Advances in Neurotechnology Acknowledgements

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Advances in Neurotechnology Balancing on the Tightrope of Discovery, Treatment, and Translation for Neurocognition

Judy Illes, CM, PHD Canada Research Chair in Neuroethics Professor of Neurology Director, Neuroethics Canada University of British Columbia International Neuropsychological Society New York City, New York February 2019

No Financial Disclosures

Acknowledgements

The team at Neuroethics Canada, distinguished advisors, and collaborators. All our participants who share their time and experiences with us.

AHS Calgary Neuromodulation Program

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Journey Today First principles for neuroethics Psychiatric neurosurgery: To the present from the past Empirical work: Neuropsychiatry, neurocognition 1. Media coverage and public perspectives 2. Patents and brain regions 3. Neurowearables Wrap-up and a call to action

First Principles

For the sciences of the central nervous system to be applied for health benefit and social good, it is critical to identify and address ethics challenges at their earliest stages. It is always a good time to do so. It is never too late.

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Ethics of neuroscience Privacy, autonomy, consent, dignity, fairness, access, beneficence, confidentiality, justice Evidence, Actionability Impact Values Neuroscience of mind

Adapted from Murphy and Illes, OHBM, 2007

Lessons, Progress

Illes and Bird, Trends in Neuroscience, Updated 2018 [Marianne Bacani]

Ethics Frameworks

Utilitarianism Deontology (outcomes) (rights)

Principlism Communitarianism (rules) (social order)

Ethics of care Health Pragmatism (relationships) ethics (science)

Practice-based approach that relies on empirical evidence

Slide: Dr. Julie Robillard [2015]

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Pragmatism and Neuroethics

Importance of empirical analyses over a priori moral principles Proactive, solution-oriented inquiry Understanding ethical behaviour in the context of real world circumstances Emphasis on pluralism and multidirectional, inclusive deliberations

In Pursuit of Brain Health

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The Ancients

Extraction of the Stone of Madness Hieronymus Bosch (c.1488–1516) Trephanation: 18th Century

The Opportunists

www.neuroethicscanada.ca The Visionaries

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The Well-Intentioned

Into the Present Radiosurgery Thermal or radiofrequency ablation Cingulotomy Capsulotomy Subcaudate tractotomy Limbic leucotomy Deep Brain Stimulation Vagal Nerve Stimulation (DBS)

Precision, Safety, Ethics

Stereotactic and Institutional Review image-guidance

research.ucr.edu

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Registered Clinical Trials

# 20 V ag al Ne rve Stim ula tio n 15 Radiosurgery Radiofrequency

10 F ocu sed Ult ra sou nd Dee p Brain Stimu latio n

OCD PTSD Bi pol ar DementiaAddict ion Anorexia Depression Schizophrenia Adapted from Cabrera et al., 2018

Regional DBS Clinical Trials

25 # 20

US A China Ital y Israe l Sp ai n Brazil Fran ce Canada En gl an d Sw ed e n Ge rma ny Belgium Denma rk Sw itzerla nd Add ictio n Ano re xia Bipolar dis order De mentia De pr essio n Ob es ity Ob se ssive com pu lsive dis ord er Pain PTSD Sch izop hr enia

Journey Today First principles for neuroethics Psychiatric neurosurgery: To the present from the past Empirical Work: Neuropsychiatry, neurocognition 1. Media coverage and public perspectives 2. Patents and brain regions 3. Neurowearables Wrap-up and a call to action

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. Media Coverage

Mass media circulates arguments and images that widely shape perceptions and attitudes of the public and policy- makers about biotechnology and new medical procedures.

Public Perceptions and Attitudes Multinational consortium Cross-cultural neuroethics

Cabrera et al., Acta Neurochirurgica, 2017

Headlines

Analytic Methods

Online media search of newspapers and magazines from 1960 to 2015. Content analysis of articles to characterize the range of ethical, social, political and scientific issues in the sample.

N= 201 N=156 N=160

www.neuroethicscanada.ca

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Search Terms

Intervention Terms Indication Terms

• Psychosurgery • Psychiatry • Psychiatric Neurosurgery • OCD • Ablative Surgery • Depression • Deep Brain Stimulation • Schizophrenia • Implantable Devices • Anorexia • Vagal Nerve Stimulation • Anxiety • Optogenetics • Addiction • Radiosurgery • Autism/ADHD • Focused Ultrasound • PTSD • Stem Cells • Obesity • Alzheimer's

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Reporting Across Time

35 N=517 30

0 1960 1974 1975 1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

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Disorders 60%

50%

40%

30%

20%

10%

OCD PTSD Pain Anx iety Dem enti a Addi ction Depressi on Schizophrenia Eating Disorders

Violence and Aggression Other Psychiatric Disorders

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Tone by Region

60% ** 50%

40% ** ** 30%

20%

10% * p < 0.05 ** p < 0.005 0% Positive Balanced Neutral Negative

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Regulatory Discourse

The Food and Drug Administration last week approved deep brain stimulation’ for the treatment of intractable obsessive-compulsive disorder, or OCD.

Dr. Joseph Fins… thinks the Food and Drug Administration may have acted too soon in granting a "humanitarian device exemption" to deep brain stimulation for severe obsessive-compulsive disorder.

Ethics Discourse

How could the mentally ill be competent enough to provide free and informed consent? Would their thinking not be clouded by the very fact they are depressed?

Solving the mystery of the brain Another question has to do with consent. Preventing competent patients in psychiatric facilities from consenting to psychosurgery is based on the assumption that the environment of a psychiatric facility impairs an individual's ability to understand the subject matter being discussed and the consequences of the act for which consent is needed... www.neuroethicscanada.ca

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Ethics Discourse

Another question is: Do we remain the same people, if our brains are routinely energized electrically? This is unclear, however, studies reveal significant personality changes in research subjects.

In the 1930s, there were reservations about electroshock therapy. Today, many reject deep brain stimulation for people with psychiatric illness as an intervention into the brain with unforeseeable consequences on personality.

Public Perspectives Reader Responses 1192 total reader comments to 115 articles (2006-2017)

After manual curation for relevance and coherence:

N= 177 N=114 N=167

Cabrera et al., Acta Neurochirurgica, 2018

Reader Responses

100%

90%

80%

70%

60%

50% * 40%

30% *

20%

10% Total Comments (% of intervention) of (% Comments Total 0% DBS (N=2 91 ) Optogenetics Contemporary Historical VNS (N = 43) (N =103 ) Ablative ( N=2 7) Ablative ( N=1 63) * p<.002 Optim ism Cautionary Realism Pessim ism Controversial

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Reader Tone

100% 90% 80% 70% ** ***** 60% ** ***** 50% 40% 30% 20% 10%

Total Comments (% of intervention) of (% Comments Total 0% DBS (N=2 91 ) Optogenetics Contemporary Historical Abla tive VNS (N = 48) *** p<.001 (N =103 ) Ablative ( N=2 7) (N =163 ) ** p<.001 Positive Balanced Negative Neutral

Public Perspectives

Focus Groups Adult, English, French, German and Spanish speaking unaffected members of the lay public across 8 focus groups

N= 14 N=22 N=12

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Focus [Identity, Personality, Authenticity] [Informed Consent] [Cost][Optimism] Group [Procedural Risk][Last Resort]

Themes [Stigma][Regulation] [Scientific Evidence] [Medicalization]

[Desperation] [Enhancement] Preliminary [Historical Comparison] [Optimism for Research] Results [Disadvantages] [Pessimism] [Effectiveness] [Cautionary Realism] [Expected Outcomes] [Collateral Events] [Justice] [Control]

Cabrera et al., in preparation

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Summary

Media focus on DBS and depression Regional variations for tone, and ethics, regulatory, philosophical issues Aversion to ablative procedures Cautionary carry-over from the past

Patents Involving the Brain

Massive capital 50 investment over the 45 40 N=279 past decades: decade 35 of the Brain, BRAIN 30 initiative, DARPA 25 funding 20 15 New actors: Google, 10 Neuralink, Facebook 5 0 19 76 19 78 19 80 19 82 19 84 19 86 19 88 19 90 19 92 19 94 19 96 19 98 20 00 20 02 20 04 20 06 20 08 20 10 20 12 20 14 20 16

US Registered Patents

Updated, Roskams-Edris et al., Nature Biotechnology, 2017

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Ethicolegal Analysis

Literature search: Google Scholar, PubMed, WestLaw, and LexusNexis

Keywords: Brain regions, disorders, and technologies

Legal status of medical method patents

Conventional Method Patents

“…any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefore…” Title 35 USC, s. 101

Unconventional Methods Patents “The method of claim 1 … wherein said stimulation site comprises at least one or more of a temporal lobe, cerebral ventricle, structure within a limbic system, pituitary gland, brainstem, and cerebral cortex” • Patent US 9327069

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Patent Characteristics

Disorders (N) Brain Regions (N) Technologies (N)

Parkinsons, Electrical Thalamus (40) movement disorders (24) stimulation (25)

Substantia Magnetic Addiction (7) nigra (17) stimulation (11) Basal Depression (27) Infusion (30) ganglia (14)

Anxiety (18) Caudate (15) MRI, fMRI (6)

Eating Cingulate (25) EEG (16) disorders (7)

Further Patent Analysis

Assignment History Lens (lens.org) and USPTO (assignment.uspto.gov) databases

Patent Detail Security, home jurisdictions of inventors and applicants, expiry of patents, and confirmatory licenses with government organizations

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Sectors

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 University, Hospital, or Non-Profit Physicians and Researchers Indust ry

Assignments and Ownership

51 of the 279 patents in the sample had been assigned

Sector # of Patents % of Total Patents

Industry 104 37.3%

Academia, Hospital, 18 6.5% and Non-Profit

Physicians and 9 3.2% Researchers

Permissibility of Patents Many jurisdictions, including Canada, do not allow List of non-US jurisdictions with US medical method patents patents Finland May interfere with the “skill Germany and judgment” of physicians Israel if they are forced to consider infringement when making South Korea treatment decisions. France Portugal Japan Australia Denmark Canada

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Neuroethical Considerations Patent-first, ask-questions-later Protecting rights prior to reliable proof of scientific validity. Tensions of profit and benefit Profitability > benefit Security Ownership by companies that do not have an interest in promoting health and may provide a vehicle for patent trolls.

Neurowearables

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Devices and Claims

Stimulating 45% Recording 166 Total Claims (N=19) 55% 19 Unique Claims (N=23)

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Content of Claims

5 overarching categories Safety “Proven to relieve stress, anxious Functional thoughts, and improve sleep Applications Health quality”

“Control machines with the power of your mind and make science Wellness fiction a reality today.” Enhancement General wellness Memory Sleep quality "ENHANCE LIFE!" General cognition Relieve stress or Concentration or anxiety symptoms Focus Augmented meditation Frequency Efficiency or Productivity Rank Claim or relaxation (Total N = 166) Learning or Training Self-awareness Physical Performance Self-regulation Improvements in 1 19 Self-regulation neurofeedback mood 2 General wellness 17 3 Sleep quality 16 4 Concentration/focus 15 5 General cognition 13

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Evidence 33/42 (79%) companies cited resources to support their claims 7/42 (16%) companies cited peer-reviewed research specifically pertaining to their device

Relevant and Peer Other Reviewed 21% Support 79% No Support Testimonials Cited Cited Broken links 79% Irrelevant peer-reviewed 21% Company/In-house Non peer-reviewed General science references

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Declared Risks and Warnings

Few made explicit safety On website? claims “The headset safely measures brainwave signals and monitors the attention levels” Yes 47 < 50% presented risks and No No Yes% 53% 53% 47% warnings (N=22) (N=20) “May cause minor side effects (headache, dizziness or skin irritation at the electrode sites) in 1% of users.”

“Extra care is required with hydrogel electrodes to prevent the risk of skin burns."

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Target Consumer Groups

12 Targeted Target Consumer Group Explicit Implicit consumer groups All Potential Users 33 18 Q: "Can I use the Athletes/Trainers 15 5 Musicians 2 1 devices on my pets?” Students 6 5 Researchers 2 8 A: “Yes, you can. The Marketers 1 1 Gamers 1 1 Pocket Miracle Providers/Professionals 2 9 (www.pocketmiracle.c Employees/Employers 8 6 om) works best” People with Medical Conditions 4 7 Other (pets, monks, military) 3 1 Indeterminable/None Stated 6 15

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Neuroethics, Neuropsychologists History tends to repeat itself; human pursuit of brain health through brain technology is unchanged Three empirical studies: 1. Invasive approaches to mental health disorders are back. The public is exposed to neurotechnology through the media. The media is positive; the public is cautious. 2. Patent protections are worrisome. 3. Current evidence does not support wide ranging claims of benefit of the non-invasives.

A Call to Action

Be informed. The modern world of neurotechnology is moving at a breathtaking pace. Uphold the highest ethics standards for communicating about advanced neurotechnology. Promote professional self-regulation over external regulatory oversight. Support justice for patients over market advantage.

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