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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. InstituteUniversity of California, Davis
1
1Thursday, October 15, 2009
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
2Thursday, October 15, 2009
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
3Thursday, October 15, 2009
Neuropsych/Cognitive ProfileRecent 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
tests were used in case of non-normally distributedvariables.
Results
Full-scale IQ ranged from to . It was normallydistributed around a mean of . (SD = .),which is about SD lower than the mean FSIQ(Mean = ; SD = ) in normally developing sub-jects. In our sample, / children showed normalintellectual development (FSIQ > ). Forty-sevenchildren showed borderline intellectual functioning(FSIQ between and ). Mild intellectual disabil-ity (FSIQ between and ) was present in chil-dren. Four children showed a moderate intellectualdisability (FSIQ < ).
VIQ (Mean = .; SD = .) was higher thanPIQ (Mean = .; SD = .) and this discrep-ancy was statistically significant [t() = .,P < .]. At the subject level, / childrenshowed a VIQ > PIQ intellectual profile, whereas/ showed the reverse pattern. A clinically sig-nificant discrepancy of more than scaled score
points was found in children: of them showeda VIQ > PIQ profile and had a PIQ > VIQdiscrepancy.
Table provides an overview of the investigatedvariables that might influence variability in IQ inVCFS. Inheritance of the deletion affected cognitiveperformance in VCFS, with children with familialdeletions having significant lower FSIQ than chil-dren with a de novo deletion [t() = .,P = .]. We further examined whether this differ-ence in FSIQ between both groups could beexplained by the educational attainment level of theparents. Parents of children with de novo deletionshad higher educational levels than parents of chil-dren with familial deletions (Wilcoxon two-sampletest, W = ., P < .). We further ran an ,with inheritance of the deletion and educationalattainment level of the parents as between-subjectfactors and FSIQ as dependent variable. There wasan effect of educational attainment level of theparents on FSIQ (F4,97 = ., P < .) and groupdifferences in FSIQ between children with de novoand familial deletions disappeared (F1,97 = .,
Table 1 Group means (SD)
P
Deletion De novo (n = 92) Familial (n = 11)FSIQ 74.50 (11.69) 65.00 (8.45) 0.01VIQ 79.79 (13.91) 69.27 (11.53) 0.02PIQ 73.42 (10.89) 66.09 (8.84) 0.03
Sex Female (n = 47) Male (n = 56)FSIQ 73.19 (10.40) 73.73 (12.84) 0.82VIQ 78.87 (12.27) 78.50 (15.43) 0.89PIQ 72.28 (10.38) 72.95 (11.39) 0.76
CHD Yes (n = 55) No (n = 48)FSIQ 74.38 (11.84) 72.46 (11.65) 0.41VIQ 79.05 (14.23) 78.23 (13.89) 0.77PIQ 73.56 (10.77) 71.58 (11.05) 0.36
Psychiatric Non-ADHD (n = 76) ADHD (n = 27)FSIQ 73.32 (12.32) 73.96 (10.10) 0.81VIQ 78.30 (14.78) 79.70 (11.76) 0.66PIQ 72.97 (11.18) 71.70 (10.19) 0.61
Non-ASD (n = 84) ASD (n = 19)FSIQ 74.56 (11.83) 68.74 (10.26) 0.05VIQ 79.32 (14.51) 75.79 (11.43) 0.32PIQ 73.71 (10.90) 67.89 (9.78) 0.03
ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; CHD, con-genital heart defect; FSIQ, full-scale IQ; PIQ, performance IQ; SD, standard deviation;VIQ, verbal IQ.
668Journal of Intellectual Disability Research
B. De Smedt et al. • Intellectual abilities in children with VCFS
© The Authors. Journal Compilation © Blackwell Publishing Ltd4
4Thursday, October 15, 2009
Neuropsych/Cognitive ProfileRecent 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
tests were used in case of non-normally distributedvariables.
Results
Full-scale IQ ranged from to . It was normallydistributed around a mean of . (SD = .),which is about SD lower than the mean FSIQ(Mean = ; SD = ) in normally developing sub-jects. In our sample, / children showed normalintellectual development (FSIQ > ). Forty-sevenchildren showed borderline intellectual functioning(FSIQ between and ). Mild intellectual disabil-ity (FSIQ between and ) was present in chil-dren. Four children showed a moderate intellectualdisability (FSIQ < ).
VIQ (Mean = .; SD = .) was higher thanPIQ (Mean = .; SD = .) and this discrep-ancy was statistically significant [t() = .,P < .]. At the subject level, / childrenshowed a VIQ > PIQ intellectual profile, whereas/ showed the reverse pattern. A clinically sig-nificant discrepancy of more than scaled score
points was found in children: of them showeda VIQ > PIQ profile and had a PIQ > VIQdiscrepancy.
Table provides an overview of the investigatedvariables that might influence variability in IQ inVCFS. Inheritance of the deletion affected cognitiveperformance in VCFS, with children with familialdeletions having significant lower FSIQ than chil-dren with a de novo deletion [t() = .,P = .]. We further examined whether this differ-ence in FSIQ between both groups could beexplained by the educational attainment level of theparents. Parents of children with de novo deletionshad higher educational levels than parents of chil-dren with familial deletions (Wilcoxon two-sampletest, W = ., P < .). We further ran an ,with inheritance of the deletion and educationalattainment level of the parents as between-subjectfactors and FSIQ as dependent variable. There wasan effect of educational attainment level of theparents on FSIQ (F4,97 = ., P < .) and groupdifferences in FSIQ between children with de novoand familial deletions disappeared (F1,97 = .,
Table 1 Group means (SD)
P
Deletion De novo (n = 92) Familial (n = 11)FSIQ 74.50 (11.69) 65.00 (8.45) 0.01VIQ 79.79 (13.91) 69.27 (11.53) 0.02PIQ 73.42 (10.89) 66.09 (8.84) 0.03
Sex Female (n = 47) Male (n = 56)FSIQ 73.19 (10.40) 73.73 (12.84) 0.82VIQ 78.87 (12.27) 78.50 (15.43) 0.89PIQ 72.28 (10.38) 72.95 (11.39) 0.76
CHD Yes (n = 55) No (n = 48)FSIQ 74.38 (11.84) 72.46 (11.65) 0.41VIQ 79.05 (14.23) 78.23 (13.89) 0.77PIQ 73.56 (10.77) 71.58 (11.05) 0.36
Psychiatric Non-ADHD (n = 76) ADHD (n = 27)FSIQ 73.32 (12.32) 73.96 (10.10) 0.81VIQ 78.30 (14.78) 79.70 (11.76) 0.66PIQ 72.97 (11.18) 71.70 (10.19) 0.61
Non-ASD (n = 84) ASD (n = 19)FSIQ 74.56 (11.83) 68.74 (10.26) 0.05VIQ 79.32 (14.51) 75.79 (11.43) 0.32PIQ 73.71 (10.90) 67.89 (9.78) 0.03
ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; CHD, con-genital heart defect; FSIQ, full-scale IQ; PIQ, performance IQ; SD, standard deviation;VIQ, verbal IQ.
668Journal of Intellectual Disability Research
B. De Smedt et al. • Intellectual abilities in children with VCFS
© The Authors. Journal Compilation © Blackwell Publishing Ltd4
4Thursday, October 15, 2009
Neuropsych/Cognitive ProfileRecent 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
tests were used in case of non-normally distributedvariables.
Results
Full-scale IQ ranged from to . It was normallydistributed around a mean of . (SD = .),which is about SD lower than the mean FSIQ(Mean = ; SD = ) in normally developing sub-jects. In our sample, / children showed normalintellectual development (FSIQ > ). Forty-sevenchildren showed borderline intellectual functioning(FSIQ between and ). Mild intellectual disabil-ity (FSIQ between and ) was present in chil-dren. Four children showed a moderate intellectualdisability (FSIQ < ).
VIQ (Mean = .; SD = .) was higher thanPIQ (Mean = .; SD = .) and this discrep-ancy was statistically significant [t() = .,P < .]. At the subject level, / childrenshowed a VIQ > PIQ intellectual profile, whereas/ showed the reverse pattern. A clinically sig-nificant discrepancy of more than scaled score
points was found in children: of them showeda VIQ > PIQ profile and had a PIQ > VIQdiscrepancy.
Table provides an overview of the investigatedvariables that might influence variability in IQ inVCFS. Inheritance of the deletion affected cognitiveperformance in VCFS, with children with familialdeletions having significant lower FSIQ than chil-dren with a de novo deletion [t() = .,P = .]. We further examined whether this differ-ence in FSIQ between both groups could beexplained by the educational attainment level of theparents. Parents of children with de novo deletionshad higher educational levels than parents of chil-dren with familial deletions (Wilcoxon two-sampletest, W = ., P < .). We further ran an ,with inheritance of the deletion and educationalattainment level of the parents as between-subjectfactors and FSIQ as dependent variable. There wasan effect of educational attainment level of theparents on FSIQ (F4,97 = ., P < .) and groupdifferences in FSIQ between children with de novoand familial deletions disappeared (F1,97 = .,
Table 1 Group means (SD)
P
Deletion De novo (n = 92) Familial (n = 11)FSIQ 74.50 (11.69) 65.00 (8.45) 0.01VIQ 79.79 (13.91) 69.27 (11.53) 0.02PIQ 73.42 (10.89) 66.09 (8.84) 0.03
Sex Female (n = 47) Male (n = 56)FSIQ 73.19 (10.40) 73.73 (12.84) 0.82VIQ 78.87 (12.27) 78.50 (15.43) 0.89PIQ 72.28 (10.38) 72.95 (11.39) 0.76
CHD Yes (n = 55) No (n = 48)FSIQ 74.38 (11.84) 72.46 (11.65) 0.41VIQ 79.05 (14.23) 78.23 (13.89) 0.77PIQ 73.56 (10.77) 71.58 (11.05) 0.36
Psychiatric Non-ADHD (n = 76) ADHD (n = 27)FSIQ 73.32 (12.32) 73.96 (10.10) 0.81VIQ 78.30 (14.78) 79.70 (11.76) 0.66PIQ 72.97 (11.18) 71.70 (10.19) 0.61
Non-ASD (n = 84) ASD (n = 19)FSIQ 74.56 (11.83) 68.74 (10.26) 0.05VIQ 79.32 (14.51) 75.79 (11.43) 0.32PIQ 73.71 (10.90) 67.89 (9.78) 0.03
ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; CHD, con-genital heart defect; FSIQ, full-scale IQ; PIQ, performance IQ; SD, standard deviation;VIQ, verbal IQ.
668Journal of Intellectual Disability Research
B. De Smedt et al. • Intellectual abilities in children with VCFS
© The Authors. Journal Compilation © Blackwell Publishing Ltd4
4Thursday, October 15, 2009
Neuropsych/Cognitive ProfileRecent 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
tests were used in case of non-normally distributedvariables.
Results
Full-scale IQ ranged from to . It was normallydistributed around a mean of . (SD = .),which is about SD lower than the mean FSIQ(Mean = ; SD = ) in normally developing sub-jects. In our sample, / children showed normalintellectual development (FSIQ > ). Forty-sevenchildren showed borderline intellectual functioning(FSIQ between and ). Mild intellectual disabil-ity (FSIQ between and ) was present in chil-dren. Four children showed a moderate intellectualdisability (FSIQ < ).
VIQ (Mean = .; SD = .) was higher thanPIQ (Mean = .; SD = .) and this discrep-ancy was statistically significant [t() = .,P < .]. At the subject level, / childrenshowed a VIQ > PIQ intellectual profile, whereas/ showed the reverse pattern. A clinically sig-nificant discrepancy of more than scaled score
points was found in children: of them showeda VIQ > PIQ profile and had a PIQ > VIQdiscrepancy.
Table provides an overview of the investigatedvariables that might influence variability in IQ inVCFS. Inheritance of the deletion affected cognitiveperformance in VCFS, with children with familialdeletions having significant lower FSIQ than chil-dren with a de novo deletion [t() = .,P = .]. We further examined whether this differ-ence in FSIQ between both groups could beexplained by the educational attainment level of theparents. Parents of children with de novo deletionshad higher educational levels than parents of chil-dren with familial deletions (Wilcoxon two-sampletest, W = ., P < .). We further ran an ,with inheritance of the deletion and educationalattainment level of the parents as between-subjectfactors and FSIQ as dependent variable. There wasan effect of educational attainment level of theparents on FSIQ (F4,97 = ., P < .) and groupdifferences in FSIQ between children with de novoand familial deletions disappeared (F1,97 = .,
Table 1 Group means (SD)
P
Deletion De novo (n = 92) Familial (n = 11)FSIQ 74.50 (11.69) 65.00 (8.45) 0.01VIQ 79.79 (13.91) 69.27 (11.53) 0.02PIQ 73.42 (10.89) 66.09 (8.84) 0.03
Sex Female (n = 47) Male (n = 56)FSIQ 73.19 (10.40) 73.73 (12.84) 0.82VIQ 78.87 (12.27) 78.50 (15.43) 0.89PIQ 72.28 (10.38) 72.95 (11.39) 0.76
CHD Yes (n = 55) No (n = 48)FSIQ 74.38 (11.84) 72.46 (11.65) 0.41VIQ 79.05 (14.23) 78.23 (13.89) 0.77PIQ 73.56 (10.77) 71.58 (11.05) 0.36
Psychiatric Non-ADHD (n = 76) ADHD (n = 27)FSIQ 73.32 (12.32) 73.96 (10.10) 0.81VIQ 78.30 (14.78) 79.70 (11.76) 0.66PIQ 72.97 (11.18) 71.70 (10.19) 0.61
Non-ASD (n = 84) ASD (n = 19)FSIQ 74.56 (11.83) 68.74 (10.26) 0.05VIQ 79.32 (14.51) 75.79 (11.43) 0.32PIQ 73.71 (10.90) 67.89 (9.78) 0.03
ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; CHD, con-genital heart defect; FSIQ, full-scale IQ; PIQ, performance IQ; SD, standard deviation;VIQ, verbal IQ.
668Journal of Intellectual Disability Research
B. De Smedt et al. • Intellectual abilities in children with VCFS
© The Authors. Journal Compilation © Blackwell Publishing Ltd4
4Thursday, October 15, 2009
Neuropsych/Cognitive ProfileRecent 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
tests were used in case of non-normally distributedvariables.
Results
Full-scale IQ ranged from to . It was normallydistributed around a mean of . (SD = .),which is about SD lower than the mean FSIQ(Mean = ; SD = ) in normally developing sub-jects. In our sample, / children showed normalintellectual development (FSIQ > ). Forty-sevenchildren showed borderline intellectual functioning(FSIQ between and ). Mild intellectual disabil-ity (FSIQ between and ) was present in chil-dren. Four children showed a moderate intellectualdisability (FSIQ < ).
VIQ (Mean = .; SD = .) was higher thanPIQ (Mean = .; SD = .) and this discrep-ancy was statistically significant [t() = .,P < .]. At the subject level, / childrenshowed a VIQ > PIQ intellectual profile, whereas/ showed the reverse pattern. A clinically sig-nificant discrepancy of more than scaled score
points was found in children: of them showeda VIQ > PIQ profile and had a PIQ > VIQdiscrepancy.
Table provides an overview of the investigatedvariables that might influence variability in IQ inVCFS. Inheritance of the deletion affected cognitiveperformance in VCFS, with children with familialdeletions having significant lower FSIQ than chil-dren with a de novo deletion [t() = .,P = .]. We further examined whether this differ-ence in FSIQ between both groups could beexplained by the educational attainment level of theparents. Parents of children with de novo deletionshad higher educational levels than parents of chil-dren with familial deletions (Wilcoxon two-sampletest, W = ., P < .). We further ran an ,with inheritance of the deletion and educationalattainment level of the parents as between-subjectfactors and FSIQ as dependent variable. There wasan effect of educational attainment level of theparents on FSIQ (F4,97 = ., P < .) and groupdifferences in FSIQ between children with de novoand familial deletions disappeared (F1,97 = .,
Table 1 Group means (SD)
P
Deletion De novo (n = 92) Familial (n = 11)FSIQ 74.50 (11.69) 65.00 (8.45) 0.01VIQ 79.79 (13.91) 69.27 (11.53) 0.02PIQ 73.42 (10.89) 66.09 (8.84) 0.03
Sex Female (n = 47) Male (n = 56)FSIQ 73.19 (10.40) 73.73 (12.84) 0.82VIQ 78.87 (12.27) 78.50 (15.43) 0.89PIQ 72.28 (10.38) 72.95 (11.39) 0.76
CHD Yes (n = 55) No (n = 48)FSIQ 74.38 (11.84) 72.46 (11.65) 0.41VIQ 79.05 (14.23) 78.23 (13.89) 0.77PIQ 73.56 (10.77) 71.58 (11.05) 0.36
Psychiatric Non-ADHD (n = 76) ADHD (n = 27)FSIQ 73.32 (12.32) 73.96 (10.10) 0.81VIQ 78.30 (14.78) 79.70 (11.76) 0.66PIQ 72.97 (11.18) 71.70 (10.19) 0.61
Non-ASD (n = 84) ASD (n = 19)FSIQ 74.56 (11.83) 68.74 (10.26) 0.05VIQ 79.32 (14.51) 75.79 (11.43) 0.32PIQ 73.71 (10.90) 67.89 (9.78) 0.03
ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; CHD, con-genital heart defect; FSIQ, full-scale IQ; PIQ, performance IQ; SD, standard deviation;VIQ, verbal IQ.
668Journal of Intellectual Disability Research
B. De Smedt et al. • Intellectual abilities in children with VCFS
© The Authors. Journal Compilation © Blackwell Publishing Ltd4
4Thursday, October 15, 2009
Neuropsych/Cognitive ProfileRecent 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
tests were used in case of non-normally distributedvariables.
Results
Full-scale IQ ranged from to . It was normallydistributed around a mean of . (SD = .),which is about SD lower than the mean FSIQ(Mean = ; SD = ) in normally developing sub-jects. In our sample, / children showed normalintellectual development (FSIQ > ). Forty-sevenchildren showed borderline intellectual functioning(FSIQ between and ). Mild intellectual disabil-ity (FSIQ between and ) was present in chil-dren. Four children showed a moderate intellectualdisability (FSIQ < ).
VIQ (Mean = .; SD = .) was higher thanPIQ (Mean = .; SD = .) and this discrep-ancy was statistically significant [t() = .,P < .]. At the subject level, / childrenshowed a VIQ > PIQ intellectual profile, whereas/ showed the reverse pattern. A clinically sig-nificant discrepancy of more than scaled score
points was found in children: of them showeda VIQ > PIQ profile and had a PIQ > VIQdiscrepancy.
Table provides an overview of the investigatedvariables that might influence variability in IQ inVCFS. Inheritance of the deletion affected cognitiveperformance in VCFS, with children with familialdeletions having significant lower FSIQ than chil-dren with a de novo deletion [t() = .,P = .]. We further examined whether this differ-ence in FSIQ between both groups could beexplained by the educational attainment level of theparents. Parents of children with de novo deletionshad higher educational levels than parents of chil-dren with familial deletions (Wilcoxon two-sampletest, W = ., P < .). We further ran an ,with inheritance of the deletion and educationalattainment level of the parents as between-subjectfactors and FSIQ as dependent variable. There wasan effect of educational attainment level of theparents on FSIQ (F4,97 = ., P < .) and groupdifferences in FSIQ between children with de novoand familial deletions disappeared (F1,97 = .,
Table 1 Group means (SD)
P
Deletion De novo (n = 92) Familial (n = 11)FSIQ 74.50 (11.69) 65.00 (8.45) 0.01VIQ 79.79 (13.91) 69.27 (11.53) 0.02PIQ 73.42 (10.89) 66.09 (8.84) 0.03
Sex Female (n = 47) Male (n = 56)FSIQ 73.19 (10.40) 73.73 (12.84) 0.82VIQ 78.87 (12.27) 78.50 (15.43) 0.89PIQ 72.28 (10.38) 72.95 (11.39) 0.76
CHD Yes (n = 55) No (n = 48)FSIQ 74.38 (11.84) 72.46 (11.65) 0.41VIQ 79.05 (14.23) 78.23 (13.89) 0.77PIQ 73.56 (10.77) 71.58 (11.05) 0.36
Psychiatric Non-ADHD (n = 76) ADHD (n = 27)FSIQ 73.32 (12.32) 73.96 (10.10) 0.81VIQ 78.30 (14.78) 79.70 (11.76) 0.66PIQ 72.97 (11.18) 71.70 (10.19) 0.61
Non-ASD (n = 84) ASD (n = 19)FSIQ 74.56 (11.83) 68.74 (10.26) 0.05VIQ 79.32 (14.51) 75.79 (11.43) 0.32PIQ 73.71 (10.90) 67.89 (9.78) 0.03
ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; CHD, con-genital heart defect; FSIQ, full-scale IQ; PIQ, performance IQ; SD, standard deviation;VIQ, verbal IQ.
668Journal of Intellectual Disability Research
B. De Smedt et al. • Intellectual abilities in children with VCFS
© The Authors. Journal Compilation © Blackwell Publishing Ltd4
4Thursday, October 15, 2009
Neuropsych/Cognitive ProfileRecent 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
tests were used in case of non-normally distributedvariables.
Results
Full-scale IQ ranged from to . It was normallydistributed around a mean of . (SD = .),which is about SD lower than the mean FSIQ(Mean = ; SD = ) in normally developing sub-jects. In our sample, / children showed normalintellectual development (FSIQ > ). Forty-sevenchildren showed borderline intellectual functioning(FSIQ between and ). Mild intellectual disabil-ity (FSIQ between and ) was present in chil-dren. Four children showed a moderate intellectualdisability (FSIQ < ).
VIQ (Mean = .; SD = .) was higher thanPIQ (Mean = .; SD = .) and this discrep-ancy was statistically significant [t() = .,P < .]. At the subject level, / childrenshowed a VIQ > PIQ intellectual profile, whereas/ showed the reverse pattern. A clinically sig-nificant discrepancy of more than scaled score
points was found in children: of them showeda VIQ > PIQ profile and had a PIQ > VIQdiscrepancy.
Table provides an overview of the investigatedvariables that might influence variability in IQ inVCFS. Inheritance of the deletion affected cognitiveperformance in VCFS, with children with familialdeletions having significant lower FSIQ than chil-dren with a de novo deletion [t() = .,P = .]. We further examined whether this differ-ence in FSIQ between both groups could beexplained by the educational attainment level of theparents. Parents of children with de novo deletionshad higher educational levels than parents of chil-dren with familial deletions (Wilcoxon two-sampletest, W = ., P < .). We further ran an ,with inheritance of the deletion and educationalattainment level of the parents as between-subjectfactors and FSIQ as dependent variable. There wasan effect of educational attainment level of theparents on FSIQ (F4,97 = ., P < .) and groupdifferences in FSIQ between children with de novoand familial deletions disappeared (F1,97 = .,
Table 1 Group means (SD)
P
Deletion De novo (n = 92) Familial (n = 11)FSIQ 74.50 (11.69) 65.00 (8.45) 0.01VIQ 79.79 (13.91) 69.27 (11.53) 0.02PIQ 73.42 (10.89) 66.09 (8.84) 0.03
Sex Female (n = 47) Male (n = 56)FSIQ 73.19 (10.40) 73.73 (12.84) 0.82VIQ 78.87 (12.27) 78.50 (15.43) 0.89PIQ 72.28 (10.38) 72.95 (11.39) 0.76
CHD Yes (n = 55) No (n = 48)FSIQ 74.38 (11.84) 72.46 (11.65) 0.41VIQ 79.05 (14.23) 78.23 (13.89) 0.77PIQ 73.56 (10.77) 71.58 (11.05) 0.36
Psychiatric Non-ADHD (n = 76) ADHD (n = 27)FSIQ 73.32 (12.32) 73.96 (10.10) 0.81VIQ 78.30 (14.78) 79.70 (11.76) 0.66PIQ 72.97 (11.18) 71.70 (10.19) 0.61
Non-ASD (n = 84) ASD (n = 19)FSIQ 74.56 (11.83) 68.74 (10.26) 0.05VIQ 79.32 (14.51) 75.79 (11.43) 0.32PIQ 73.71 (10.90) 67.89 (9.78) 0.03
ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; CHD, con-genital heart defect; FSIQ, full-scale IQ; PIQ, performance IQ; SD, standard deviation;VIQ, verbal IQ.
668Journal of Intellectual Disability Research
B. De Smedt et al. • Intellectual abilities in children with VCFS
© The Authors. Journal Compilation © Blackwell Publishing Ltd4
4Thursday, October 15, 2009
Objects, Space & NumbersSpace 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 22q11.2DSShould guide design for novel interventions we hope to build soon!
5
5Thursday, October 15, 2009
Spatiotemporal ResolutionRepresentations 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
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6Thursday, October 15, 2009
Reduced Space & Time Resolution
7Thursday, October 15, 2009
“Crowding” & Attentional Resolution
From Cavanagh, 20048Thursday, October 15, 2009
Piggy
Measuring Parts of Space
Fozzie
NeitherTask: Press button to choosewho Kermit the Frog is closer to (Miss Piggy or Fozzie Bear?)
When Kermit is not close to oneend or at the center, error occurs
9
9Thursday, October 15, 2009
Piggy
Measuring Parts of Space
Fozzie
NeitherTask: Press button to choosewho Kermit the Frog is closer to (Miss Piggy or Fozzie Bear?)
When Kermit is not close to oneend or at the center, error occurs
9
9Thursday, October 15, 2009
Piggy
Measuring Parts of Space
Fozzie
NeitherTask: Press button to choosewho Kermit the Frog is closer to (Miss Piggy or Fozzie Bear?)
When Kermit is not close to oneend or at the center, error occurs
9
9Thursday, October 15, 2009
Measuring Space
0
10
20
30
40
50
60
70
80
90
-20-16-12 -8 -4 0 4 8 12 16 20
DS22q11.2Control
Error
Bigger “pixels” reduce spatial accuracy (resolution) when location in space is unclear (i.e. not center or ends)
Fozzie PiggyKermit is nearer to?
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10Thursday, October 15, 2009
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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11Thursday, October 15, 2009
Spatiotemporal Attention - MOT
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12Thursday, October 15, 2009
Spatiotemporal Attention - MOT
MOT TouchScreen "k" Statistic - 30fps & 60fps
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
2.2
2.4
2.6
2.8
3.0
One Two ThreeNumber of Targets
Ave
rage
"k"
Val
ues
TD-30fps22q-30fpsTD-60fps22q-60fps
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13Thursday, October 15, 2009
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”
6 1 People represent quantities in mental space (small L A R G E) • smaller “distance” = less distinct
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14Thursday, October 15, 2009
15
Comparing Quantities
Distance EffectCon=18, 22q=29, TS=15, FX=5
400
500
600
700
800
900
1000
1100
1200
1300
1400
One Two Three Five Six SevenDifference
Adj
uste
d R
T (m
s)
Con22q
Impairment (∂<5) due to reduced resolution of mental space representations and NOT general impairment
15Thursday, October 15, 2009
Navigating Space to get NumbersTask: 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 = 7Small N not dependent on spatial attention, Large N is
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16Thursday, October 15, 2009
Navigating Space to get NumbersTask: 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 = 7Small N not dependent on spatial attention, Large N is
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16Thursday, October 15, 2009
17
Navigating Space to get Numbers
Enumeration Con=30, 22q=29, TS=12, FXS=5
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
5500
6000
6500
7000
One Two Three Four Five Six Seven EightQuantity
Adj
uste
d R
T (m
s)
22q RTCon RT
NO impairment with small sets but searching and counting errors when groups are large and complex
TD undercounts here = 54%22q undercounts here = 70%
17Thursday, October 15, 2009
Brain Structure & ConnectionsWell-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!18
18Thursday, October 15, 2009
Time & Space Related CircuitsIdentified in animals & humans. Midline, subcortical areas critical
320 nature neuroscience • volume 4 no 3 • march 2001
T and P conditions (Table 2), and included the inferior frontalgyrus (Broca’s area, BA 44/45), intraparietal sulcus (BA 40), supe-rior parietal lobule/precuneus (BA 7) and DLPF cortex.
The results from the T minus P subtraction were similar tothe results for the T minus C subtraction (Fig. 6). During the
earlier imaging epochs (2.5 and 5.0 s), subcortical activationsunique to the T condition were in the right hemisphere andincluded the putamen (x, y, z = 24, 7, –2), caudate (15, 6, 13) andinsula/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 theT condition (Fig. 6).
DISCUSSIONThe present findings provide compelling evidence for the involve-ment of the basal ganglia in formulating representations of time.Activation in the right putamen and caudate were uniquely asso-ciated with encoding time intervals. These results corroboratestudies in Parkinson’s disease showing that dopaminergic treat-ment improves motor timing30,31 and time perception32. Phar-macological challenges in animals also suggest that dopaminergicantagonists and agonists respectively slow down and speed uptiming operations12,13. Contrary to one proposal33, these andother studies10,11,27 show that the basal ganglia are involved intiming a wide range of intervals, from hundreds of milliseconds(300 ms) to tens of seconds (20 s). Collectively, these resultsimplicate striatal dopaminergic neurotransmission in hypothet-ical internal timekeeping mechanisms.
articles
Fig. 4. Activation foci in the basal ganglia (a), cerebellum (b), and pre-supplementary motor area/anterior cingulate (c) resulting from subtrac-tion 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 scaledenoting greater activation for the T or P conditions. Slices are displayedin neurological view (left is on the viewer’s left). Location of slices definedby the distance (mm) from anterior commissure: x, right (+)/left (–); y,anterior (+)/posterior (–); z, superior (+)/inferior (–). Caud, caudatenucleus; Cing, anterior cingulate area; Ins, insula; Oper, frontal opercu-lum; Put, putamen; Thal, thalamus; SMA, supplementary motor area.
Table 2. Stereotaxic brain atlas coordinates49 for regions commonly activated in subtractions of Time and Pitchperception conditions relative to Control condition.
Time > Control Pitch > Control
Location (Brodmann Area) Hemisphere 2.5 5.0 7.5 10.0 2.5 5.0 7.5 10.0
Frontal
Insula/operculum (47) R 31, 17, 3 35, 16, 3 34, 17, 4 34, 17, 0
L –35, 11, 5 –34, 15, 2 –36, 12, 4 –34, 18, 1 –36, 17, 0
PreSMA (6),
Anterior cingulate (32) L –4, –1, 56 –4, 6, 49 –7, 10, 45 –5, 12, 43 –6, 7, 48 –4, 8, 49
Inferior frontal gyrus (44/45) R 37, 1, 32 37, 4, 28
L –46, 4, 21 –47, 5, 18 –45, 4, 22 –44, 7, 26
Dorsolateral (46/10/9) L –39, 42, 12 –36, 46, 13 –36, 40, 8
–42, 26, 28 –40, 14, 29
Parietal
Intraparietal sulcus,
Angular gyrus (40) L –31, –49, 37 –29, –52, 33
–36, –53, 44 –32, –47, 38–30, –55, 36
Superior parietal lobule,
Precuneus (7) L –21, –66, 49 –28, –49, 43 –13, –72, 50 –43, –57, 50
–21, –63, 51 –25, –65, 50
R, right; L, left; B, bilateral
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© 2001 Nature Publishing Group http://neurosci.nature.com
From Rao et al., 2001
Tim
e
From Karnath et al., 2002
Spac
e
Bish, 2004; Shapiro, 200819
19Thursday, October 15, 2009
20
TD > 22q• Interhemisphere
• Cerebel, Culmen
• Mid/Post. Cingulate
• Fronto-Temporal
• Thalamus, Caudate
22q > TD• R. Insula,
• R. MFG
Simon et al. NeuroImage, 2005
Volumetric Findings - Gray
20Thursday, October 15, 2009
Cavum Septum PellucidumWhen 2 sides of ventricles donot 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 notcorrelate with IQBeaton et al., submitted
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21Thursday, October 15, 2009
Hippocampal Changes
DeBoer et al., 2007
Measured hippocampus & amygdala volume in 72 7-14 yr-olds• 36 22q11.2DS, 36 TDNo differences in amygdala• unlike Kates et al, 2006Left, not right, hippocampal volume smaller in 22q11.2DS• 2.31cm3 vs 2.56cm3, p<.01Volume correlated differentiallywith IQ measures
Controls (n=20) DS22q11.2 (n=21)
Left Right Left Right
VC / VCI
Pearson's r 0.30 0.37 .49* .62**
PO / PRI
Pearson's r .60** .57* 0.25 0.42†
FSIQ
Pearson's r 0.38 0.31 .48* .58*
† p<.10
* p<.05
** p<.01
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22Thursday, October 15, 2009
Cerebellar ChangesVermis/Lobes traced from mid-sagittal sliceRelative to controls, smaller:• 22q total cerebellum• 22q anterior lobe• 22q neocerebellum• 22q cerebellar tonsils Bish et al., 2006
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23Thursday, October 15, 2009
Dysconnectivity & Spatial Attention
x
y
zConnectivity relates to water diffusion aswhite matter has highwater content
Clusters suggestdifferent connectivityregions in 22q vs TD• strong correlation with spatial attentionSimon et al., 2008
Axial = x (primary)Radial = average(y+z)FA = Axial/Total
In all clusters:FA: 22q>TD, p<.0001RD: TD>FA, p<.0001
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24Thursday, October 15, 2009
Dysconnectivity & Spatial Attention
x
y
zConnectivity relates to water diffusion aswhite matter has highwater content
Clusters suggestdifferent connectivityregions in 22q vs TD• strong correlation with spatial attentionSimon et al., 2008
Axial = x (primary)Radial = average(y+z)FA = Axial/Total
In all clusters:FA: 22q>TD, p<.0001RD: TD>FA, p<.0001
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24Thursday, October 15, 2009
Gyrification in 22q11.2DS
Gyrification changes capture key structural/connective changesIndicate joint impact of genetic & neuroconstructive influences?
(a) (b)
Figure 2: Significant vertices, and clusters where the LGI for TD was signif-icantly greater than those for the 22q11.2DS population, controlling for ageand cortical volume, and projected on the average pial surface of the popula-tion specific template. (a) Significant vertices, explored with FDR correctedSPM at α = 0.05. The image shows large bilateral areas of LGI deficit in22q11.2DS population, involving most of the mid-line structures, and a bilat-eral ares of deficit involving the superior parietal, inferior parietal, central andsuperior pre-central areas. (b) Only the significant vertices that were in themidline regions, and right parietal / pre-frontal areas were included in signifi-cant clusters, after thresholding for both the peak height and extent (t ≥ 4.01,extent ≥ 0.52 resels). The coordinates of peak vertices within the clusters andother discriptive statistics are tabulated in table 1
than LGI in 22q11.2DS population, while allowing for variations due to effectsof age and cortical volume. The resulting SPM revealed a widespread decreasein LGI for the 22q11.2DS group, along the midline of the brain, spanning mul-tiple regions along the medial wall, including the cuneus, corpus callosum, andanterior cingulate regions (figure 2(a)). These findings were highly significant5
(SPM{t} ≥ 4.01, table 1), and involved both the hemispheres. In addition tomedial findings, the analysis also showed a seemingly bilateral area of LGI reduc-tion along the central, dorsal aspect of the brains of children with 22q11.2DS (ta-ble 1, figure 2(a)). These regions also encompass multiple regions, and includeinferior and superior parietal areas. However, after thresholding for both the10
peak height and cluster extent, only 3 clusters with regionally specific differencesin LGI were confirmed as significant (figure 2(b),table 1). To examine how theLGI distribution of the study population is affected by age, we extended theGLM to include an interaction term between the factors age and diagnosis (2levels, TD and 22q11.2DS), while allowing for the cortical volume. The t scores15
for a main effect of age across both groups is shown in figure 3(a). The LGIin the left temporal areas, and right dorsal pre-frontal areas show a trend levelpositive and negative correlations with age, however, none of these correlationsare significant (t < 4.17 at p = 0.05 (FDR)). On examining the correlationsonly within group, areas where the LGI was correlated positively with age in20
6
Left Right
Ant. Post.
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25Thursday, October 15, 2009
Object Tracking Brain Differences
7 TD8 22q11.2DS
1 target > passive
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26Thursday, October 15, 2009
SummaryNew hypotheses MAY explain cognitive problems• changes can be seen in parietal & frontal networkBUT, may result from problems in more basic circuitsNot 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 impairmentsIdentification rates are very low - have to find kids before we can help them - hopefully you can help!
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27Thursday, October 15, 2009
ThanksMOST important: Kids who participated & their families!!NICHD/NICH for funding 2R01HD42974 8/2009-7/2013Majority 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 MendozaUC Davis Center of Excellence in Developmental Disabilities
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28Thursday, October 15, 2009
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