Workshop on Cognition and Cognitive
Enhancement in Psychiatric Disorders
Ken Duckworth, MD, Matcheri Keshavan, MD, Larry J.
Seidman, PhD
National Alliance of Mental Illness of Massachusetts
Annual Meeting, October 19, 2013
Bob
Public Presentation:
• Bright 14 yr old male
• History of severe early neglect
• Socially anxious
• Grades dropped from A’s to B’s, then C’s,
eventually D’s
• By junior yr of HS, he was failing classes
• Few friends, not initiating peer contact
Academic Difficulties
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Concentration
Initiative
Organization
Reading
Writing
Memory
Academic supports put in place
Discontinued brief psychotherapy
What are reasons for neuropsychological
assessment?
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Problems in organization and planning
Forgetfulness
Difficulty concentrating and sustaining studying
First-time evaluation - many adults have never
received a proper diagnosis.
Re-evaluation to determine change over time.
Assessment of treatment effects.
Request for accommodations in college, exams,
etc..
Understanding of own strengths and weaknesses
for self and significant others (e.g., parents,
spouse).
Central Neuropsychological Deficits in
Schizophrenia
• Executive Functions, Abstraction,
Thought Disorder
• Sustained and Selective Attention
• Working Memory
• Verbal Declarative Memory (VDM) Encoding, Storage and Retrieval
• Language
Age and Neuropsychological Function in
Schizophrenia (Fucetola, Seidman et al., 1999)
People with Schizophrenia
Healthy Controls
0.5
0.5
Young
Middle
Old
Z-Scores
0
0
-0.5
-0.5
-1
-1
-1.5
Young
Middle
Old
-1.5
-2
Verbal
Abstraction
Visual
Executive
Mental
Motor
Control
Verbal
Perceptual
Sustained
Memory
Motor
Attention
-2
Verbal
Abstraction
Visual
Executive
Mental
Motor
Verbal
Perceptual Control Sustained
Memory
Motor
Attention
Neurocognitive Deficits are related to Functional
Outcome
Community Functioning
Neurocognitive
Deficits
Large -
Medium -
Small -
Instrumental &
Problem Solving Skills
Psychosocial
Rehabilitation
Programs
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
All P’s <.0001
Verbal
Memory
Immediate
Memory
Executive
Functions
Vigilance Summary
Scores
Green et al, 2000
Schizophrenia: some numbers
1
•
10
•
Percent of population prevalence
Percent of patients gainfully employed
• 20
• Years of reduced longevity
• 40
• Percent of patients who do not
respond to antipsychotics
• 80 • Partial or total noncompliance with treatment
• 90 • Percent of patients with
cognitive impairment
• 100 • Percent of patients with
loss of insight at some
point or other
Nash suffered from
paranoid schizophrenia
Key points
• Brain is remarkably plastic
• Altered neuroplasticity and schizophrenia
• Plasticity based interventions may remedy
cognitive deficits
Ramon Cajal 1901
• The nerve
pathways are
something fixed,
ended and
immutable…
• ….It is for the
science of the
future to change, if
possible, this harsh
decree.
William James 1890
• ..Nervous tissue, seems
endowed with a very
extraordinary degree of
plasticity … the
phenomena of habit in
living beings are due to
the plasticity
Critical periods where environmental
enrichments might have larger effects
Environment
CRITICAL PERIOD
Genotype
conception
Phenotype
birth
postnatal
adolescence
adulthood
Hubel and Weisel experiments with kitten
Neuroplasticity and Critical windows
Higher cognitive function
Language
Psychiatric disorders
Dyslexia
Primary
Sensory
(Visual,
Auditory)
Amblyopia
0
Birth
1
Years
2 4 6 8 10 12 18 24 30 40------(Nelson CA in Neurons to Neighborhoods 2000)
•“The more the neurons fire together, the more they wire together”
Donald Hebb 1949
Or “Use it or lose it”
Long term potentiation
Long term plasticity
Environmental enrichment leads to neuronal proliferation
Van Praag 2000
The neuronal handshake
The power of plasticity
Physical Practice
MEG activity
Motor cortex
Mental Practice
Day 1
2
3
4
5
Pascual-Leone et al. JNP 94
London Taxi drivers have larger
hippocampi than matched control
subjects
McGuire 2009
• Brain is remarkably plastic
• Altered neuroplasticity may underlie
cognitive deficits in schizophrenia
• Plasticity based interventions may remedy
cognitive deficits
Schizophrenia is..
• A disorder of stages
• A cognitive disorder caused by deficits in
brain plasticity
• A disorder of affect caused by
uncontrolled overactivity of emotional brain
regions
Psychosisof
is actually
a “late” stage of schizophrenia!
Phases
the schizophrenic
illness.
Prodromal
Transitional
Premorbid
Recovery
Psychotic
Premorbid
alterations
Decline begins
in prodrome
Post-illness onset
Functional decline
Psychosis
Typically begins in
adolescence
Excessive (Positive) symptoms
(40-50 %)
Hallucinations
Delusions
Loose associations
Cognitive deficits
(80-90%)
Working memory
Selective attention
Functional
Impairment
Deficit (negative) symptoms
(60-70 %)
Avolition
Anhedonia
Anergia
Asociality
Alogia
Name the color of the word…
Blue
Did you have a
Yellow
STR OOPs! Effect?
Red
Green
Blue
Green
Healthy persons activate
Anterior cingulate when they
Detect errors
Selective ATTENTION
N- Back Test
Press when you see the number (n) 2 digits ago
6
Hold
7
Hold
3
Hold
7
Press
5
Hold
Normally activates
WORKING MEMORY
3
Hold
5
Press
Wisconsin card sort
Number
Color
Shape
Normally activates
Reasoning and conceptual
flexibility
TACT, or Social cognition: Decreased ventral prefrontal
activity with the Baron-Cohen “eyes task”
AFFECT PERCEPTION
Brain regions engaged in
Emotion recognition minus
Gender recognition
Amygdala
Inferior frontal cortex and insula
Social perception is that part of perception that allows
people to understand the other people in their social world.
Faux Pas vignette
Baron-Cohen 1999
Helen's husband was throwing a surprise party
for her birthday. He invited Sarah, a friend of
Helen's, and said, "Don't tell anyone, especially
Helen." The day before the party, Helen was
over at Sarah's and Sarah spilled some coffee
on a new dress that was hanging over her chair.
"Oh!" said Sarah, "I was going to wear this to
your party!" "What party?" said Helen. "Come
on," said Sarah, "Let's go see if we can get the
Did stain
anyone out."
say something they shouldn't have said or something awkward?
PERSPECTIVE TAKING: Hinting task
Jane is with her father in a mall, and walks
by a pet store where she sees a cute
puppy. Looking at it, she tells her father “
dad, do you remember it is my birthday
next week?”
Question: What does Jane want her dad to do?
“Getting the gist”
Nornally induces
Synchronous oscillations
(such as gamma waves)
PERCEIVING FRAGMENTS as parts of a whole
can be difficult for people with schizophrenia.
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Speed
Memory
Attention
Reasoning
Tact/Social cognition
Synthesis
Effect Size (Cohen's d )
Cognitive deficits in Schizophrenia
0.2
0
-0.2
-0.4
-0.6
-0.8
-1
-1.2
-1.4
-1.6
-1.8
-2
Memory
Cognitive deficits
in schizophrenia are
Pervasive
Persistent
Present early
Progress early
Predict functional disability
ProblemSolving
IQ
Attention
Perspective- Social Cue
taking
Recognition
Effects Sizes (Cohen’s r):
Neurocognitive Deficits and Functional Outcome
Community Functioning
Neurocognitive
Deficits
Instrumental &
Problem Solving Skills
Skill Acquisition
0 .7
0 .6
Large - 0 .5
0 .4
Medium - 0 .3
0 .2
Small - 0 .1
0 .0
Verbal
Memory
Green et al. 2000
Immediate
Memory
Executive
Functions
Vigilance Summary
Scores
2. Schizophrenia is a disorder of brain
development.
At Birth
6 Years Old
14 Years Old
Synapse density
Normal adolescence is characterized by brain maturational
Refinements including synaptic pruning.
0
5
Feinberg 1982, Keshavan 1994;
Hoffmann and McGlashan 2000
10
15
20
Schizophrenia is related to
excessive pruning of gray
matter in higher brain regions
Schizophrenia also may be related
to failure of white matter expansion
Gogtay et al 2008
Brain structure: Frontal and
temporal gray matter
loss in early schizophrenia
VBM (n=400)
Meda et al 2008
Brain function: Reduced prefrontal
Function
Meta-analysis, Glahn et al 2005
Brain physiology:: Reduced Gamma oscillations
Spencer, McCarley 2004
Reduced brain plasticity in schizophrenia may impair learning
Impaired learning in schizophrenia
Reduced cortical stimulation with TMS
Daskalaikis 2010; Pascual-Leone 2011
Decreased cortical plasticity correlates with
Impaired learning
Cortex
Dopamine/
Glutamatergic
deficit
Impaired
affect
expression
Increased
arousal,
Dysregulation,
Psychosis
Impaired
cortico-limbic
connectivity
Cognitive
deficits,
Negative
symptoms
Limbic
Regions
(i.e. amygdala)
Increased
Mesolimbic
Dopamine
Mid-brain
3. Such deficits higher brain regions lead to “disinhibition” of emotional brain regions
Leading to psychosis and mood instability
Aleman and Kahn 2005; Weinberger 1987
• What is brain plasticity?
• Altered neuroplasticity may underlie cognitive
deficits in schizophrenia
• Plasticity based interventions may remedy
cognitive deficits and improve outcome
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The PRISM Principles of cogntive remediation
CET and how it is applied
Does CET work?
How does it work?
What are the next steps?
COGNITION AND NEUROTRANSMITTERS
Norepinephrine
Acetylcholine
Stimulants
Dopamine
Atomoxetine
(nicotinergic)
COMT antagonists
Modafinil
Nicotinic agonists
Acetylcholine
(muscarinic)
Histamine
H3 antagonists
Ach-ase antagonists
Muscarinic agonists
Cannabinoid
receptors
GABA
GABA agonists
Glutamate
CB1 antagonists
Glutamate agonists
NMDA antagonists
Several pharmacologic agents being tried now for cognitive deficits in schizophrenia,
but have little benefit
Pharmacological Treatments for
Cognition
Effect Size (Cohen's d )
Enter: cognitive remediation
1
0.9
(L) 0.8
0.7
0.6
(M) 0.5
0.4
0.3
(S) 0.2
0.1
0
Antipsychotics d-Cycloserine
(Keefe
(Buchanan et
et al., 2007)
al., 2007)
Glycine
(Buchanan et
al., 2007)
Galantamine Practice Effect
(Buchanan et (Goldberg et
al., 2008)
al., 2007)
Worse
Better
Cognitive
remediation
works!
Til Wykes et al 2011
The meta-analysis (2,104
participants) yielded durable
effects on global cognition
and functioning.
PRINCIPLES OF COGNITIVE REMEDIATION #1: PROGRESSIVE.. AND
BOTTOM-UP.
Psychophysical Improvement on the Auditory discrimination Training Exercise
predicts Improvement in Global Cognition Composite Score
Adcock, R. A. et al. Schizophr Bull 2009 35:1132-1141; doi:10.1093/schbul/sbp068
“Bottom-up”Improvements in elemental cognitions predict global
cognitive benefits
Copyright restrictions may apply.
PRINCIPLES OF COGNITIVE REMEDIATION #2: REPETITION AND PRACTICE.
•“The more the neurons fire together, the more they wire together”
Long term plasticity
PRINCIPLES OF COGNITIVE REMEDIATION #3..
Individualizing the cognitive training.
• intrinsically motivating
instructional approach
– (a) Tailoring the
interventions to the
individual’s cognitive
style.
– (b) Personalizing
elements of the learning
materials into themes of
high interest value,
– (c) Autonomy. so patients
can increase their control
over the learning
process.
Choi and Medalia 2009
PRINCIPLES OF COGNITIVE REMEDIATION #4
Stress management
High level of stress/ arousal diminishes performance.
4. Strategy and Top-down
approaches work better
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
McGurk et al
CR+
CR+
Rehab
Rehab
CRCR- Rehab
Rehab
PRINCIPLES OF COGNITIVE REMEDIATION #5: MOTIVATION.
Gard et al 2009
(a) personalizing elements of the
learning materials into themes
of high interest value,
(b) Autonomy. so patients can
increase their control over the
learning process.
(c) Using exercises that are
engaging.
Intrinsic motivation
Principles of CET
• Progressive, “Bottom-up”
• Repetition, and Practice.
• Individualized to patient’s cognitive style, ability
and progress
• Stress Free, Success oriented and Strategic,
Top-Down
• Motivation, Focus on Intrinsic motivation
Components of CET
• Support, education, Internal coping
• Neurocognitive remediation
– Attention, memory, and problemsolving modules (1 – 1.5
hours/week; ~60 hours)
– Done in pairs; computer exercises;
Computer exercises done in pairs
coaching by clinician
• Social-Cognitive Group Therapy
– Training in perspective-taking,
gistfulness,
– non-verbal communication,
emotional temperature
perception, etc (1.5 hours/week;
about 45 sessions)
Group sessions with homework
– Acting wisely in social situations;
–www.CognitiveEnhancementTherapy.com
Appraising the social context;
CET is effective in chronic as well as early course
schizophrenia
Hogarty.. et al 2004;
Eack…Keshavan 2009
CET has Real-world benefits on Functioning and
Symptoms (3 year follow up)
• Functioning (pervasive)
– Employment (CET=58%; EST=19%)
– Social functioning
– Global adjustment
– Activities of daily living
• Symptoms
– Negative symptoms
– Anxiety and depression
– No effects on positive symptoms, as expected
Eack, Greenwald, Keshavan Psychological Medicine 2010
What predicts response to CET?
More gray and white matter (“brain reserve”) to begin with,
the better is the response to CET Keshavan et al 2011
The more the brain change, the larger was
the improvement in social cognition
Eack et al Arch Gen Psychiatry 2010
CET benefits are durable in early course
schizophrenia even after discontinuing treatment
ESSENCE study
Eack..Keshavan Schiz Res 2010
Cognitive impairments and remediation effects are
agnostic to diagnoses
Cognitive
flexibility
Attention bias (
Emotion
regulation
WM
interference
Social cognition
deficits
ADHD (Wexler,
Tamm, Halperin)
*
*
*
**
-
Anxiety d/o (Etkin,
Bar-Heim))
*
**
**
*
-
MDD (Etkin)
Bipolar disorder
(Dickstein)
**
**
**
**
**
**
**
**
*
Autism (Eack,
Scherf)
**
**
**
*
***
Schizophrenia
(Eack, Vinogradov,
Keshavan),
VLFS (Kates)
***
***
***
***
***
Healthy aging
(Gazzaly)
NIH workshop April 2012;
Keshavan et al Am J Psychiatry Under Review
*
Cognitive remediation releases
Brain derived neurotrophic factor
BDNF also powerfully
Induced by:
Physical exercise
SSRIs
Ampakines
TMS
Serum brain-derived neurotrophic factor (BDNF) levels (ng/mL) in schizophrenia subjects
participating in 50 hours of computerized auditory training (AT) versus subjects participating
in 50 hours of computer games (CG).
Vinogradov et al 2009
Can brain stimulation enhance benefits with
cognitive remediation?
• Repetitive transcranial magnetic stimulation for
negative symptoms of schizophrenia: review and metaanalysis. Dlabac-de Lange JJ, Knegtering R, Aleman A. J
Clin Psychiatry. 2010 Apr;71(4):411-8. Epub 2010 Feb 23.
Studies with a longer duration of treatment (> or =3 weeks) had a larger mean
effect size when compared to studies with a shorter treatment duration:
d = 0.58 (95% CI, 0.19-0.97) and d = 0.32 (95% CI, -0.3 to 0.95), respectively.
New directions
0.7
0.6
0.5
•
CR+ other psychosocial
(e.g. Supportive
employment,
Metacognitive therapy,
Motivation enhancement,
CBT)
•
CR+Pharmacologic;
addition as well as
subtraction?
•
CR+Brain stimulation/other
non-pharmacological
approaches (TBS, TDC,
rTMS
•
CR+ Motor/physical
exercise
0.4
Adjunctive PR
No Adjunctive PR
0.3
0.2
0.1
0
McGurk et al., 2007
N=11
Wykes et al., 2011
N=19
Key question:
Value of strategic combinations
Combining treatments: more than
the sum of its parts
Medication “subtractions” can help
cognition
• Unnecessary use of anticholinergic (antiparkinson), sedatives and antihistamine
medications (such as diphenhydramine) to be
avoided
• Some mood stabilizers may interfere with
cognition (e.g. Topiramate)
• Too many medications in general and use of too
high a dose to be avoided
Other approaches:Cognitive adaptation
is of value as well (Velligan et al 2006)
Global Cognition Improved After training
in schizophrenia prodrome
MATRICS T-Scores
60
p=.008*
[d=.43]
T-Score
55
p=.056
50
[d=.25]
p=.055
Pre TCT
[d=.26]
Post TCT
45
40
Hooker et al unpublished
Cognitive Domain
Prodromal Positive Symptoms
Improved After Training
SIPS: Structured Interview for
Prodromal Syndromes
16
p=.05*
[.28]
severity level
14
12
10
8
6
Pre TCT
4
Post TCT
2
0
Positive
Hooker et al unpublished
Negative
Disorganization
Symptoms
General
Take home points
• The brain has a remarkable ability to repair itself, a
phenomenon known as plasticity
• Cognitive deficits (Speed, Memory, Attention, Reasoning,
Tact, Synthesis) are related to altered brain plasticity
• Cognitive deficits and the brain changes may be
reversible with neuroplasticity based cognitive
remediation, have durable real-world benefits
• Cognitive remediation works best when it is Progressive,
Repetitive, Individualized,Strategic and includes a
Motivational component.
• Deficits in brain plasticity may set in early. Early
intervention may have large positive implications for
outcome
Thanks to
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Mary Carter PhD
Susan Cooley
Raymond Cho MD
Anne-Louis DiBarry
Shaun Eack PhD
Sam Flesher PhD
Debbie Greenwald PhD
Susan Hogarty MSN
Summer Mcknight
Diana Mermon MA
Jean Miewald MA
Debra Montrose PhD
Konasale Prasad MD
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Alyssa Alfieri MA
Angelica Daiello BS
Ann Findiessen
Irakles Giakoumatos
Chiara Haller PhD
Rosa Johnson
Raquelle MesholamGateley PhD
Tom Monteleone
Corin Pilo MSW
Larry Seidman PhD
Heidi Thermenos PhD
Joanne Wojcik PhD
AND OF COURSE ALL OUR STUDY PARTICIPANTS