Transcript Lack of Specificity for Brain Function Results in Lack of

Flexibility in Brain and
Behavioral Functioning in
ADHD: Implications for
Treatment
Julie
Schweitzer,
Ph.D. Ph.D.
Julie
Schweitzer,
• M.I.N.D. Institute
• Department of Psychiatry &
Behavioral Sciences
A Lack of Flexibility Is Consistent with
Impairment in “Separating the Wheat from
the Chaff”
• Review behavioral
and neural symptoms
consistent with this
model
• Consequences of this
impairment
• Behavioral and
pharmacological
treatment implications
In separating the wheat from
the chaff, you select what is
useful or valuable and reject
what is useless or worthless.
ADHD

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

Most prevalent childhood psychiatric disorder
Greater than 2 million in United States
3% to 5% of childhood population
4% of adults
5 males to 1 females
Females more inattention & cognitive problems;
males more conduct & impulse problems

Key symptoms
Attention, hyperactivity (restlessness), impulsivity
Comorbidity
•
•
•
•
•
•
Learning disabilities
Anxiety
Depression
Oppositional Defiant Disorder
Conduct Disorder
Autism
ADHD Individuals Have Difficulty Matching
Their Behavior and Brain Functioning to
Current Task Demands
• flex·i·bility (flex'i·bil'i·ty)
The ability to adjust readily to different conditions
A lack of specificity for
brain function
symptomatic of lack of
flexibility
Underlying Mechanism for
Impaired Flexibility: One Hypothesis
• Intra-individual variability (IIV)
– Measure of variability in performance within
an individual
– Usually measured via response time
– Fluctuations occur over a period of seconds
and is distinguished from systematic changes
related to practice or learning
– Observable in natural situations
• Children with ADHD are “consistently inconsistent”
• Appears to be heritable
• Responds to medication
Example of IIV in
Working Memory
– Predominant research in IIV in ADHD until
recently has been in response inhibition
– If IIV is a more general phenomenon expect
to see in other areas of ADHD impairment
– Working memory known to be impaired in
ADHD
• Working memory is the ability to maintain and
manipulate information over short periods of time
– Is there evidence for IIV differences between
ADHD and controls in working memory?
No Group Differences in Working Memory
Accuracy, Only Omission Errors
1.00
ADHD N=25
Controls N=24
0.90
Accuracy (%)
• No group differences in
accuracy
• Thus, no global impairment in working memory
0.80
0.70
0.60
0.50
• Omission errors
• Omission errors reflective of
“inattention” loss of focus
2
3
Level of Task Difficulty
25
O mission Errors (%)
Differences in Group, Level,
Group X Level
1
20
15
10
5
0
Buzy et al., in press, Child
Neuropsychology
1
2
Le ve l of Task Difficulty
3
IIV Group Differences in Working
Memory Paradigm
ADHD significantly more IIV in response time
Group main effects
600
Tau (d = .90); p < 0.01
ADHD N=25
Controls N=24
Tau (ms)
500
400
300
200
100
Buzy et al., in press
Child Neuropsychology
0
1
2
Level of Task Difficulty
3
Measures of IIV Are Significantly Correlated with
Hyperactivity & Restlessness/Impulsivity (n=25)
Accuracy
Omission
Errors
Mu
Sigma
Tau
.30
-.02
.27
.17
.37
Hyperactivity
.41*
.27
.54**
.35
.49*
Restlessness-Impulsivity
.28
.23
.40*
.16
.35
ADHD Index
.27
.04
.22
.06
.13
CPRS–R:L Scales
Cognitive Problems /
Inattention
Increased PreSMA Activation in ADHD
Associated with > Variability; Opposite for HCs
Pre-SMA; Region significantly
different in correlation between
ADHD & HC
% signal change
Are ADHD subjects using prefrontal & motor
regions to compensate at the expense of
availability for higher-order tasks?
Intrasubject Variability on
No-Go Condition
Suskauer et al., 2008
Default Network and Attention
•Regions along brain’s medial wall that are deactive
during demanding task performance (Raichle et
al.,2001)
•Regions are active when
-monitoring the environment, body or emotional
state
- internal thought processes or mind wandering
•Suppression of these regions (i.e., deactivation)
during cognitively-demanding tasks is linked to
successful performance Raichle et al., (2001)
•Inability to suppress activation in this network is
linked to distraction, errors or momentary attention
lapses
Anticorrelation between Default Network and
Task-Related Regions During Resting State
Study in Adults with ADHD
Castellanos et al., 2008: Bio Psych
Decreased functional connectivity
between dorsal ACC seed & posterior
components of default-mode network (i.e.,
precuneus and post cingulate) in ADHD.
Relationship between Task Difficulty
and Deactivation
• Degree of suppression in controls related to task
difficulty, with greater deactivation associated with
increasing difficulty McKiernan et al., (2003)
• Our data (Fassbender et al., under review) suggest that
in ADHD medial PFC activation is not different from
baseline, with the exception to moderate deactivation in
ACC/medial PFC.
• HC children display significant deactivation in medial
PFC during control and WM tasks with increased
deactivation during the more difficult WM task.
Deactivation in Default Mode Network during WM and
Control Task Performance in ADHD and HC Groups
4
0
-4
-8
-12
-16
x = -3
Signal
change
PC/precuneus
4
1
2
*
*
*VSAT
AT
2
x=0
x=3
3
3
2
x=6
4
1
ACC/mPFC
4
0
-4
-8
-12
-16
4
0
-4
-8
-12
-16
4
0
-4
-8
-12
-16
ADHD
1
2
*
*
Med PFC
1
2
*
*
Pc/cun
1
2
*
*
* *
Both groups deac
Under review
x = -6
HC
Fassbender et al.,
1
Correlation between IIV & Medial
PFC Activity in Subjects with ADHD
Greater activity in the medial PFC linked to greater IIV on task. Thus,
those ADHD participants with the greatest IIV are least able to suppress
activity in medial PFC within the default attention network
Fassbender et al., under review
Working-Memory Associated Task
Performance Activation Reveals A Lack of
Specialization for WM in ADHD
HCs more likely
to show different
activation
pattern between
control (AT) &
WM (VSAT)
task; ADHD
group does not.
Schweitzer et al., under
review
• Is lack of specialization of brain
function consistent with greater
activation than HCs in alternate
regions?
Working Memory Related Changes In
Adults with ADHD – Compensation?
HC > ADHD
Control group demonstrates
WM activation associated
with verbal rehearsal
strategies & inhibitory
control
ADHD > HC
ADHD group demonstrates WM
activation associated with motor &
visual processing suggestive
of compensatory brain regions and
strategies.
Schweitzer et al, Biological Psychiatry, 2004
Grey Matter Difference Maps (A) and Statistical
Maps (B) in Children with ADHD and Controls
ADHD subjects show a 20–30% increase in greymatter density in bilateral temporal & inferior parietal
Sowell et al., 2003
regions
Children with ADHD Demonstrate Delayed
Cortical Maturation in Most Areas
An exception is in the primary
motor cortex where the
ADHD group demonstrated
earlier cortical maturation
Shaw, P. et al. 2007,
PNAS.
How Does ADHD Affect The Ability
to Use Environmental Cues?
Wide Attention
focus
Take in both relevant arrow plus
distracter arrows
<<><<
High
Conflict
Narrow Attention
focus
Take in center arrow only
<<><<
Low
Conflict
DSM subtypes
Combined
Inattentive
HyperactiveImpulsive
Is there any difference in how different ADHD
subtypes perceive environment & cues?
Cognitive Control
Cued flanker paradigm
Incongruent <<><<
Uninformative
Cue
General Cue
Informative Cue
(No information)
conflict
(Prepare for an
incongruent flanker)
alerting
(Prepare to press
with your right hand)
atten control/
preparation
PERCENT CORRECT
RESPONSES TO TARGET
100
ADHD-CO
ADHD-IA
90
HC
80
70
60
50
NULL CUE
(No information)
WARNING CUE
RESPONSE
PREPARATION
(Prepare for an
CUE
incongruent flanker)
(Prepare to press
with your right hand)
CUE
TARGET
<<><<
IA not benefiting
from specific
cue
Performance Monitoring/Response
Preparation in ADHD Subtypes
•
Treatment implications: Different subtypes
may benefit more from one type of cueing
than another e.g., IA with general cues
Effect of MPH on WM Brain
Activation: Narrows the Focus
MPH may enhance
performance by
improving PFC’s ability
to filter out distracters.
med
frontal
gyrus
thalamus
Schweitzer et al, 2004
mid frontal
gyrus
precentral
gyrus
Conclusions/Future Directions
• Individuals with ADHD display greater IIV than HCs
in behavior and brain functioning
• Findings from IIV-brain imaging studies and general
imaging studies suggest ADHD use alternate, wider
range of activations suggesting
–
–
–
–
Lack of specificity for function
Lack of efficiency and utility in brain activation
Effect of behavioral/task strategies
Leads to lack of flexibility & ability to make use of
environmental cues
• Does inflexibility limit ability to generalize
behavioral tx from one setting to another?
When you separate the wheat from the
chaff, you select what is useful or valuable
and reject what is useless or worthless.
(Wikipedia?)
Acknowledgements
University of California
Davis/MIND Institute
Catherine Fasbender, Ph.D
Joan Gunther, Psy.D.
Danielle Mizuiri, B.S.
Faye Dixon, Ph.D.
Sharon Coffey Corina, B.S.
Ron Mangun, Ph.D.
Cameron Carter, M.D.
University of Maryland
Baltimore
Wendy Buzy, Ph.D
Mark Cochran, Psy.D.
Carlos Cortes, M.D.
Rao Gullapalli, Ph.D
Deborah Medoff, Ph.D
Gloria Reeves, M.D.
Malle Tagamets, Ph.D.
Jiachen Zhuo, M.S.
Thomas A. Windsor, B.A.
Disclosures
• NIMH
• NIDA
• UC Davis School of Medicine