P 137 An ethical perspective on deep brain stimulation as an investigational treatment for Alzheimer’s disease

Abstract

Question Deep brain stimulation (DBS) has been investigated as intervention to slow down the progression of Alzheimer’s disease (AD). Although there is urgent need for improvement of AD treatments, any novel interventions has to fulfill high ethical requirements to protect participants’ safety. In particular, a solid base of prior empirical evidence is required. However, what exactly constitutes sufficient evidence that outweighs the risk of investigational research is a matter of discussion. Since the rationale of DBS for AD assumes that AD is a “brain circuit pathology” it is relevant for both clinical neurophysiology and functional brain imaging. While the question “what degree of empirical evidence supports the given hypothesis?” has scientific answer, the question “when is evidence sufficient to warrant trials in humans?” is a normative one and requires ethical justification in addition to state-of-the-art scientific knowledge. Methods We assessed DBS trials ( https://clinicaltrials.gov/ ) enrolling patients with AD and conducted a comprehensive literature search ( https://www.ncbi.nlm.nih.gov/pubmed/ ). Our first aim was to identify the scientific rationale for the hypothesis of DBS as intervention for AD. The second aim was to ethically evaluate this rationale on the basis of normative standards as established in pharmacological research. Results We identified three clinical trials (total n = 56) and assessed comments, letters to editors and reviews. One trial did not make failure to provide informed consent an exclusion criterion (consent by caregivers was sufficient). We also found wide-ranging epistemic uncertainties involved in the rationale that go beyond the conventional risk of clinical trials on investigational treatments. These range from the adequacy of different neuroanatomical targets, an unrefined analogy to DBS for Parkinson disease, to diverse hypothetical mechanisms of action and the question of clinically relevance of cut-offs for outcome measures like “pathological brain circuits”. In sum, we found many open questions amenable to neuroimaging or translational research, but also that the respective clinical trials started before these questions were thoroughly examined and before the scientific rationale was proven in rodents modelling the specific pathology of AD. Conclusion There is a continuum from therapeutic protectionism to experimental adventurism. Protectionism impedes scientific progress and hampers the development of new treatment options. However, uncertainties can also pose severe risks to participants. DBS as an investigational intervention for AD did not adhere to the same ethical requirements that are legally binding for pharmacological research in Germany. In particular, whether the evidence for the scientific rationale is sufficiently robust is questionable. DBS involves invasive neurosurgery and belongs to Class III of medical devices with the highest risk (European Parliament), but is less strictly regulated than pharmaceutical agents (largely voluntary agreement among industrial stakeholders and neurosurgeons is sufficient). Ethical evaluation hinges on empirical progress and technical innovation. It is therefore imperative to promote research in clinical neurophysiology and brain imaging with the clear research objective to find robust criteria for clinical relevance of pathological brain circuit aberrations in AD.