Table 2 Ethical issues in DBS for AD research with human subjects. Answering these questions is crucial for deciding whether some novel intervention is ready for clinical testing

Risk of compromised scientific validity

Threats to internal validity:

Is the heterogeneity in small samples regarding age, gender, disease stage, brain atrophy, AD pathology and potential confounding variables to large? Are clear criteria to evaluate study endpoints predefined?

Insufficient statistical power:

Is the sample large enough to validly conclude that there are no significant adverse effects when there are none observed (type II error)? Is the sample size sufficient to draw reliable inferences?

Open questions:

Which is the best brain target? What are effective stimulation parameters? What is the hypothetical mechanism of action? What are potential disease-specific challenges?

Risk of insufficient feasibility

Electrode insertion:

Is it technically feasible to reach the target with sufficient precision given the brain atrophy and vascular alterations or trajectory required?

Recruitment:

Is the study feasible and cost-effective enough to recruit a sufficient sample for adequately powered phase I and II clinical trials?

Stimulation:

Is the range of therapeutically effective stimulation parameters limited by potential side effects?

Risk of therapeutic misconception

Regulation:

Are patients aware of the research context or is it masked as therapeutic “compassionate use” or “clinical innovation” instead of nontherapeutic research e.g. under FDA’s Investigational Device Exemption label?

Interpretation of results:

Are published results appropriately presented, avoiding reference to any speculative benefits that may result in unrealistic expectations? Are alternative explanations properly discussed? Are conclusions drawn in scientific valid ways?

Media hype:

Is early media coverage disseminating exaggerated benefit expectations to lay people and potential participants while the evidence on any therapeutic effect is still speculative?

Risk of undermined informed consent

Lack of information on efficacy and safety:

Are there concordant, valid and disease-specific preclinical findings replicated in different animal models and species?

Mild, moderate to severe cognitive deficits:

Are participants able to properly understand the potential risk of innovative nontherapeutic trials without established direct benefit?

Progressive loss of autonomy:

Given the foreseeable incapacity to consent, which provisions are installed for the lifelong follow-up period (e.g. adaption of stimulation parameters, hardware exchange)?