different axonal pathways in the subthalamic region. The DF PAM was markedly more accurate than the VTA PAMs, but none of these simplified models were able to match the results of the patient-specific FC PAM across all pathways and combinations of stimulus parameters. These results highlight the limitations of using simplified predictors to estimate axonal stimulation and emphasize the need for novel algorithms that are both biophysically realistic and computationally simple.

Project description:BackgroundDeep brain stimulation (DBS) as investigational intervention for symptomatic relief from Alzheimer disease (AD) has generated big expectations. Our aim is to discuss the ethical justification of this research agenda by examining the underlying research rationale as well as potential methodological pitfalls. The shortcomings we address are of high ethical importance because only scientifically valid research has the potential to be ethical.MethodWe performed a systematic search on MEDLINE and EMBASE. We included 166 publications about DBS for AD into the analysis of research rationale, risks and ethical aspects. Fifty-eight patients were reported in peer-reviewed journals with very mixed results. A grey literature search revealed hints for 75 yet to be published, potentially enrolled patients.ResultsThe results of our systematic review indicate methodological shortcomings in the literature that are both scientific and ethical in nature. According to our analysis, research with human subjects was performed before decisive preclinical research was published examining the specific research question at stake. We also raise the concern that conclusions on the potential safety and efficacy have been reported in the literature that seem premature given the design of the feasibility studies from which they were drawn. In addition, some publications report that DBS for AD was performed without written informed consent from some patients, but from surrogates only. Furthermore, registered ongoing trials plan to enroll severely demented patients. We provide reasons that this would violate Art. 28 of the Declaration of Helsinki, because DBS for AD involves more than minimal risks and burdens, and because its efficacy and safety are not yet empirically established to be likely.ConclusionBased on our empirical analysis, we argue that clinical research on interventions of risk class III (Food and Drug Administration and European Medicines Agency) should not be exploratory but grounded on sound, preclinically tested, and disease-specific a posteriori hypotheses. This also applies to DBS for dementia as long as therapeutic benefits are uncertain, and especially when research subjects with cognitive deficits are involved, who may foreseeably progress to full incapacity to provide informed consent during the required follow-up period.

Dataset Information

Animal Models and Animal Experimentation in the Development of Deep Brain Stimulation: From a Specific Controversy to a Multidimensional Debate.

Publications

Animal Models and Animal Experimentation in the Development of Deep Brain Stimulation: From a Specific Controversy to a Multidimensional Debate.

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