Harnessing Brain Plasticity

Adam Gazzaley, MD PhD

Professor - Neurology, Physiology and PsychiatryDirector- Gazzaley Lab, Neuroscape Lab

Neuroscience Imaging CenterUniversity of California, San Francisco

Akili Interactive Labs

Co-founder and Chief Science Advisor

Pending patents:

“Enhancing Cognition in the Presence of Distraction and/or Interruption”

“Method of Suppressing Irrelevant Stimuli”

“Methods of Enhancing Performance on a Cognitive Task By Improved Self-Regulation of Internal Distraction and

Computer Readable Medium and Devices for Practicing the Same”

“Methods of Enhancing Cognition and Systems for Practicing the Same”

Disclosures

Challenge

Develop an effective approach to enhance cognition

in both healthy and impaired individuals

• Poor characterization

• Poor targeting

• Non-personalized

• Unimodal

• Open Loop

60 year old with mild cognitive impairment

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Current Approach

Create a New Approach

closed-loop

targeted

personalized

multimodal

fMRI EEG TMSEEEEGGfMfMRIRI

Create a New Approach

Step 1: Understand the target

Our mental abilities that allow us to dynamically interact with our

complex environment based on our goals

Cognitive Control

Attention Working Memory

Goal Management

Early sensory processing modulation mediated by prefrontal cortical networks

Declines as we age

- Gazzaley et al. Cerebral Cortex (2007)

- Wais et al. Journal of Neuroscience (2010)

- Zanto et al. Nature Neuroscience (2011)

- Gazzaley, et al. Journal of Cognitive Neuroscience (2005)

- Clapp, Rubens and Gazzaley Cerebral Cortex (2010)

- Berry et al. Journal of Neurophysiology (2009)

- Zanto & Gazzaley Journal of Neuroscience (2010)

- Rutman et al. Journal of Cognitive Neuroscience (2009)

- Chadick & Gazzaley Nature Neuroscience (2011)

- Wais & Gazzaley Psychonomic Bulletin and Review (2011)

- Wais, Kim & Gazzaley Cerebral Cortex ((2011)

- Mishra & Gazzaley Journal of Neuroscience (2012)

- Zanto, Rubens & Gazzaley Neuroimage (2010)

Gazzaley Neuropsychologia (2011) Gazzaley Principles of Frontal Lobe Function (2011)

- Gazzaley et al. PNAS (2008)

- Gazzaley et al. Nature Neuroscience (2005)

- Zanto, et al. Cortex (2010)

- Clapp & Gazzaley Neurobiology of Aging (2010)

- Zanto & Gazzaley Neuropsychologia (2010)

- Gazzaley et al. Neuropsychology (2007)

- Clapp, Rubens & Gazzaley PNAS (2011)

- Wais & Gazzaley Brain Research (2012)

- Anguera & Gazzaley Clinical Neurophysiology (2011)

- Cashdollar et al. Psychology and Aging (2013)

- Berry et al. PLoS One (2010)

- Mishra & Gazzaley Neuropsychologia (2013)

- Zanto et al. PLoS One (2013)

Cognitive Control

Step 2: Build an engine

Step 1: Understand the target

Create a New Approach

Step 2: Build an engineCreate a New Approach

• Targeting

• Personalized

• Multimodal

• Closed Loop

Adaptivity / Feedback

cognitive exercises and video game training

Enhance cognitive control abilities in

healthy older adults

Attention Working Memory

Goal Management

Interference Training Study

2008-2013

Anguera, Boccanfuso, Rintoul, Al-Hashimi, Faraji, Janowich, Kong, Larraburo, Rolle, Johnston & Gazzaley

Video game training enhances cognitive control in older adults

Nature 2013

Joaquin Anguera

Funded by Robert Wood Johnson Foundation

Interference Training

Training Study

1 monthlater

12 hours

Multitasking Performancemmmmmmmmmmmmmmmaaaaaaaaaaaaaaaaaaaaaaaaaannnnnnnnnnnnnnnnnnncccccccccccccccccccceeeeeeeeeeeeeeeeeeee

-100%

-80%

-60%

-40%

-20%

0%

20s 30s 40s 50s 60s 70s

Multi-

task

ing

Inde

x

Decades of Life

Anguera et al. Nature 2013

0%0%0%0%0%0%0%0%0%0%0%0%0%0%0%0%0%0%0%0%0%0%0%0%0%0%0%0%0%

Midline Frontal Theta

-27%-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-27%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%7%

-63%-6-6-6-6-6-6-6-6-63%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%3%

12 hours12 h12 h12 h12 hoursoursours

6 monthslater

Transfer of Benefits

&

Attention Span

Working Memory

12 hours

Anguera et al. Nature 2013

A Neural Bridge

Pre -Training

12 hoursPre & Post

Attention Span

Transfer of Benefits Sustained Benefits

Multitasking on Game

Post -Training

Anguera et al. Nature 2013

! Adaptivity / feedback video game

training of interference processing

drives enhancements of cognitive

control abilities in older adults.

! Task improvements are associated

with changes in engagement of

prefrontal cortex networks.

Move to the Real World

Akili Interactive Labs Co-founder and Chief Science Advisor

Patent-pending: “Enhancing Cognition in the Presence of Distraction and/or Interruption”

AkiAkiAkili li li IntIntInt cticticti LabLabLabAkiAkiAkiAkiAkiAkiAkiAkili li li li li li li li IntIntIntIntIntIntIntInteraeraeraeraeractictictictictictictictive ve ve ve ve LabLabLabLabLabLabLabLabs s s s s

World

! Attention Deficit Disorder (ADD)• Scott Kollins, Duke University / Andrew Cutler, FLCRC

• [Shire Pharmaceuticals]

! Depression• Patricia Arean, UCSF

• [NIH]

! Traumatic Brain Injury (TBI)• Kristine Yaffe, UCSF

! Alzheimer’s Disease• [Pfizer]

! Autism • Elysa Marco, UCSF

• [Wallace Foundation / James Gates Family Foundation]

Evaluate as Diagnostics & Therapeutics

r,

Familmily Fy Fy Foundatdatdationionion] ] ]

Bridging the Gap Between Technology and Neuroscience

Neuroscapelab.com

Mobile / Wireless

New Technology

Virtual Reality Motion Capture

New Technology

New Games...

Physical Rhythm

Meditation

Attention

Neuro Crossfit

Step 3: Enhance the effects

Step 2: Build the engine

Step 1: Understand the target

Create a New Approach

Neuromodulation Neurofeedback

Video Games

Enhance the Effects Real-Time EEG

Close the LoopBehavior

Environment

Electrical

Neural

20152020020152015202020152015

EEGEEG

targeted / personalized / multimodal / closed-loop

GG

Alzheimer’s Disease

Anxiety Disorder

Attention Deficit Disorder

Depression

Post Traumatic Stress Disorder

Autism

Schizophrenia

Traumatic Brain Injury

Parkinson’s Disease

Multiple Sclerosis

Over the Next 10 Years ...

Education

Addiction

Thanks for your attention

Many thanks• Omar Alhashimi

• Alan Legitt

• Benjamin Dorn

• Cammie Rolle

• Jacki Janowich

• Roger Anguera

• Rajat Jain

StudentsAssociates

Financial Support

• David Ziegler

• Morgan Hough

• WanYu Hsu

• Yixuan Ku

• Martine Schouwenburg

Fellows

www.gazzlab.com

Game Development

• Matt Omernick

• Dmitri Ellingson

• Eric Johnson

• Noah Fahlstein

Faculty• Ted Zanto

• Judy Pa

• Jyoti Mishra

• Peter Wais

• Joaquin Anguera

Hardware

• Apple • NVIDIA

• National Institute on Aging

• National Institute of Mental Health

• American Federation of Aging Research

• Robert Wood Johnson Foundation

• Zynga.org Foundation

• Center 17 Foundation

• Sandler Foundation

• Ellison Medical Foundation

• James Gates Family Foundation

• Rose Family Foundation

• Feldman Family Foundation

• Grammy Foundation

• Biggelsworth Foundation

• Laney and Pasha Thornton

• UCSF CTSI

• Posit Science

• Pfizer / Eisai

• Tim Ferriss

• William Getty

• Tully and Elise Friedman

• Sara and Evan Williams Foundation

GlassBrain

• Tim Mullen

• Christian Kothe

• Oleg Konigs

• John Fesenko

• Oculus VR• Ty Clark

• Matt Whitman

• Mike Gonzales

• Mickey Hart

• to Gazzlab alumni, collaborators,

research and industry partners ...

• Myers Sound

Move to the Real World

Akili Interactive Labs

Co-founder and Chief Science Advisor

Patent-pending: “Enhancing Cognition in the Presence of Distraction and/or Interruption”

AkiAkiAkiAkiAkiAkiAkiAkiAkiAkili li li li li li li li li li IntIntIntIntIntIntIntIntIntInteraeraeraeraeractictictictictictictictictictive ve ve ve ve LabLabLabLabLabLabLabLabLabLabs s s s s

World

Physical / Cognitive

Body-Brain Trainer

Collaborators: Anthony Luke & Christian ThompsonGame Developer Leads: Ty Clark & Roger Anguera

Rhythm

Rhythmicity

Collaborator: Mickey HartGame Developer Lead: Studio Bee

Distributed Attention

Virtual Attention

Internal Attention

Meditrain

Collaborator: Jack KornfieldGame Developer Lead: Zynga

-100%

-80%

-60%

-40%

-20%

0%

20s 30s 40s 50s 60s 70s

%

%

%

Mu

lti-

task

ing

In

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’

-27%

No Cost

-63%

Decades of Life

Anguera et al. Nature 2013

Interference Training

12 hours

-100%

-80%

-60%

-40%

-20%

0%

20s 30s 40s 50s 60s 70s

%

%

%

Mu

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ing

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No Cost

-63%

Decades of Life Training Study

-13%

Pre 1 mo. 6 mo.

-27%

Single-task trainMulti-task train

No-contact control Anguera et al. Nature 2013

Interference Training

-100%

-80%

-60%

-40%

-20%

0%

20s 30s 40s 50s 60s 70s

%

%

Mu

lti-

task

ing

In

de

x d

’

No Cost

Decades of Life Training Study

Pre 1 mo. 6 mo.

Single-task trainMulti-task train

No-contact control

-40%

-20

%-40%

-20-20-20-20-20-20-20-20-20-20-20-20-20-20-20-20-20-20%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%

%

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Anguera et al. Nature 2013

Interference Training

Frontal Theta Power0 - 600 ms

Before Training After Training

12 hours

Anguera et al. Nature 2013

Interference Training

†

Initial

*

Older Adults Younger Adults

Older Adults Post-Training

Single-Task

Training

Si lelelele-T kMulti-Task

Training

††

No Contact

Control

dedededer r r r

Older Adults Post-Training ng ng ng

Frontal Theta Power12 hours

Interference Training

†

Initial

*

Older Adults Younger Adults

Older Adults Post-Training

Single-Task

Training

Si lele-T kMulti-Task

Training

†

No Contact

Control

dedededer r r r

OldOlder Adults Post-Training ng ng ng ng

Initial

Long-Range Theta Coherence12 hours

†

Interference Training

Multi-task training Single-task training No-contact control

-150

-75

0

75

150P

re-P

ost R

T (

mse

c)

*†

Working Memory

Delayed-Recognition Task Tests of Variables of Attention (TOVA)

a)

-5

6

18

29

40

Pre

-Po

st R

T (

mse

c)

Sustained Attention

*

†

Anguera et al. Nature 2013

12 hours

Interference Training

-22.5

0

22.5

45

67.5

90

-1.25 0 1.25 2.5 3.75 5

R² = 0.3163

Pre

-Po

st T

OV

A R

T

Post-Pre mf Theta

Magnitude of Theta Enhancement

Correlates with Gains in Sustained Attention (TOVA)

Pre-Train Post-Train

12 hours

Interference Training

-1.75

-1.5

-1.25

-1

-0.75

-0.5

-0.25

0

-1 0 1 2 3 4 5

R² = 0.5738

Post-Pre mf Theta

Magnitude of Theta Enhancement

Correlates with Sustained Performance Gains at 6 months

6 m

on

th -

Po

st T

rain

Mu

lti-

task

ing

co

st

12 hours

Pre-Train Post-Train

Interference Training