An Explanatory Account of (Some)
Cognitive Impairments in Children
With Chromosome 22q11.2 Deletion
Syndrome
Tony J. Simon Ph.D.
Cognitive Analysis and Brain Imaging Lab
(http://cabil.mindinstitute.org)
M.I.N.D. Institute
University of California, Davis
Thursday, October 15, 2009
1
1
Objectives
• Present a description of the typical profile in areas of
cognitive function in children with 22q11.2DS
• Present a possible explanatory account of why (and
how) nonverbal impairments occur in 22q11.2DS
• Provide ways to think about not just what cognitive
problems these children have but how and why
• Stimulate thinking about informal & clinical
responses to impairments to complement possible
interventions
2
Thursday, October 15, 2009
2
Neuropsych/Cognitive Profile
•Standardized tests show a stable pattern for DS22q11.2
•Full Scale IQ: 70-85 (±15)
• Verbal IQ > Performance IQ (in most children)
• Receptive>Expressive language below 5yrs of age, pattern
•
•
•
reversed after that (Solot et al 2001)
Reading/Spelling (low average) are relative strengths but
comprehension is poor (Woodin et al 2001)
Rote memory strong , complex memory verbal and all spatial
memory is poor (Woodin). Working memory is poor (Sobin et al
2005)
Attention (selective and “executive”) is impaired (Woodin/Sobin)
3
Thursday, October 15, 2009
3
PIQ (Mean = .; SD = .) and this discrepancy was statistically significant [t() = .,
P < .]. At the subject level, / children
showed a VIQ > PIQ intellectual profile, whereas
/ showed the reverse pattern. A clinically significant discrepancy of more than  scaled score
Neuropsych/Cognitive Profile
Recent large study De Smedt
et al., 2007
•
•
•
•
•
•
•
•
•
103 children (56 male)
4-17yrs (mean 7yrs 9mos)
FSIQ 50-109 (mean 74.38)
ADHD = 27 (26%)
ASD = 19 (18%)
No other diagnoses
Lower IQ in ASD (not ADHD)
Lower IQ w/ familial deletion
No effects of CHD
attainment level o
factors and FSIQ
an effect of educat
parents on FSIQ (
differences in FSIQ
and familial deletio
P
Deletion
FSIQ
VIQ
PIQ
Sex
FSIQ
VIQ
PIQ
CHD
FSIQ
VIQ
PIQ
Psychiatric
FSIQ
VIQ
PIQ
FSIQ
VIQ
PIQ
De novo (n = 92)
74.50 (11.69)
79.79 (13.91)
73.42 (10.89)
Female (n = 47)
73.19 (10.40)
78.87 (12.27)
72.28 (10.38)
Yes (n = 55)
74.38 (11.84)
79.05 (14.23)
73.56 (10.77)
Non-ADHD (n = 76)
73.32 (12.32)
78.30 (14.78)
72.97 (11.18)
Non-ASD (n = 84)
74.56 (11.83)
79.32 (14.51)
73.71 (10.90)
Familial (n = 11)
65.00 (8.45)
69.27 (11.53)
66.09 (8.84)
Male (n = 56)
73.73 (12.84)
78.50 (15.43)
72.95 (11.39)
No (n = 48)
72.46 (11.65)
78.23 (13.89)
71.58 (11.05)
ADHD (n = 27)
73.96 (10.10)
79.70 (11.76)
71.70 (10.19)
ASD (n = 19)
68.74 (10.26)
75.79 (11.43)
67.89 (9.78)
0.01
0.02
0.03
0.82
0.89
0.76
0.41
0.77
0.36
0.81
0.66
0.61
0.05
0.32
0.03
ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; CHD, congenital heart defect; FSIQ, full-scale IQ; PIQ, performance IQ; SD, standard deviation;
VIQ, verbal IQ.
©  The Authors. Journal Compilation ©  Blackwell
Publishing Ltd
4
Thursday, October 15, 2009
4
PIQ (Mean = .; SD = .) and this discrepancy was statistically significant [t() = .,
P < .]. At the subject level, / children
showed a VIQ > PIQ intellectual profile, whereas
/ showed the reverse pattern. A clinically significant discrepancy of more than  scaled score
Neuropsych/Cognitive Profile
Recent large study De Smedt
et al., 2007
•
•
•
•
•
•
•
•
•
103 children (56 male)
4-17yrs (mean 7yrs 9mos)
FSIQ 50-109 (mean 74.38)
ADHD = 27 (26%)
ASD = 19 (18%)
No other diagnoses
Lower IQ in ASD (not ADHD)
Lower IQ w/ familial deletion
No effects of CHD
attainment level o
factors and FSIQ
an effect of educat
parents on FSIQ (
differences in FSIQ
and familial deletio
P
Deletion
FSIQ
VIQ
PIQ
Sex
FSIQ
VIQ
PIQ
CHD
FSIQ
VIQ
PIQ
Psychiatric
FSIQ
VIQ
PIQ
FSIQ
VIQ
PIQ
De novo (n = 92)
74.50 (11.69)
79.79 (13.91)
73.42 (10.89)
Female (n = 47)
73.19 (10.40)
78.87 (12.27)
72.28 (10.38)
Yes (n = 55)
74.38 (11.84)
79.05 (14.23)
73.56 (10.77)
Non-ADHD (n = 76)
73.32 (12.32)
78.30 (14.78)
72.97 (11.18)
Non-ASD (n = 84)
74.56 (11.83)
79.32 (14.51)
73.71 (10.90)
Familial (n = 11)
65.00 (8.45)
69.27 (11.53)
66.09 (8.84)
Male (n = 56)
73.73 (12.84)
78.50 (15.43)
72.95 (11.39)
No (n = 48)
72.46 (11.65)
78.23 (13.89)
71.58 (11.05)
ADHD (n = 27)
73.96 (10.10)
79.70 (11.76)
71.70 (10.19)
ASD (n = 19)
68.74 (10.26)
75.79 (11.43)
67.89 (9.78)
0.01
0.02
0.03
0.82
0.89
0.76
0.41
0.77
0.36
0.81
0.66
0.61
0.05
0.32
0.03
ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; CHD, congenital heart defect; FSIQ, full-scale IQ; PIQ, performance IQ; SD, standard deviation;
VIQ, verbal IQ.
©  The Authors. Journal Compilation ©  Blackwell
Publishing Ltd
4
Thursday, October 15, 2009
4
PIQ (Mean = .; SD = .) and this discrepancy was statistically significant [t() = .,
P < .]. At the subject level, / children
showed a VIQ > PIQ intellectual profile, whereas
/ showed the reverse pattern. A clinically significant discrepancy of more than  scaled score
Neuropsych/Cognitive Profile
Recent large study De Smedt
et al., 2007
•
•
•
•
•
•
•
•
•
103 children (56 male)
4-17yrs (mean 7yrs 9mos)
FSIQ 50-109 (mean 74.38)
ADHD = 27 (26%)
ASD = 19 (18%)
No other diagnoses
Lower IQ in ASD (not ADHD)
Lower IQ w/ familial deletion
No effects of CHD
attainment level o
factors and FSIQ
an effect of educat
parents on FSIQ (
differences in FSIQ
and familial deletio
P
Deletion
FSIQ
VIQ
PIQ
Sex
FSIQ
VIQ
PIQ
CHD
FSIQ
VIQ
PIQ
Psychiatric
FSIQ
VIQ
PIQ
FSIQ
VIQ
PIQ
De novo (n = 92)
74.50 (11.69)
79.79 (13.91)
73.42 (10.89)
Female (n = 47)
73.19 (10.40)
78.87 (12.27)
72.28 (10.38)
Yes (n = 55)
74.38 (11.84)
79.05 (14.23)
73.56 (10.77)
Non-ADHD (n = 76)
73.32 (12.32)
78.30 (14.78)
72.97 (11.18)
Non-ASD (n = 84)
74.56 (11.83)
79.32 (14.51)
73.71 (10.90)
Familial (n = 11)
65.00 (8.45)
69.27 (11.53)
66.09 (8.84)
Male (n = 56)
73.73 (12.84)
78.50 (15.43)
72.95 (11.39)
No (n = 48)
72.46 (11.65)
78.23 (13.89)
71.58 (11.05)
ADHD (n = 27)
73.96 (10.10)
79.70 (11.76)
71.70 (10.19)
ASD (n = 19)
68.74 (10.26)
75.79 (11.43)
67.89 (9.78)
0.01
0.02
0.03
0.82
0.89
0.76
0.41
0.77
0.36
0.81
0.66
0.61
0.05
0.32
0.03
ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; CHD, congenital heart defect; FSIQ, full-scale IQ; PIQ, performance IQ; SD, standard deviation;
VIQ, verbal IQ.
©  The Authors. Journal Compilation ©  Blackwell
Publishing Ltd
4
Thursday, October 15, 2009
4
PIQ (Mean = .; SD = .) and this discrepancy was statistically significant [t() = .,
P < .]. At the subject level, / children
showed a VIQ > PIQ intellectual profile, whereas
/ showed the reverse pattern. A clinically significant discrepancy of more than  scaled score
Neuropsych/Cognitive Profile
Recent large study De Smedt
et al., 2007
•
•
•
•
•
•
•
•
•
103 children (56 male)
4-17yrs (mean 7yrs 9mos)
FSIQ 50-109 (mean 74.38)
ADHD = 27 (26%)
ASD = 19 (18%)
No other diagnoses
Lower IQ in ASD (not ADHD)
Lower IQ w/ familial deletion
No effects of CHD
attainment level o
factors and FSIQ
an effect of educat
parents on FSIQ (
differences in FSIQ
and familial deletio
P
Deletion
FSIQ
VIQ
PIQ
Sex
FSIQ
VIQ
PIQ
CHD
FSIQ
VIQ
PIQ
Psychiatric
FSIQ
VIQ
PIQ
FSIQ
VIQ
PIQ
De novo (n = 92)
74.50 (11.69)
79.79 (13.91)
73.42 (10.89)
Female (n = 47)
73.19 (10.40)
78.87 (12.27)
72.28 (10.38)
Yes (n = 55)
74.38 (11.84)
79.05 (14.23)
73.56 (10.77)
Non-ADHD (n = 76)
73.32 (12.32)
78.30 (14.78)
72.97 (11.18)
Non-ASD (n = 84)
74.56 (11.83)
79.32 (14.51)
73.71 (10.90)
Familial (n = 11)
65.00 (8.45)
69.27 (11.53)
66.09 (8.84)
Male (n = 56)
73.73 (12.84)
78.50 (15.43)
72.95 (11.39)
No (n = 48)
72.46 (11.65)
78.23 (13.89)
71.58 (11.05)
ADHD (n = 27)
73.96 (10.10)
79.70 (11.76)
71.70 (10.19)
ASD (n = 19)
68.74 (10.26)
75.79 (11.43)
67.89 (9.78)
0.01
0.02
0.03
0.82
0.89
0.76
0.41
0.77
0.36
0.81
0.66
0.61
0.05
0.32
0.03
ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; CHD, congenital heart defect; FSIQ, full-scale IQ; PIQ, performance IQ; SD, standard deviation;
VIQ, verbal IQ.
©  The Authors. Journal Compilation ©  Blackwell
Publishing Ltd
4
Thursday, October 15, 2009
4
PIQ (Mean = .; SD = .) and this discrepancy was statistically significant [t() = .,
P < .]. At the subject level, / children
showed a VIQ > PIQ intellectual profile, whereas
/ showed the reverse pattern. A clinically significant discrepancy of more than  scaled score
Neuropsych/Cognitive Profile
Recent large study De Smedt
et al., 2007
•
•
•
•
•
•
•
•
•
103 children (56 male)
4-17yrs (mean 7yrs 9mos)
FSIQ 50-109 (mean 74.38)
ADHD = 27 (26%)
ASD = 19 (18%)
No other diagnoses
Lower IQ in ASD (not ADHD)
Lower IQ w/ familial deletion
No effects of CHD
attainment level o
factors and FSIQ
an effect of educat
parents on FSIQ (
differences in FSIQ
and familial deletio
P
Deletion
FSIQ
VIQ
PIQ
Sex
FSIQ
VIQ
PIQ
CHD
FSIQ
VIQ
PIQ
Psychiatric
FSIQ
VIQ
PIQ
FSIQ
VIQ
PIQ
De novo (n = 92)
74.50 (11.69)
79.79 (13.91)
73.42 (10.89)
Female (n = 47)
73.19 (10.40)
78.87 (12.27)
72.28 (10.38)
Yes (n = 55)
74.38 (11.84)
79.05 (14.23)
73.56 (10.77)
Non-ADHD (n = 76)
73.32 (12.32)
78.30 (14.78)
72.97 (11.18)
Non-ASD (n = 84)
74.56 (11.83)
79.32 (14.51)
73.71 (10.90)
Familial (n = 11)
65.00 (8.45)
69.27 (11.53)
66.09 (8.84)
Male (n = 56)
73.73 (12.84)
78.50 (15.43)
72.95 (11.39)
No (n = 48)
72.46 (11.65)
78.23 (13.89)
71.58 (11.05)
ADHD (n = 27)
73.96 (10.10)
79.70 (11.76)
71.70 (10.19)
ASD (n = 19)
68.74 (10.26)
75.79 (11.43)
67.89 (9.78)
0.01
0.02
0.03
0.82
0.89
0.76
0.41
0.77
0.36
0.81
0.66
0.61
0.05
0.32
0.03
ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; CHD, congenital heart defect; FSIQ, full-scale IQ; PIQ, performance IQ; SD, standard deviation;
VIQ, verbal IQ.
©  The Authors. Journal Compilation ©  Blackwell
Publishing Ltd
4
Thursday, October 15, 2009
4
PIQ (Mean = .; SD = .) and this discrepancy was statistically significant [t() = .,
P < .]. At the subject level, / children
showed a VIQ > PIQ intellectual profile, whereas
/ showed the reverse pattern. A clinically significant discrepancy of more than  scaled score
Neuropsych/Cognitive Profile
Recent large study De Smedt
et al., 2007
•
•
•
•
•
•
•
•
•
103 children (56 male)
4-17yrs (mean 7yrs 9mos)
FSIQ 50-109 (mean 74.38)
ADHD = 27 (26%)
ASD = 19 (18%)
No other diagnoses
Lower IQ in ASD (not ADHD)
Lower IQ w/ familial deletion
No effects of CHD
attainment level o
factors and FSIQ
an effect of educat
parents on FSIQ (
differences in FSIQ
and familial deletio
P
Deletion
FSIQ
VIQ
PIQ
Sex
FSIQ
VIQ
PIQ
CHD
FSIQ
VIQ
PIQ
Psychiatric
FSIQ
VIQ
PIQ
FSIQ
VIQ
PIQ
De novo (n = 92)
74.50 (11.69)
79.79 (13.91)
73.42 (10.89)
Female (n = 47)
73.19 (10.40)
78.87 (12.27)
72.28 (10.38)
Yes (n = 55)
74.38 (11.84)
79.05 (14.23)
73.56 (10.77)
Non-ADHD (n = 76)
73.32 (12.32)
78.30 (14.78)
72.97 (11.18)
Non-ASD (n = 84)
74.56 (11.83)
79.32 (14.51)
73.71 (10.90)
Familial (n = 11)
65.00 (8.45)
69.27 (11.53)
66.09 (8.84)
Male (n = 56)
73.73 (12.84)
78.50 (15.43)
72.95 (11.39)
No (n = 48)
72.46 (11.65)
78.23 (13.89)
71.58 (11.05)
ADHD (n = 27)
73.96 (10.10)
79.70 (11.76)
71.70 (10.19)
ASD (n = 19)
68.74 (10.26)
75.79 (11.43)
67.89 (9.78)
0.01
0.02
0.03
0.82
0.89
0.76
0.41
0.77
0.36
0.81
0.66
0.61
0.05
0.32
0.03
ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; CHD, congenital heart defect; FSIQ, full-scale IQ; PIQ, performance IQ; SD, standard deviation;
VIQ, verbal IQ.
©  The Authors. Journal Compilation ©  Blackwell
Publishing Ltd
4
Thursday, October 15, 2009
4
PIQ (Mean = .; SD = .) and this discrepancy was statistically significant [t() = .,
P < .]. At the subject level, / children
showed a VIQ > PIQ intellectual profile, whereas
/ showed the reverse pattern. A clinically significant discrepancy of more than  scaled score
Neuropsych/Cognitive Profile
Recent large study De Smedt
et al., 2007
•
•
•
•
•
•
•
•
•
103 children (56 male)
4-17yrs (mean 7yrs 9mos)
FSIQ 50-109 (mean 74.38)
ADHD = 27 (26%)
ASD = 19 (18%)
No other diagnoses
Lower IQ in ASD (not ADHD)
Lower IQ w/ familial deletion
No effects of CHD
attainment level o
factors and FSIQ
an effect of educat
parents on FSIQ (
differences in FSIQ
and familial deletio
P
Deletion
FSIQ
VIQ
PIQ
Sex
FSIQ
VIQ
PIQ
CHD
FSIQ
VIQ
PIQ
Psychiatric
FSIQ
VIQ
PIQ
FSIQ
VIQ
PIQ
De novo (n = 92)
74.50 (11.69)
79.79 (13.91)
73.42 (10.89)
Female (n = 47)
73.19 (10.40)
78.87 (12.27)
72.28 (10.38)
Yes (n = 55)
74.38 (11.84)
79.05 (14.23)
73.56 (10.77)
Non-ADHD (n = 76)
73.32 (12.32)
78.30 (14.78)
72.97 (11.18)
Non-ASD (n = 84)
74.56 (11.83)
79.32 (14.51)
73.71 (10.90)
Familial (n = 11)
65.00 (8.45)
69.27 (11.53)
66.09 (8.84)
Male (n = 56)
73.73 (12.84)
78.50 (15.43)
72.95 (11.39)
No (n = 48)
72.46 (11.65)
78.23 (13.89)
71.58 (11.05)
ADHD (n = 27)
73.96 (10.10)
79.70 (11.76)
71.70 (10.19)
ASD (n = 19)
68.74 (10.26)
75.79 (11.43)
67.89 (9.78)
0.01
0.02
0.03
0.82
0.89
0.76
0.41
0.77
0.36
0.81
0.66
0.61
0.05
0.32
0.03
ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; CHD, congenital heart defect; FSIQ, full-scale IQ; PIQ, performance IQ; SD, standard deviation;
VIQ, verbal IQ.
©  The Authors. Journal Compilation ©  Blackwell
Publishing Ltd
4
Thursday, October 15, 2009
4
Objects, Space & Numbers
Space and Time are very abstract concepts that have “scale”
but no actual values attached to them
•
•
•
we use mental “units” to break them up meaningfully
have to learn “how” much is a(n): inch/second, foot, hour
numbers were invented to describe “how many” units
What if your “mental units” don’t match parts of the real world
accurately?
•
•
space/time estimates will be wrong, numbers won’t make sense
following account explains many (not all) cognitive impairments
of those with 22q11.2DS
Should guide design for novel interventions we hope to build
soon!
5
Thursday, October 15, 2009
5
Spatiotemporal Resolution
Representations are configurations of elements
• of given size, orientation, color, intensity ......
– digital image (picture) elements are pixels
Size of elements (grains) is called “granularity”
Larger, (& thus fewer) elements to represent space and time
would lower resolution & impact mental computations
• mental image is “grainer” (like digital camera)
• so resolution of mental pictures is worse
• discriminating requires “more difference” to be accurate
6
Thursday, October 15, 2009
6
Reduced Space & Time Resolution
Thursday, October 15, 2009
7
“Crowding” & Attentional Resolution
From Cavanagh, 2004
Thursday, October 15, 2009
8
Measuring Parts of Space
Task: Press button to choose
who Kermit the Frog is closer to
(Miss Piggy or Fozzie Bear?)
Neither
Fozzie
Piggy
When Kermit is not close to one
end or at the center, error occurs
9
Thursday, October 15, 2009
9
Measuring Parts of Space
Task: Press button to choose
who Kermit the Frog is closer to
(Miss Piggy or Fozzie Bear?)
Neither
Fozzie
Piggy
When Kermit is not close to one
end or at the center, error occurs
9
Thursday, October 15, 2009
9
Measuring Parts of Space
Task: Press button to choose
who Kermit the Frog is closer to
(Miss Piggy or Fozzie Bear?)
Neither
Fozzie
Piggy
When Kermit is not close to one
end or at the center, error occurs
9
Thursday, October 15, 2009
9
Measuring Space
90
80
70
E
r
r
o
r
60
50
DS22q11.2
Control
40
30
20
10
20
16
12
8
4
0
-4
-8
2
-1
6
-1
-2
0
0
Kermit is nearer to?
Fozzie
Piggy
Bigger “pixels” reduce spatial accuracy (resolution) when
location in space is unclear (i.e. not center or ends) 10
Thursday, October 15, 2009
10
Measuring Time
Duration comparison:
Judge longer of two
durations:
400ms vs +/- 10ms diff.
(staircase method)
Auditory & visual
From Debbané et al., 2005
Increased threshold (bigger difference) due to “bigger pixels”
thus reduced resolution of mental time representations.
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11
Spatiotemporal Attention - MOT
12
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12
Spatiotemporal Attention - MOT
3.0
MOT TouchScreen "k" Statistic - 30fps &
60fps
2.8
2.6
Average "k" Values
2.4
2.2
2.0
1.8
1.6
TD-30fps
22q-30fps
TD-60fps
22q-60fps
1.4
1.2
1.0
0.8
0.6
One
Two
Three
Number of Targets
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13
Comparing Quantities
Task: Choose the “bigger” of the two
bars or numbers
• difference between values is varied
Much easier to confuse two values
when they are “close together”
61
People represent quantities in
mental space (small L A R G E)
• smaller “distance” = less distinct
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14
Comparing Quantities
Impairment (∂<5) due to reduced resolution of mental space
representations and NOT general impairment
1400
Distance Effect
Con=18, 22q=29, TS=15, FX=5
Con
22q
1300
1200
Adjusted RT (ms)
1100
1000
900
800
700
600
500
400
One
Two
Three
Five
Difference
Thursday, October 15, 2009
Six
Seven
15
15
Navigating Space to get Numbers
Task: Say out loud, as fast as possible, how many green
boxes you see
Mental pictures of 3 or fewer usually created “all at once”
But for larger sets must find and count one object at a time
• then treat all the collected parts as a whole = 7
Small N not dependent on spatial attention, Large N is
16
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16
Navigating Space to get Numbers
Task: Say out loud, as fast as possible, how many green
boxes you see
Mental pictures of 3 or fewer usually created “all at once”
But for larger sets must find and count one object at a time
• then treat all the collected parts as a whole = 7
Small N not dependent on spatial attention, Large N is
16
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Navigating Space to get Numbers
NO impairment with small sets but searching and counting
errors when groups are large and complex
7000
6500
Enumeration
Con=30, 22q=29, TS=12, FXS=5
22q RT
Con RT
6000
5500
5000
Adjusted RT (ms)
4500
4000
3500
3000
2500
2000
1500
TD undercounts here = 54%
22q undercounts here = 70%
1000
500
0
One
Two
Three
Four
Five
Quantity
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Six
Seven
Eight
17
17
Brain Structure & Connections
Well-defined brain circuits typically process space/time info
• described in mature humans and animals
• many components are atypical in DS22q11.2
• critical ones are early-developing subcortical regions
Changes might create suboptimal spatiotemporal circuits
• output impairs typical development
• weaker cortical circuits for space/time/number cognition
Connectivity should be responsive target for intervention!
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Time & Space Related Circuits
© 2001 Nature Publishing Group http://neurosci.nature.com
a r t icles
Identified in animals & humans. Midline, subcortical areas critical
Time
© 2001 Nature Publishing Group http://neurosci.nature.com
earlier imaging epochs (2.5 and 5.0 s), subcortical activations
unique to the T condition were in the right hemisphere and
included the putamen (x, y, z = 24, 7, –2), caudate (15, 6, 13) and
insula/frontal operculum (29, 16, 2). The later region, however,
was also activated during the 7.5-s epoch in the pitch condition
(Table 2, Fig. 4a). During the later imaging epochs
(7.5 s), the right DLPF cortex (21, 21, 30) was also unique to the
T condition (Fig. 6).
b
Space
Fig. 4. Activation foci in the basal ganglia (a), cerebellum (b), and presupplementary motor area/anterior cingulate (c) resulting from subtraction of the control (C) condition from the time (T) and the pitch (P)
perception conditions at 2.5, 5.0, 7.5 and 10.0 s after trial onset.
Significant foci (p < 0.001) are displayed with a red-yellow intensity scale
denoting greater activation for the T or P conditions. Slices are displayed
in neurological view (left is on the viewer’s left). Location of slices defined
by the distance (mm) from anterior commissure: x, right (+)/left (–); y,
anterior (+)/posterior (–); z, superior (+)/inferior (–). Caud, caudate
nucleus; Cing, anterior cingulate area; Ins, insula; Oper, frontal operculum; Put, putamen; Thal, thalamus; SMA, supplementary motor area.
a
DISCUSSION
c
From Rao et al., 2001
T and P conditions (Table 2), and included the inferior frontal
gyrus (Broca’s area, BA 44/45), intraparietal sulcus (BA 40), superior parietal lobule/precuneus (BA 7) and DLPF cortex.
Thursday, October
15, 2009
The results
from the T minus P subtraction were similar to
The present findings provide compelling evidence for the involvement of the basal ganglia in formulating representations of time.
Activation in the right putamen and caudate were uniquely associated with encoding time intervals. These results corroborate
studies in Parkinson’s disease showing that dopaminergic treatment improves motor timing30,31 and time perception32. Pharmacological challenges in animals also suggest that dopaminergic
antagonists and agonists respectively slow down and speed up
timing operations12,13. Contrary to one proposal33, these and
19
other studies10,11,27 show that the basal ganglia are involved in
timing a wide range of intervals, from hundreds of milliseconds
(300 ms) to tens of seconds (20 s). Collectively, these results
implicate striatal dopaminergic neurotransmission in hypothet-
From Karnath et al., 2002
Bish, 2004; Shapiro, 2008
19
Volumetric Findings - Gray
TD > 22q
• Interhemisphere
• Cerebel, Culmen
• Mid/Post.
Cingulate
• Fronto-Temporal
• Thalamus,
Caudate
22q > TD
• R. Insula,
• R. MFG
Simon et al. NeuroImage, 2005
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Cavum Septum Pellucidum
When 2 sides of ventricles do
not grow together after infancy
Introduced new “extreme”
category of CSP >15mm length
• 80% of TD no/normal CSP
• 36% of 22q abnormal CSP
• 24% extreme
CSP volume did not
correlate with IQ
Beaton et al., submitted
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Hippocampal Changes
Measured hippocampus &
amygdala volume in 72 7-14 yrolds
• 36 22q11.2DS, 36 TD
No differences in amygdala
• unlike Kates et al, 2006
Left, not right, hippocampal
volume smaller in 22q11.2DS
• 2.31cm3 vs 2.56cm3, p<.01
Volume correlated differentially
with IQ measures
Controls (n=20)
DS22q11.2 (n=21)
Left
Right
Left
Right
0.30
0.37
.49*
.62**
.60**
.57*
0.25
0.42†
0.38
0.31
.48*
.58*
VC / VCI
Pearson's r
PO / PRI
Pearson's r
FSIQ
Pearson's r
† p<.10
* p<.05
** p<.01
DeBoer et al., 2007
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Cerebellar Changes
Vermis/Lobes traced from midsagittal slice
Relative to controls, smaller:
• 22q total cerebellum
• 22q anterior lobe
• 22q neocerebellum
• 22q cerebellar tonsils
Bish et al., 2006
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Dysconnectivity
&
Spatial
Attention
y
x
z
Connectivity relates
to water diffusion as
white matter has high
water content
Clusters suggest
different connectivity
regions in 22q vs TD
• strong correlation
with spatial attention
Simon et al., 2008
Thursday, October 15, 2009
Axial = x (primary)
Radial = average(y+z)
FA = Axial/Total
In all clusters:
FA: 22q>TD, p<.0001
RD: TD>FA, p<.0001
24
24
Dysconnectivity
&
Spatial
Attention
y
x
z
Connectivity relates
to water diffusion as
white matter has high
water content
Clusters suggest
different connectivity
regions in 22q vs TD
• strong correlation
with spatial attention
Simon et al., 2008
Thursday, October 15, 2009
Axial = x (primary)
Radial = average(y+z)
FA = Axial/Total
In all clusters:
FA: 22q>TD, p<.0001
RD: TD>FA, p<.0001
24
24
Gyrification in 22q11.2DS
Left
Right
Ant.
Post.
Gyrification changes capture key(a)
structural/connective changes
Indicate joint impact of genetic & neuroconstructive influences?
25
Figure 2: Significant vertices, and clusters where
the LGI
icantly greater than those for the 22q11.2DS population,25 c
Thursday, October 15, 2009
Object Tracking Brain Differences
7 TD
8 22q11.2DS
1 target >
passive
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26
Summary
New hypotheses MAY explain cognitive problems
• changes can be seen in parietal & frontal network
BUT, may result from problems in more basic circuits
Not all areas of nonverbal function are impaired
• where they are, they are not due to general dysfunction
So areas of strength provide:
• pathways to improved learning in problem areas
• target levels to be reached by interventions on impairments
Identification rates are very low - have to find kids before we
can help them - hopefully you can help!
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Thanks
MOST important: Kids who participated & their families!!
NICHD/NICH for funding 2R01HD42974 8/2009-7/2013
Majority of the work presented here was done by:
• Joel Bish Ph.D., Lijun Ding Ph.D., Vy Nguyen, Leeza
Gabriel, Margie Cabaral, Zhongle Wu Ph.D, Elliott Beaton
Ph.D., Siddarth Srivastava, Ph.D.
With important contributions from:
• Brian Avants Ph.D., Tracy DeBoer Ph.D., Yukari Takarae
Ph.D., Gary Zhang Ph.D., Marisol Mendoza
UC Davis Center of Excellence in Developmental Disabilities
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