EMBO/EMBLHeidelberg, Germany

November 2006

From Genetics to Neuroethics:Is Imaging “Visualizing”

Human Thought?

Judy Illes, Ph.D.

Program in Neuroethics Stanford Center for Biomedical Ethics

andDepartment of Pediatrics, Medical Genetics

Stanford University

Outline

• Definitions and key questions

• Imaging capabilities and state of the art

• Tackling some key questions

• Conclusions

NeuroethicsAdina 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.

Key Questions

Does imaging visualize human thought?

Why is neuroethics interested in the question of thought visualization?

How does neuroethics interact with this question?

Outline

• Definition and key questions

• Imaging capabilities and the state of the art

• Tackling the key questions

• Conclusions

NEURO-TECHNOLOGY DESCRIPTION THERAPEUTIC 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 testsInform life planning.Make lifestyle choices.Inform healthcare decisions.

Neuroimaging Structural and functional imaging

Advance the neurobiology ofhuman cognition. Improve diagnosis of neurological diseases. Plan for and monitor neurosurgical intervention.

Frontier Neurotechnology

From Antiquity to Present

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

Imaging Imaging

NeurosciencesNeurosciences

Critical Pillars in Neuroethics

Mapping the Field, The Dana Foundation, 2002; Illes et al., Neuroscience Imaging,2005

EEG: Electrical signals

PET and SPECT:Blood flow and metabolic activity

MEG: Current sources and sinks

Functional MRI

ActivationMap

IncreasedNeuronalActivity

IncreasedOxygenatedBlood Flow

HbO2 Hbarterial venous

Performa Task

Non-invasive, small clinical risk

BehaviorFunctional

Brain Anatomy

The fMRI Experiment

Stimulus

Response

A A A AB B B

- =

"A" state images Activation map”B" state images

Courtesy of Gary Glover, PhD

Year

1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001

% o

f A

rtic

les

0.0

20.0

40.0

60.0

80.0

100.0 motor sensory1 sensory2 cognition1 cognition2 emotion

Illes et al., Nat. Neuroscience, 2003

Trends in Research with fMRI

Trends in Research with fMRI

“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

0

5

10

15

20

25

30

35

40

45

92 93 94 95 96 97 98 99 0 1 2 3 4*

Coverage of fMRI in theInternational Print Press

#

Year

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

Bra

in A

ctiv

ity%

ch

ang

e M

R s

igna

l

Medial Frontal Cortex

Dorsolateral Prefrontal Cortex (PFC)

Emotional/Social Cognition Areas

“Cognitive” Areas

Personality

Canli et al., Science, 2002

Mean Correlation

Scatterplot

-1

0

1

2

3

r = .20

p = .24

T S

core

-1

0

1

2

3

30 40 50

r = .71

p < .002

T S

core

Extraversion Score

Fear

Happy

Activation Correlation with Extraversion

T Value

L R

“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

Patient

Schiff et al., Neurology, 2005

Control

Owen et al., Science 2006

A Picture is Worth 100 Words: Disorders of Consciousness

“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

Structural Fetal MRI

(Courtesy of D. Levine, BIDMC)

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

PaperScissors

Rock

Courtesy of M. Kawato and Y. Kamitani, ATR Computational Neurosci. Labs and Masahiro Kumura, Honda Res. Inst., Japan

Outline

• Definitions and key questions

• Imaging capabilities and state of the art

• Tackling the key questions

• Conclusions

Does imaging visualize human thought?

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

Why is neuroethics interested in the question of thought visualization?

“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

Lessons from ELSI Genetics

• Discrimination, stigma, coercion

• Medical privacy

• Secondary and extended uses of data

• Distributive justice

• Commercial potential

• Public perception

Lessons from ELSI Genetics(cont’d)

• Diagnostic potential

• Predictive potential

Benefits for life planning Incidental findings Risks of false positives and negatives

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.

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

Source of Neuroethics Interest in Neuroimaging

Unique neuro ethical, legal and social implications.

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

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

IntegrationEvaluation

DiscoveryEthics analysisTools

DiscoveryEthics analysis

Discovery/Pre-discovery

Commercialization Stakeholder engagement Regen. Med., Mol. Imaging

Incidental findings

Surrogate and bio markers

20062001

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 findingsIRB protocol & informed consent articulate plan for managing incidental findings

Incidental findings are managed

Subjectoption 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 detectedAll scansreviewed

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

Interaction of Neuroethics and Neuroimaging

(cont’d)

Proactively engage deliberation from multiple stakeholders at multiple junctures

Improve science literacy and communication

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

International Neuroethics

International Neuroethics Networkan arm of the

Neuroethics Society

To foster international collaboration in neuroethics through the identification of common priorities and joint funding opportunities.

Outline

• Definitions and key questions

• Imaging capabilities and the state-of-the-

art

• Tackling the key questions

• Conclusions

Conclusions

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

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

Responsiveness Pursue a duty of care within the research setting and extended roles outside

Democratic and civic involvement

Participate in a partnership that promotes public understanding of the brain, and democratic debate

Prospective responsibility Proactively manage real and imagined future uses of neurotechnology

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.

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 8-17-04The National Science FoundationThe Dana FoundationThe Greenwall FoundationThe Henry J. Kaiser FoundationThe New York Academy of SciencesThe Children’s Health Initiative at Stanford

Acknowledgements

http://neuroethics.stanford.edu