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Under what conditions
does
brain training work?
Under what conditions does
brain training work?
Chaired by: Dr. Peter Whitehouse,
Professor of Neurology at
Case Western Reserve University
Alvaro Fernandez,
CEO & Co-Founder of SharpBrains
Dr. Bruce E. Wexler,
Professor of Psychiatry
at Yale University
Roy Hamilton,
Assistant Professor in
Neurology at the
University of Pennsylvania
UNDER WHAT CONDITIONS DOES
BRAIN TRAINING WORK?
Alvaro Fernandez
Japanese edition in 1-2 months
(Hankyu Communications)
Complex & longer lives place new demands on our
brains…
…so “work” is about brain functionality and fitness,
not about disease
Improve
performance Delay
decline
No one shoe fits all
AGE
PERFORMANCE
25 50 75 100
PERFORMANCE
AGE
Source: The SharpBrains Guide to Brain Fitness (second edition)
Mental activity vs. mental exercise
Source: Maguire, Woollett, & Spiers, 2006
Cross-training our brains
Five conditions to maximize transfer
To maximize real-world value of training…
1. Target neural processes that support real-world
activities
2. Minimum “dose” of ~15 hours of training per
targeted improvement
3. Address an individual’s bottleneck/ deficit
4. Adaptive challenge
5. Continued practice
Source: The SharpBrains Guide to Brain Fitness
What does the “BBC brain training study” (2010, 2015)
prove?
We better start educating
users and professionals
Conditions Under Which Brain
Training Works
Bruce E. Wexler
Professor of Psychiatry, Yale University
Founder and Chief Scientist, C8 Sciences
Conditions Under Which Brain Training Works
• Clear neurocognitive target for training
– For diseases, you must understand the pathology
– For enhancing normal function, you must have a
consistent neural system target
• Effective training program
– Multi-dimensional and systematic
– Sophisticated data-driven individualization of
training
– Good training schedule: dose, duration, frequency
• Engaged users
Geriatric Depression:
A Clear Target, Good Results
• Pre-identified neurocognitive dysfunction
associated with failure to respond to medication
– Cognitive executive dysfunction
– Hypo-activation on fMRI stroop paradigm in dorsal ACC (BA 24/32),
superior prefrontal cortices (BA 6), and the middle frontal gyrus
• Rx trial in 11 pts who had failed to respond at all to
12 weeks of supervised medication
• 8/11 met criteria for remission (MADRS < 11) in 4
weeks, one more met criteria in 6 weeks, one did not
reach remission and one dropped out
Neuroplasticity-based computerized cognitive remediation for
treatment resistant geriatric depression
Morimoto SS, Wexler BE, Liu J, Hu W, Seirup J, Alexopoulos GS
Nature Communications: August 5, 2014
• Executive Functions Improved
– Stroop color word, p = .014
– Trails B, p = .024
– Design Fluency (Delis Kaplan EF System), p = .002
– Semantic Clustering (Mattis Dementia Rating), p =.052
• Verbal WM did not improve
• Improvement on Trails B was correlated with
improvement on the MADRS, spearman r = .72, p = .018.
Neuroplasticity-based computerized cognitive remediation for
treatment resistant geriatric depression
Morimoto SS, Wexler BE, Liu J, Hu W, Seirup J, Alexopoulos GS
Nature Communications: August 5, 2014
Group: F(1,49.2)=0.019, p=0.892
Week: F(1,71.2)=30.97, p<0.0001
Group*Week: F(1,61.8)=5.32, p=0.024
Lexipro group: historical controls, unselected for prior failure to respond to treatment
Neuroplasticity-based computerized cognitive remediation for
treatment resistant geriatric depression
Morimoto SS, Wexler BE, Liu J, Hu W, Seirup J, Alexopoulos GS
Nature Communications: August 5, 2014
Neural System that Supports Executive Functions
Sustain Attention, Resist Distraction, Category Use, Emotion Regulation, Memory, Flexibility
Inattention, Distractibility, Impulsivity, Decreased Memory, Rigidity, Limited Categorizing
Multi-Dimensional Brain Training for Depression
Neuropathology
Memory Training
• Memory function is affected by factors along multiple
dimensions
– Number of things to remember
– Study time, inter-stimulus interval, retention interval
– Similarity of things to remember to each other and to things in recent
memory
– Distraction during encoding, maintenance or recall
– Requirement to manipulate the information in memory
• Many memory training games only train recall of
increasingly long lists of things. These are likely to
improve function in only limited ways in limited
situations.
• With a more complex and multidimensional training, a
new problem arises: when to move a user from training
along one dimension to training along another?
List Sorting WM test from NIH Toolbox: Children are shown pictures of animals or furniture and
have to report them back in order from smallest to largest. If they get 2 correct, they are shown
3, then 4, etc; score is total correct. After Activate all grades are above Fall score of next grade.
Enhancing brain training with electrical stimulation:
Promises and perils
Roy Hamilton, MD, MS
Assistant Professor of Neurology & Physical
Medicine & Rehabilitation
Director, Laboratory for Cognition & Neural
Stimulation (LCNS)
University of Pennsylvania
NO RELEVANT DISCLOSURES
9-Volt Nirvana
9-Volt Nirvana
“Zap your brain into the zone: Fast track to pure focus”
New Scientist, 2012
9-Volt Nirvana
“Zap your brain into the zone: Fast track to pure focus”
New Scientist, 2012
Is Sally right?
9-Volt Nirvana
“Zap your brain into the zone: Fast track to pure focus”
New Scientist, 2012
Is Sally right?
What if she is? What if she isn’t?
9-Volt Nirvana
“Zap your brain into the zone: Fast track to pure focus”
New Scientist, 2012
Is Sally right?
What if she is? What if she isn’t?
What else do we need to think about?
Transcranial Direct Current Stimulation
(tDCS)
Transcranial Direct Current Stimulation
(tDCS)
• Subthreshold
stimulation
Transcranial Direct Current Stimulation
(tDCS)
• Subthreshold
stimulation
• Neurons alter firing
rates
Transcranial Direct Current Stimulation
(tDCS)
• Subthreshold
stimulation
• Neurons alter firing
rates
• Anodal or cathodal
stimulation may
have different
effects.
Transcranial Direct Current Stimulation
(tDCS)
Transcranial Direct Current Stimulation
(tDCS)
• No known serious
adverse side-effects
Transcranial Direct Current Stimulation
(tDCS)
• No known serious
adverse side-effects
• Portable
Transcranial Direct Current Stimulation
(tDCS)
• No known serious
adverse side-effects
• Portable
• Can be worn during
other therapies
Transcranial Direct Current Stimulation
(tDCS)
• No known serious
adverse side-effects
• Portable
• Can be worn during
other therapies
• Costs ranging from
$100s-$1000s
Transcranial Direct Current Stimulation
(tDCS)
• No known serious
adverse side-effects
• Portable
• Can be worn during
other therapies
• Costs ranging from
$100s-$1000s
• Usable without
advanced training
Motor learning
Motor learning
Task-dependent working
memory enhancement
Gill et al., Brain Stimulation. 2015
Task-dependent working
memory enhancement
Gill et al., Brain Stimulation. 2015
Online domain-specific cognitive task+atDCS results in offline
improvement in performance within-domain
“Use it to
hammer
nails?”
Novel Uses
Chrysikou et al., Cognition, 2013
Frontal lobe functions
Impulse Control, Cognitive Control & Creativity
http://www.thync.com
Repurposed
Iontophoresis
Units
tDCS Device Kits
Homemade
Devices
Wexler, 2014
DIY-tDCS
Repurposed
Iontophoresis
Units
tDCS Device Kits
Homemade
Devices
DIY-tDCS
Unintended
tradeoffs…
Iuculano & Cohen Kadosh, 2013
6 days of training + TES
•Posterior parietal cortex
•Dorsolateral prefrontal cortex
Unintended
tradeoffs…
Iuculano & Cohen Kadosh, 2013
6 days of training + TES
•Posterior parietal cortex
•Dorsolateral prefrontal
cortex
• PPC: Increased
learning but reduced
automaticity
• DLPFC: Increased
automaticity but
decreased learning
Unintended
tradeoffs…
Trait and individual-specific
outcomes…
Sarkar et al., 2014
tDCS & psychopharmacology
• Glutamate/NMDA modulators
– Blocking receptors eliminates aftereffects; enhancement
enhances facilitatory plasticity
• GABA modulators (e.g. lorazepam)
– Delayed then enhanced & prolonged anodal excitability
• Monoamine modulators (e.g. amphetamines)
– May enhance facilitatory plasticity
• Dopamine modulators
– L-dopa: converts facilitatory plasticity to inhibition,
prolongs inhibitory plasticity
– D2 antagonists: abolish induced plasticity; D2 agonists:
variable dose-dependent effects
• Acetylcholinergic modulators
– Reuptake inhibitor: similar effect to L-dopa
• Serotonergic modulators
– Reuptake inhibitor enhances facilitatory plasticity, converts
inhibitory plasticity to facilitation
Brunoni et al., 2013
Conclusions
• Neither snake oil nor
panacea
• Potential for a different
kind of harm/risk?
• Different research
(mechanisms &
mechanics) needed
Conclusions
• Neither snake oil nor
panacea
• Potential for a different
kind of harm/risk?
• Different research
(mechanisms &
mechanics) needed
Conclusions
• Neither snake oil nor
panacea
• Potential for a different
kind of harm/risk?
• Different research
(mechanisms &
mechanics) needed
Follow us on Twitter @PennMedLCNS
LCNS email: braintms@mail.med.upenn.edu
LCNS website: http://www.med.upenn.edu/lcns
Faculty
Roy Hamilton, MD, MS
H. Branch Coslett, MD
Sudha Kessler, MD
Research Staff
Olufunsho Faseyitan, MS
Daniela Sacchetti
Juliann Purcell
Nicole White
Quan Wan
Postdoctoral Fellows
Rachel Wurzman, PhD
Denise Harvey, PhD
John Medaglia, PhD
Perelman School Of Medicine
Catherine Norise
Daniel Cristancho
Penn School of Nursing
Darina Petrovsky, MSN
Undergraduates
Jonathan Muruakuo
Joely Mass
Students
Special thanks to Martha Farah, PhD, Anna Wexler,
and the Penn ELSIs of NBS Focus Group
Watercooler chats:
Time to meet 
To learn more, visit sharpbrains.com

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Under what con­di­tions does brain train­ing work?

  • 2. Under what conditions does brain training work? Chaired by: Dr. Peter Whitehouse, Professor of Neurology at Case Western Reserve University Alvaro Fernandez, CEO & Co-Founder of SharpBrains Dr. Bruce E. Wexler, Professor of Psychiatry at Yale University Roy Hamilton, Assistant Professor in Neurology at the University of Pennsylvania
  • 3. UNDER WHAT CONDITIONS DOES BRAIN TRAINING WORK? Alvaro Fernandez
  • 4. Japanese edition in 1-2 months (Hankyu Communications)
  • 5. Complex & longer lives place new demands on our brains…
  • 6. …so “work” is about brain functionality and fitness, not about disease Improve performance Delay decline
  • 7. No one shoe fits all AGE PERFORMANCE 25 50 75 100 PERFORMANCE AGE
  • 8. Source: The SharpBrains Guide to Brain Fitness (second edition)
  • 9. Mental activity vs. mental exercise Source: Maguire, Woollett, & Spiers, 2006
  • 11. Five conditions to maximize transfer To maximize real-world value of training… 1. Target neural processes that support real-world activities 2. Minimum “dose” of ~15 hours of training per targeted improvement 3. Address an individual’s bottleneck/ deficit 4. Adaptive challenge 5. Continued practice Source: The SharpBrains Guide to Brain Fitness What does the “BBC brain training study” (2010, 2015) prove?
  • 12. We better start educating users and professionals
  • 13. Conditions Under Which Brain Training Works Bruce E. Wexler Professor of Psychiatry, Yale University Founder and Chief Scientist, C8 Sciences
  • 14. Conditions Under Which Brain Training Works • Clear neurocognitive target for training – For diseases, you must understand the pathology – For enhancing normal function, you must have a consistent neural system target • Effective training program – Multi-dimensional and systematic – Sophisticated data-driven individualization of training – Good training schedule: dose, duration, frequency • Engaged users
  • 15. Geriatric Depression: A Clear Target, Good Results
  • 16. • Pre-identified neurocognitive dysfunction associated with failure to respond to medication – Cognitive executive dysfunction – Hypo-activation on fMRI stroop paradigm in dorsal ACC (BA 24/32), superior prefrontal cortices (BA 6), and the middle frontal gyrus • Rx trial in 11 pts who had failed to respond at all to 12 weeks of supervised medication • 8/11 met criteria for remission (MADRS < 11) in 4 weeks, one more met criteria in 6 weeks, one did not reach remission and one dropped out Neuroplasticity-based computerized cognitive remediation for treatment resistant geriatric depression Morimoto SS, Wexler BE, Liu J, Hu W, Seirup J, Alexopoulos GS Nature Communications: August 5, 2014
  • 17. • Executive Functions Improved – Stroop color word, p = .014 – Trails B, p = .024 – Design Fluency (Delis Kaplan EF System), p = .002 – Semantic Clustering (Mattis Dementia Rating), p =.052 • Verbal WM did not improve • Improvement on Trails B was correlated with improvement on the MADRS, spearman r = .72, p = .018. Neuroplasticity-based computerized cognitive remediation for treatment resistant geriatric depression Morimoto SS, Wexler BE, Liu J, Hu W, Seirup J, Alexopoulos GS Nature Communications: August 5, 2014
  • 18. Group: F(1,49.2)=0.019, p=0.892 Week: F(1,71.2)=30.97, p<0.0001 Group*Week: F(1,61.8)=5.32, p=0.024 Lexipro group: historical controls, unselected for prior failure to respond to treatment Neuroplasticity-based computerized cognitive remediation for treatment resistant geriatric depression Morimoto SS, Wexler BE, Liu J, Hu W, Seirup J, Alexopoulos GS Nature Communications: August 5, 2014
  • 19. Neural System that Supports Executive Functions Sustain Attention, Resist Distraction, Category Use, Emotion Regulation, Memory, Flexibility Inattention, Distractibility, Impulsivity, Decreased Memory, Rigidity, Limited Categorizing Multi-Dimensional Brain Training for Depression Neuropathology
  • 20. Memory Training • Memory function is affected by factors along multiple dimensions – Number of things to remember – Study time, inter-stimulus interval, retention interval – Similarity of things to remember to each other and to things in recent memory – Distraction during encoding, maintenance or recall – Requirement to manipulate the information in memory • Many memory training games only train recall of increasingly long lists of things. These are likely to improve function in only limited ways in limited situations. • With a more complex and multidimensional training, a new problem arises: when to move a user from training along one dimension to training along another?
  • 21.
  • 22.
  • 23. List Sorting WM test from NIH Toolbox: Children are shown pictures of animals or furniture and have to report them back in order from smallest to largest. If they get 2 correct, they are shown 3, then 4, etc; score is total correct. After Activate all grades are above Fall score of next grade.
  • 24. Enhancing brain training with electrical stimulation: Promises and perils Roy Hamilton, MD, MS Assistant Professor of Neurology & Physical Medicine & Rehabilitation Director, Laboratory for Cognition & Neural Stimulation (LCNS) University of Pennsylvania NO RELEVANT DISCLOSURES
  • 25.
  • 27. 9-Volt Nirvana “Zap your brain into the zone: Fast track to pure focus” New Scientist, 2012
  • 28. 9-Volt Nirvana “Zap your brain into the zone: Fast track to pure focus” New Scientist, 2012 Is Sally right?
  • 29. 9-Volt Nirvana “Zap your brain into the zone: Fast track to pure focus” New Scientist, 2012 Is Sally right? What if she is? What if she isn’t?
  • 30. 9-Volt Nirvana “Zap your brain into the zone: Fast track to pure focus” New Scientist, 2012 Is Sally right? What if she is? What if she isn’t? What else do we need to think about?
  • 31. Transcranial Direct Current Stimulation (tDCS)
  • 32. Transcranial Direct Current Stimulation (tDCS) • Subthreshold stimulation
  • 33. Transcranial Direct Current Stimulation (tDCS) • Subthreshold stimulation • Neurons alter firing rates
  • 34. Transcranial Direct Current Stimulation (tDCS) • Subthreshold stimulation • Neurons alter firing rates • Anodal or cathodal stimulation may have different effects.
  • 35. Transcranial Direct Current Stimulation (tDCS)
  • 36. Transcranial Direct Current Stimulation (tDCS) • No known serious adverse side-effects
  • 37. Transcranial Direct Current Stimulation (tDCS) • No known serious adverse side-effects • Portable
  • 38. Transcranial Direct Current Stimulation (tDCS) • No known serious adverse side-effects • Portable • Can be worn during other therapies
  • 39. Transcranial Direct Current Stimulation (tDCS) • No known serious adverse side-effects • Portable • Can be worn during other therapies • Costs ranging from $100s-$1000s
  • 40. Transcranial Direct Current Stimulation (tDCS) • No known serious adverse side-effects • Portable • Can be worn during other therapies • Costs ranging from $100s-$1000s • Usable without advanced training
  • 43. Task-dependent working memory enhancement Gill et al., Brain Stimulation. 2015
  • 44. Task-dependent working memory enhancement Gill et al., Brain Stimulation. 2015 Online domain-specific cognitive task+atDCS results in offline improvement in performance within-domain
  • 45. “Use it to hammer nails?” Novel Uses Chrysikou et al., Cognition, 2013 Frontal lobe functions Impulse Control, Cognitive Control & Creativity
  • 50. Iuculano & Cohen Kadosh, 2013 6 days of training + TES •Posterior parietal cortex •Dorsolateral prefrontal cortex Unintended tradeoffs…
  • 51. Iuculano & Cohen Kadosh, 2013 6 days of training + TES •Posterior parietal cortex •Dorsolateral prefrontal cortex • PPC: Increased learning but reduced automaticity • DLPFC: Increased automaticity but decreased learning Unintended tradeoffs…
  • 53. tDCS & psychopharmacology • Glutamate/NMDA modulators – Blocking receptors eliminates aftereffects; enhancement enhances facilitatory plasticity • GABA modulators (e.g. lorazepam) – Delayed then enhanced & prolonged anodal excitability • Monoamine modulators (e.g. amphetamines) – May enhance facilitatory plasticity • Dopamine modulators – L-dopa: converts facilitatory plasticity to inhibition, prolongs inhibitory plasticity – D2 antagonists: abolish induced plasticity; D2 agonists: variable dose-dependent effects • Acetylcholinergic modulators – Reuptake inhibitor: similar effect to L-dopa • Serotonergic modulators – Reuptake inhibitor enhances facilitatory plasticity, converts inhibitory plasticity to facilitation Brunoni et al., 2013
  • 54. Conclusions • Neither snake oil nor panacea • Potential for a different kind of harm/risk? • Different research (mechanisms & mechanics) needed
  • 55. Conclusions • Neither snake oil nor panacea • Potential for a different kind of harm/risk? • Different research (mechanisms & mechanics) needed
  • 56. Conclusions • Neither snake oil nor panacea • Potential for a different kind of harm/risk? • Different research (mechanisms & mechanics) needed
  • 57. Follow us on Twitter @PennMedLCNS LCNS email: braintms@mail.med.upenn.edu LCNS website: http://www.med.upenn.edu/lcns Faculty Roy Hamilton, MD, MS H. Branch Coslett, MD Sudha Kessler, MD Research Staff Olufunsho Faseyitan, MS Daniela Sacchetti Juliann Purcell Nicole White Quan Wan Postdoctoral Fellows Rachel Wurzman, PhD Denise Harvey, PhD John Medaglia, PhD Perelman School Of Medicine Catherine Norise Daniel Cristancho Penn School of Nursing Darina Petrovsky, MSN Undergraduates Jonathan Muruakuo Joely Mass Students Special thanks to Martha Farah, PhD, Anna Wexler, and the Penn ELSIs of NBS Focus Group
  • 59. To learn more, visit sharpbrains.com