1. EMBO/EMBL Heidelberg, Germany November 2006 From Genetics to Neuroethics: Is Imaging “Visualizing” Human Thought? Judy Illes, Ph.D. Program in Neuroethics Stanford Center for Biomedical Ethics and Department of Pediatrics, Medical Genetics Stanford University

2. Outline Definitions and key questions Imaging capabilities and state of the art Tackling some key questions Conclusions

3. Neuroethics Adina Roskies, Neuron, 2002 Ethics of neuroscience; neuroscience of ethics William Safire, The Dana Foundation, 2002: “… the examination of what is right and wrong and good and bad about the treatment of, perfection of, or unwelcome invasion of and worrisome manipulation of the human brain […] It deals with our consciousness – our sense of self – and as such is central to our being.” Michael Gazzaniga, The Ethical Brain, 2005: “… the examination of how we want to deal with the social issues of disease, normality, mortality, lifestyle, and the philosophy of living informed by our understanding of underlying brain mechanisms.” Judy Illes, Society for Neuroscience, 2006: A discipline that aligns the exploration and discovery of neurobiological knowledge with human value systems.

4. Key Questions Does imaging visualize human thought? Why is neuroethics interested in the question of thought visualization? How does neuroethics interact with this question?

5. Outline Definition and key questions Imaging capabilities and the state of the art Tackling the key questions Conclusions

6. NEURO- TECHNOLOGY DESCRIPTIONTHERAPEUTIC POTENTIAL Neuro- Engineering; Neuro- nanotechnology Functional interfaces Restore motor function. Relieve major psychiatric illnesses. Enable better drug delivery Neuro- pharmacology; Neuro- nanotechnology Targeted molecules Treat psychiatric illnesses. Improve outcome in acute neurological disease. Slow neurodegeneration. Neurogenetics Neurogenetic tests Inform life planning. Make lifestyle choices. Inform healthcare decisions. Neuroimaging Structural and functional imaging Advance the neurobiology of human cognition. Improve diagnosis of neurological diseases. Plan for and monitor neurosurgical intervention. Frontier Neurotechnology

7. From Antiquity to Present

8. CLINICAL PRACTICE Diagnosis Medical screening and prediction Self referral Safety Technology transfer Therapy Image guided neurosurgery SELF Responsibility Free will Consciousness Reasoning SOCIAL POLICY Lie detection Non-medical screening Surveillance Cognitive enhancement DISSEMINATION Scientists as disseminators as well as citizens of scientific information Self-referral (advertising and marketing) Interfacing with the media and public Data sharing Training the next generation of neuroscientists ImagingNeurosciences Critical Pillars in Neuroethics Mapping the Field, The Dana Foundation, 2002; Illes et al., Neuroscience Imaging,2005

9. EEG: Electrical signals PET and SPECT: Blood flow and metabolic activity MEG: Current sources and sinks

10. Functional MRI Activation Map Increased Neuronal Activity Increased Oxygenated Blood Flow HbO 2 Hb arterialvenous Perform a Task Non-invasive, small clinical risk Behavior Functional Brain Anatomy

11. The fMRI Experiment Stimulus Response AAAABBB -= "A" state imagesActivation map”B" state images Courtesy of Gary Glover, PhD

12. Illes et al., Nat. Neuroscience, 2003 Trends in Research with fMRI

14. “The brain can’t lie: Brain scans reveal how you think and even how you might behave.” --The Guardian, 2003 Racine, Bar-Ilan, Illes, fMRI in the Public Eye, NRN, 2005 Coverage of fMRI in the International Print Press # Year

15. De Martino et al., Science, 2006 Rational Decision-making Moral Judgement Greene et al., Science, 2001 Superior Temporal Sulcus Posterior Cingulate/Precuneus Impersonal Moral Dilemmas Non-moral Dilemmas Personal Moral Dilemmas Brain Activity % change MR signal Medial Frontal Cortex Dorsolateral Prefrontal Cortex (PFC) Emotional/Social Cognition Areas “Cognitive” Areas Personality Canli et al., Science, 2002 Mean Correlation Scatterplot 0 1 2 3 r =.20 p =.24 T Score 0 1 2 3 304050 r =.71 p <.002 T Score Extraversion Score Fear Happy Activation Correlation with Extraversion T Value LR

16. “Eventually we’ll be able to know a lot more about people through understanding more about how their brains work… This is a domain that offers enough that’s novel in the area of information about one’s own persona, that we ought to be thinking very seriously about it.” - Participant 201NS/M/AA

17. Patient Schiff et al., Neurology, 2005 Control Owen et al., Science 2006 A Picture is Worth 100 Words: Disorders of Consciousness

18. “These results confirm that despite fulfilling the clinical criteria for a diagnosis of vegetative state, this patient retained the ability to understand spoken commands and to respond to them through her brain activity rather than through speech or movement. Moreover, her decision to cooperate with the authors by imagining particular tasks when asked to do so represents a clear act of intention.” Owen et al., Science, 2006

19. Structural Fetal MRI (Courtesy of D. Levine, BIDMC)

20. Real-Time fMRI Decoding グー チョキ パー Image Data Feature Vectors Pattern recognition analysis Commands to Robot Brain activity measurement every second by fMRI Robot hand moves Extraction of brain areas related to movement control Pattern Extraction of Brain Activity Pattern Recognition Anterior Posterior RightLeft f ＭＲＩ Paper Scissors Rock Courtesy of M. Kawato and Y. Kamitani, ATR Computational Neurosci. Labs and Masahiro Kumura, Honda Res. Inst., Japan

21. Outline Definitions and key questions Imaging capabilities and state of the art Tackling the key questions Conclusions

22. Does imaging visualize human thought?

23. No: Thought is a composite of cognitive functions involving - information processing, - the disposition of an individual to information, and - individual methods of integrating information into an internal schema and responding to it. Imaging does, however, visualize correlates of the cognitive functions that humans harness to create thought. Visualizing Human Thought

24. Why is neuroethics interested in the question of thought visualization?

25. “Far more than our genomes, our brains are us, collectively defining us as human, and individually marking out the special character of our personal capacities, emotions and convictions.” - Kennedy, Society for Neuroscience, 2003

26. Lessons from ELSI Genetics Discrimination, stigma, coercion Medical privacy Secondary and extended uses of data Distributive justice Commercial potential Public perception

27. Lessons from ELSI Genetics (cont’d) Diagnostic potential Predictive potential  Benefits for life planning  Incidental findings  Risks of false positives and negatives

28. ELSI Unique to Neuroimaging Physiologic variability due to day-to-day variation in physiology, gender Paradigmatic variability due to design issues (protocols for data acquisition, statistics for data interpretation) Interpretative variability due to investigator- subject bias, values and culture True bridging of technique and technology. Imaging genomics may be one of most powerful new tools.

29. ELSI Unique to Neuroimaging (cont’d) Decision and discovery in that brain is both the seat of ethical decision-making and the target of ethics discovery Experience of brain health and brain disease is different than the experience of health and disease of other organ systems  Chimeras  Tissue engineering

30. Source of Neuroethics Interest in Neuroimaging Unique neuro ethical, legal and social implications.

31. How does neuroethics interact with the question of thought visualization with imaging?

32. Interaction of Neuroethics and Neuroimaging Identify pragmatic starting points for imaging and alternatives for resolution of difficult ethical challenges through a negotiated scientific-social process Empower, not encumber the scientific process

33. Integration Evaluation Discovery Ethics analysis Tools Discovery Ethics analysis Discovery/ Pre-discovery Commercialization Stakeholder engagementRegen. Med., Mol. Imaging Incidental findings Surrogate and bio markers 2006 2001

34. Illes, Kirschen, Edwards, Stanford et al., SfN 2005 and based on Science 2006 Research protocol anticipates incidental findings A IRB protocol & informed consent articulate plan for managing incidental findings Incidental findings are managed Subject option to decline to be informed Incidental findings are not managed B Research Study Principal Investigator or Designee Physician qualified to read scans Incidental finding is detected All scans reviewed C Principal Investigator or Designee Research subject or surrogate is encouraged to initiate clinical follow-up Incidental finding is evaluated Incidental finding is communicated No action taken D

35. Interaction of Neuroethics and Neuroimaging (cont’d) Proactively engage deliberation from multiple stakeholders at multiple junctures Improve science literacy and communication

36. Scientists and scholars seeking standards of practice and a common voice and language Critical voice of caregivers, stakeholders, and the public in matters of neuroscience discovery Knowledge Cycle Engaged world press dedicated to a close partnership between science and journalism

37. International Neuroethics

38. International Neuroethics Network an arm of the Neuroethics Society To foster international collaboration in neuroethics through the identification of common priorities and joint funding opportunities.

39. Outline Definitions and key questions Imaging capabilities and the state-of-the- art Tackling the key questions Conclusions

41. There are compelling reasons for anticipating neuroethical issues at the bench, at the bedside, and in the public domain.

42. Adapted from Illes, Racine, Kirschen, in Neuroethics: Defining the Issues in Theory, Practice and Policy, Oxford University Press, 2006 Expanded Roles in Neuroscience and Neurotechnology

43. Roles for Neuroethicists Draw upon history of bioethics, genetics and other disciplines to inform the unique challenges that are raised by the opportunity to study and probe the brain. Keep up with the pulse of neuroscience and pursue an ethically coherent agenda based on the needs of the neuroscience community and its interface with society. Bridge cultural, linguistic and disciplinary barriers Develop capacity on an internationally relevant scale. Develop research, resource and reference tools that are flexible, practical and useful.

45. Bruce Arnow Vivian Chin Mildred Cho Pamela S.-Desmond Ray De Vries Margaret Eaton Martha Farah Agnieszka Jaworska Gary Glover Mike Grecius Henry T. (Hank) Greely Katrina Karkazis Matthew P. Kirschen Sophia Lombera Allyson Mackey Gladys Maestre David Magnus Eric Racine Allyson Rosen Jennifer Singh Jane Stewart HFM Van der Loos Adri, Kiah Van der Loos RO1 Advisory Board Many others collaborators NIH RO1 #NS 045831 & #CSI 8-17-04 The National Science Foundation The Dana Foundation The Greenwall Foundation The Henry J. Kaiser Foundation The New York Academy of Sciences The Children’s Health Initiative at Stanford Acknowledgements http://neurohttp://neuroethics.stanford.edu