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Transcranial Brain Stimulation: Science and Ethics

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Better Living Through Brain Stimulation: The Promise and Peril of the TMS and tDCS in the age of cosmetic neurology Roy Hamilton, MD, MS Laboratory for Cognition and Neural Stimulation University of Pennsylvania
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Page 1: Transcranial Brain Stimulation: Science and Ethics

Better Living Through �Brain Stimulation:�The Promise and Peril of the TMS and tDCS in the age of cosmetic neurology�

Roy Hamilton, MD, MS

Laboratory for Cognition and Neural Stimulation

University of Pennsylvania

Page 2: Transcranial Brain Stimulation: Science and Ethics

Topics •  The Primer

–  TMS

–  tDCS

•  The Promise –  Cognitive enhancement

–  Mood enhancement

–  Manipulation of social cognition

•  The Peril

–  Safety –  Character

–  Justice

–  Autonomy

Page 3: Transcranial Brain Stimulation: Science and Ethics

•  Based on Faraday Principle

•  Rapidly fluxing magnetic field

•  Induces current in underlying cortex

•  Noninvasive •  Permits focal

manipulation of cortical activity

Transcranial Magnetic Stimulation (TMS)

Page 4: Transcranial Brain Stimulation: Science and Ethics

Administration of TMS

Page 5: Transcranial Brain Stimulation: Science and Ethics

Transcranial Direct Current Stimulation (tDCS)

•  Application of weak (1-2 mA) electrical current to cortical neurons

•  Neurons respond to static (DC) electrical fields by altering firing rates.

•  Anodal or cathodal stimulation have different effects.

•  Safe, noninvasive, and painless

George & Aston-Jones, Neuropsychopharmacology, 2010

Page 6: Transcranial Brain Stimulation: Science and Ethics

The ‘thoughtspace’ of noninvasive brain stimulation

Walsh & Cowey, 2000

Categories of Manipulation TMS •  Neurostimulation/depolarization •  Neuromodulation

tDCS •  Neuromodulation

Effects of Manipulation TMS and tDCS •  Inhibition •  Facilitation

Page 7: Transcranial Brain Stimulation: Science and Ethics

Virtual lesions elucidate cortical function •  Avoids confounds from

pathological brains

•  Acute studies minimize

plastic reorganization

•  Repeated studies in the

same subject

•  Multiple subjects with same

experimental manipulation; directional hypotheses

Page 8: Transcranial Brain Stimulation: Science and Ethics

TMS tDCS Temporal resolution Milliseconds Minutes

Spatial resolution Millimeters Centimeters

Duration of effects Weeks to months after repeated sessions, possibly longer

Not yet well characterized

Ease of localization High spatial precision requires an MRI-guided stereotactic system. Less precise localization possible using the 10-20 system or other scalp measurements.

Large area of effect allows for localization using 10-20 system or other scalp measurements.

Safety Safe when applied within established safety guidelines. The additional risk is conferred by prior stroke is not fully known.

No lasting adverse effects reported within currently used stimulation parameters. Additional risk conferred by prior stroke is not fully known.

Patient Discomfort Mild muscle twitches during stimulation uncomfortable to some subjects. Transient mild headaches reported. Rare cases of dental pain reported.

Itchiness and occasional mild burning sensation has been reported under scalp electrodes. Usually well tolerated.

Ability to Use Sham Control Condition

Sham often readily distinguished from real stimulation. Newer sham coils may simulate stimulation more realistically.

Realistic sham stimulation is easily administered by briefly delivering current.

Portability Typical setup includes TMS unit, stimulation coils, devices for securing the subject and coil position, and hardware for MRI-guided localization.

Highly portable. Can be used in any traditional experimental or clinical setting.

Cost Relatively expensive: Approximately $100,000 - $150,000 for TMS unit, coils, and MRI-guided localization system.

Very cost-effective: Approximately $10,000 for tDCS unit.

Page 9: Transcranial Brain Stimulation: Science and Ethics

Cognition TMS and tDCS have been used to transiently improve cognition across multiple domains…

•  Language •  Learning & Memory •  Spatial Attention •  Problem-solving •  “Savant Skills”

Page 10: Transcranial Brain Stimulation: Science and Ethics

Language

De Vries et al., JOCN, 2009

•  TMS & tDCS: Faster naming (Mottaghy et al., 1999; Sparing

et al.,2008)

•  tDCS: Improved acquisition of novel names

(Flöel et al., 2009)

•  tDCS: Better acquisition of grammar

(de Vries et al, 2009)

•  tDCS: Increased verbal fluency

(Iyer et al 2005)

Page 11: Transcranial Brain Stimulation: Science and Ethics

Learning and Memory •  TMS: Enhances

phonological memory (Kirschen et al., 2006)

•  TMS & tDCS: Motor skill learning

(e.g. Nitsche et al., 203; Kobayahi et al., 2009; Kim et al, 2004; Vines et al., 2006)

•  tDCS: Improves verbal working memory

(Fregni et al., 2005) Fregni et al., 2005

Page 12: Transcranial Brain Stimulation: Science and Ethics

Spatial Attention

Hildetag et al., 2001

•  600 pulses of 1 Hz rTMS for over right and left parietal cortex

•  Induced extinction for contralateral targets

•  Improvement in ipsilateral target detection.

•  Supports model of interhemispheric competition in visuospatial processing.

Page 13: Transcranial Brain Stimulation: Science and Ethics

Problem Solving

Cerruti et al., 2009

•  Identify common linguistic association between three words: e.g. scan, wash, child

•  Associations to creative thought, executive function and general intelligence.

•  “Aha” moment •  Anodal tDCS of left

DLPFC associated with improved performance

Remote association test (RAT)

Page 14: Transcranial Brain Stimulation: Science and Ethics

“Savant Skills”

•  Left anterior temporal lobe low-frequency TMS

•  Improved drawing skills (4/11 subjects)

•  Improved self-reporting of visual details

•  Improved proofreading (2/11) •  Numerousity judgment (10/12)

•  Hypothesis: All persons possess masked “savant skills”: art, music, calendar calculating mathematics, mechanical/ spatial skills

•  Access to lower-level “less-processed” information

Snyder, 2003

Page 15: Transcranial Brain Stimulation: Science and Ethics

“Savant Skills” •  Diminished LATL “hypothesis/

concept formation” about incoming information. •  Inhibitory TMS of LATL shown

to reduce false memory formation.

(Gallate et. al., 2005) •  Diminished ability to interpret

opaque idioms (Oliveri et al., 2004)

Page 16: Transcranial Brain Stimulation: Science and Ethics

•  Now considerable evidence that TMS is effective in treating depression

•  Largest RCT conducted in 23 sites in US, Canada, and Australia

•  301 medication-refractory patients

•  10 Hz, 4sec trains 120% MT

•  3000 pulses/session

•  5x/week for 4-6 weeks

•  3x remission rate (14.2% vs 5.5% sham) compared to placebo

•  23.9% response rate (12.3% sham)

•  Approved by FDA for treatment of major depression in July 2008

Page 17: Transcranial Brain Stimulation: Science and Ethics

Mood enhancement •  TMS currently being studied for

OCD, PTSD, & schizophrenia

•  Promising recent studies in the use of tDCS for depression

(Fregni et al., 2006; Boggio et al., 2006)

•  Mood effects noted in healthy individuals after stimulation

For patients trapped by depression and its treatment side effects...

Introducing the new way back to the true you™

Through a treatment coil, the NeuroStar TMS Therapy system generates highly concentrated, magnetic fields which turn on and off very rapidly. These magnetic fields are the same type and strength as those produced by a magnetic resonance imaging (MRI) machine.

The treatment coil is applied to the head above the left prefrontal cortex. This part of the brain is involved with mood regulation, and therefore is the location where the magnetic fields are focused. These magnetic fields do not directly affect the whole brain; they only reach about 2-3 centimeters into the brain directly beneath the treatment coil. As these magnetic fields move into the brain, they produce very small electrical currents. These electrical currents activate cells within the brain, which are thought to release neurotransmitters. It is believed that the symptoms of depression can be alleviated by increasing the levels of these neurotransmitters.

NeuroStar TMS Therapy has been demonstrated to be safe and tolerable.2

Over 10,000 active treatments were safely performed with NeuroStar TMS Therapy during the clinical trials.

! No side effects such as weight gain, sexual problems, stomach problems, sleepiness, or dry mouth were seen during trials

! There were no negative effects on memory or ability to concentrate

The most commonly reported side effect related to treatment was scalp pain or discomfort during the treatment session. This side effect was generally mild to moderate, and occurred less frequently after the first week of treatment. Less than 5% of patients treated with NeuroStar TMS Therapy discontinued treatment due to side effects.

NeuroStar TMS Therapy has been demonstrated to be effective in Major Depressive Disorder.*

Efficacy was established in a controlled clinical trial comparing active treatment with the NeuroStar TMS Therapy system to an inactive device. Patients treated with active NeuroStar TMS Therapy experienced an average reduction in their depression symptom score of 22.1% compared to a 9% average reduction in patients receiving inactive treatment.3 NeuroStar-treated patients also experienced significant improvement in anxiety, appetite changes, aches and pains, and lack of energy associated with depression.4

In an open label trial, which is most like a real world clinical practice, approximately 1 out of 2 patients treated with NeuroStar TMS Therapy experienced significant improvement in depression symptoms. Approximately 1 out of 3 patients treated with NeuroStar TMS Therapy experienced complete symptom relief at the end of six weeks.4 As with any antidepressant treatment, patients should be monitored for symptoms of worsening depression.

How Does NeuroStar TMS Therapy Work?1 What are the Benefits and Risks of NeuroStar TMS Therapy?

* NeuroStar TMS Therapy® is indicated for the treatment of Major Depressive Disorder in adult patients who have failed to achieve satisfactory improvement from one prior antidepressant medication at or above the minimal effective dose and duration in the current episode.

Page 18: Transcranial Brain Stimulation: Science and Ethics

Social Cognition •  Noninvasive brain

stimulation can elucidate neural mechanisms of social cognition that inform our understanding of ethical behavior:

•  Bias and prejudice* •  Altruism and self-interest •  Deception

•  The ability to manipulate these cognitive constructs introduces ethical questions

Page 19: Transcranial Brain Stimulation: Science and Ethics

Social Cognition

Ultimatum GameUltimatum Game

ProposerProposer ResponderResponder

1616 44

Self-interestSelf-interestFairness Fairness •• Equity Equity

ReciprocityReciprocity

Knoch et al. Science 2006

Altruistic punishment

•  High rejection rates when offers are below 25%

•  Responders reject low offers as high as 3 months income

•  Balance of self interest and fairness/reciprocity

•  fMRI data indicates that DLPFC activated when offer is unfair (Sanfey et al., 2003)

Page 20: Transcranial Brain Stimulation: Science and Ethics

Social Cognition Ultimatum GameUltimatum Game

Acceptance rate for the 16/4 offer in the

human offer condition

0

10

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Left TMS Right TMS Sham

Ac

ce

pta

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Perceived unfairness of the 16/4 offer in the

human offer condition

1

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Left TMS Right TMS Sham

Fa

irn

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1=

ve

ry u

nfa

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7=

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air

)

Reaction time for accepted 16/4 offer in the

human offer condition

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5000

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7000

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9000

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Left TMS Right TMS Sham

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ac

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(m

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Fig. 1

A B C

Acceptance rate for the 16/4 offer in the

human offer condition

0

10

20

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40

50

60

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80

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Left TMS Right TMS Sham

Ac

ce

pta

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(%

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Perceived unfairness of the 16/4 offer in the

human offer condition

1

2

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Left TMS Right TMS Sham

Fa

irn

es

s (

1=

ve

ry u

nfa

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7=

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Reaction time for accepted 16/4 offer in the

human offer condition

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1000

2000

3000

4000

5000

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7000

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Left TMS Right TMS Sham

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Fig. 1

A B C

Knoch et al. Science 2006

Ultimatum GameUltimatum Game

Acceptance rate for the 16/4 offer in the

human offer condition

0

10

20

30

40

50

60

70

80

90

100

Left TMS Right TMS Sham

Ac

ce

pta

nc

e r

ate

(%

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Perceived unfairness of the 16/4 offer in the

human offer condition

1

2

3

4

5

6

7

Left TMS Right TMS Sham

Fa

irn

es

s (

1=

ve

ry u

nfa

ir;

7=

ve

ry f

air

)

Reaction time for accepted 16/4 offer in the

human offer condition

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

Left TMS Right TMS Sham

Re

ac

tio

n t

ime

(m

s)

Fig. 1

A B C

Acceptance rate for the 16/4 offer in the

human offer condition

0

10

20

30

40

50

60

70

80

90

100

Left TMS Right TMS Sham

Ac

ce

pta

nc

e r

ate

(%

)

Perceived unfairness of the 16/4 offer in the

human offer condition

1

2

3

4

5

6

7

Left TMS Right TMS Sham

Fa

irn

es

s (

1=

ve

ry u

nfa

ir;

7=

ve

ry f

air

)

Reaction time for accepted 16/4 offer in the

human offer condition

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

Left TMS Right TMS Sham

Re

ac

tio

n t

ime

(m

s)

Fig. 1

A B C

Knoch et al. Science 2006

Ultimatum GameUltimatum Game

Acceptance rate for the 16/4 offer in the

human offer condition

0

10

20

30

40

50

60

70

80

90

100

Left TMS Right TMS Sham

Ac

ce

pta

nc

e r

ate

(%

)

Perceived unfairness of the 16/4 offer in the

human offer condition

1

2

3

4

5

6

7

Left TMS Right TMS Sham

Fa

irn

es

s (

1=

ve

ry u

nfa

ir;

7=

ve

ry f

air

)

Reaction time for accepted 16/4 offer in the

human offer condition

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

Left TMS Right TMS Sham

Re

ac

tio

n t

ime

(m

s)

Fig. 1

A B C

Acceptance rate for the 16/4 offer in the

human offer condition

0

10

20

30

40

50

60

70

80

90

100

Left TMS Right TMS Sham

Ac

ce

pta

nc

e r

ate

(%

)

Perceived unfairness of the 16/4 offer in the

human offer condition

1

2

3

4

5

6

7

Left TMS Right TMS Sham

Fa

irn

es

s (

1=

ve

ry u

nfa

ir;

7=

ve

ry f

air

)

Reaction time for accepted 16/4 offer in the

human offer condition

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

Left TMS Right TMS Sham

Re

ac

tio

n t

ime

(m

s)

Fig. 1

A B C

Knoch et al. Science 2006

Knoch et al., Science. 2006

Manipulation of self-interest using brain stimulation

•  Increased acceptance rates of unfair offers after inhibitory TMS of right DLPFC

•  Shown in large groups of subjects using tDCS.

(Knoch et al., 2007)

•  TMS/tDCS of DLPFC manipulates performance on a variety of other tasks involving risk-taking and addiction cravings.

Page 21: Transcranial Brain Stimulation: Science and Ethics

•  Greater TMS-induced MEPs generated during deceitful responses vs. truthful ones (Lo et al., 2003)

•  Guilty Knowledge Test (Priori et al., 2007) –  Anodal tDCS over bilateral

DLPFC –  Increased RT for false

compared to true responses

Social Cognition Deception: Neural mechanisms and ‘lie detecting’

Page 22: Transcranial Brain Stimulation: Science and Ethics
Page 23: Transcranial Brain Stimulation: Science and Ethics

Acknowledgement

Special thanks to Anjan Chatterjee, MD for consultation and feedback regarding the ethical implications of neurologic self-enhancement.

Page 24: Transcranial Brain Stimulation: Science and Ethics

The perils of brain enhancement

•  Safety •  Character •  Justice •  Autonomy

Page 25: Transcranial Brain Stimulation: Science and Ethics

Safety

Known Risks •  Seizure induction •  Effects on Cognition •  Effects on Mood •  Endocrine effects •  Transient effects on

lymphocytes •  Transient auditory

threshold shift •  Local pain and headache •  Burns from scalp

electrodes

Theoretical Risks •  Histotoxicity •  Kindling

•  Long-term Potentiation •  Long-term Depression

•  Social and psychological consequences of a seizure

Risks associated with TMS

To date, there are no known or theoretical or serious risks associated with tDCS.

Page 26: Transcranial Brain Stimulation: Science and Ethics

Safety

•  Important but familiar problem

•  Ubiquitous to any therapeutic or cosmetic intervention

•  Good risk/benefit ratio

•  No conflict of interest

Page 27: Transcranial Brain Stimulation: Science and Ethics

Justice •  Equitable distribution of

resources

•  Boutique cognitive enhancement regimens for the wealthy

•  Problematic but mirrors existing problems

•  Brain stimulation may be less problematic than pharmacologic agents “The future is here. It’s just

not evenly distributed yet.” -William Gibson

Page 28: Transcranial Brain Stimulation: Science and Ethics

Character •  Issues of identity and

meaning in life

•  Enduring discomfort linked to concept of personal growth

•  Painful experiences may engender valuable qualities

•  Painful experience may be important for developing empathy

•  Clearly, we do not believe in enduring all suffering

•  Who decides?

NO PAIN, NO GAIN

That which does not kill you makes you stronger.

Page 29: Transcranial Brain Stimulation: Science and Ethics

Autonomy

•  Hard (explicit) coercion

•  The “greater good”

•  Historical precedent

•  Forced mood or attitude adjustment •  Military applications •  Prison populations

•  Forced revelation of cognitive states •  Lie detection

“Hard” & “soft” coercion

Page 30: Transcranial Brain Stimulation: Science and Ethics

Autonomy

•  Soft (implicit) coercion

•  Demand for competitive advantage

•  Progress defined by ever-improving performance/productivity

•  Examples: •  Professional sports •  Stimulants use among students

and professionals

“Hard” & “soft” coercion

Page 31: Transcranial Brain Stimulation: Science and Ethics

Next steps? •  Awareness of issues and

their plausibility

•  Learning from other examples of elective self-enhancement: – Cosmetic surgery – Cosmetic neurology

• Monolithic policies unlikely to be useful.

31 General Warren Blvd. Malvern, PA 19355-1245

Tel: 1-877-600-7555 Fax: 610-640-4206 www.neurostartms.com

NeuroStar® and NeuroStar TMS Therapy® are registered trademarks of Neuronetics, Inc.

©2009 Neuronetics, Inc., Malvern, PA 52-50033-000 Rev C

Ask Your Doctor if NeuroStar TMS Therapy is Right for You.

Additional Information Resources

For more information about NeuroStar TMS Therapy, please visit www.neurostartms.com.For more information on depression, please contact:

! The Depression and Bipolar Support Alliance (DBSA)www.dbsalliance.org

! National Alliance on Mental Illnesswww.nami.org

References: 1. Richelson, E. Mechanisms of Action of Repetitive Transcranial magnetic Stimulation (rTMS) and Vagus Nerve

Simulation (VNS). Psychiatric Annals, 2007: Vol 37-No. 3, 181-187.

2. Janicak, Philip G., et al. Transcranial Magnetic Stimulation in the Treatment of Major Depressive Disorder: A Comprehensive Summary of Safety Experience From Acute Exposure, Extended Exposure, and During Reintroduction Treatment. Journal of Clinical Psychiatry, January 23, 2008.

3. Lisanby SH, Husain MM, Rosenquist PB, et al. Daily Left Prefrontal Repetitive Transcranial Magnetic Stimulation in the Acute Treatment of Major Depression: Clinical Predictors of Outcome in a Multisite, Randomized Controlled Clinical Trial. Neuropsychopharmacology. 2009;34(1):522-534.

4. Data on file.

31 General Warren Blvd. Malvern, PA 19355-1245

Tel: 1-877-600-7555 Fax: 610-640-4206 www.neurostartms.com

NeuroStar® and NeuroStar TMS Therapy® are registered trademarks of Neuronetics, Inc.

©2009 Neuronetics, Inc., Malvern, PA 52-50033-000 Rev C

Ask Your Doctor if NeuroStar TMS Therapy is Right for You.

Additional Information Resources

For more information about NeuroStar TMS Therapy, please visit www.neurostartms.com.For more information on depression, please contact:

! The Depression and Bipolar Support Alliance (DBSA)www.dbsalliance.org

! National Alliance on Mental Illnesswww.nami.org

References: 1. Richelson, E. Mechanisms of Action of Repetitive Transcranial magnetic Stimulation (rTMS) and Vagus Nerve

Simulation (VNS). Psychiatric Annals, 2007: Vol 37-No. 3, 181-187.

2. Janicak, Philip G., et al. Transcranial Magnetic Stimulation in the Treatment of Major Depressive Disorder: A Comprehensive Summary of Safety Experience From Acute Exposure, Extended Exposure, and During Reintroduction Treatment. Journal of Clinical Psychiatry, January 23, 2008.

3. Lisanby SH, Husain MM, Rosenquist PB, et al. Daily Left Prefrontal Repetitive Transcranial Magnetic Stimulation in the Acute Treatment of Major Depression: Clinical Predictors of Outcome in a Multisite, Randomized Controlled Clinical Trial. Neuropsychopharmacology. 2009;34(1):522-534.

4. Data on file.

Page 32: Transcranial Brain Stimulation: Science and Ethics

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