An Explanatory Account of (Some) Cognitive Impairments in ... · distributed around a mean of . (SD...

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

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

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

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)

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

Results

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!

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

Reduced Space & Time Resolution

“Crowding” & Attentional Resolution

From Cavanagh, 20048Thursday, October 15, 2009

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

Fozzie

Measuring Space

-20-16-12 -8 -4 0 4 8 12 16 20

DS22q11.2Control

Bigger “pixels” reduce spatial accuracy (resolution) when location in space is unclear (i.e. not center or ends)

Fozzie PiggyKermit is nearer to?

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.

Spatiotemporal Attention - MOT

MOT TouchScreen "k" Statistic - 30fps & 60fps

One Two ThreeNumber of Targets

TD-30fps22q-30fpsTD-60fps22q-60fps

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

Comparing Quantities

Distance EffectCon=18, 22q=29, TS=15, FX=5

One Two Three Five Six SevenDifference

Con22q

Impairment (∂<5) due to reduced resolution of mental space representations and NOT general impairment

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

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

Navigating Space to get Numbers

Enumeration Con=30, 22q=29, TS=12, FXS=5

One Two Three Four Five Six Seven EightQuantity

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%

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

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

From Rao et al., 2001

From Karnath et al., 2002

Bish, 2004; Shapiro, 200819

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

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

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†

Pearson's r 0.38 0.31 .48* .58*

† p<.10

* p<.05

** p<.01

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

Dysconnectivity & Spatial Attention

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

Dysconnectivity & Spatial Attention

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

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

Left Right

Ant. Post.

Object Tracking Brain Differences

7 TD8 22q11.2DS

1 target > passive

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!

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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