Here we visualized for the first time the profile of cortical anomalies associated with the genetic deletion in 22q11DS. Cortical thickness was significantly decreased (by 10–15%) in localized anatomical regions encompassing parietal and lateral occipital cortices, areas critical for visuospatial information processing. These regions, particularly in the RH, process spatial information and are critical for directing spatial attention, cognitive areas of disproportionate deficit in patients with 22q11DS. These results are quite consistent with prior anatomical parcellations that suggested disproportionately smaller parietal and occipital lobes and suggest that reduction in thickness of the cortical mantle may underlie the observed volumetric deficits (Eliez et al. 2000
; Kates et al. 2001
We also identified a localized decrease in cortical thickness in the pars orbitalis region of the IFG. Functional neuroimaging studies have found that this region (corresponding to BA 47, in the LH) is selectively involved in processing the semantic aspects of a sentence (Dapretto and Bookheimer 1999
), and Lu et al. (2006)
recently found that GM thickening in IFG was associated with developmental improvement in phonological processing abilities. Although patients with 22q11DS have a relative strength in verbal as compared with visuospatial memory, virtually all patients with this syndrome have early language delays, and language comprehension remains an area of relative weakness (Gerdes et al. 1999
; Woodin et al. 2001
). This region is slightly anterior to the frontal region in which we had anticipated finding increased cortical thinning in 22q11DS, the pars opercularis, based on prior findings of enlarged Sylvian fissures in infants with 22q11DS (Bingham et al. 1997
). However, given the close proximity of these brain regions, it is possible that this localized area of cortical thinning may be related to abnormal prenatal development of perisylvian cortex. Interestingly, the infants studied in Bingham et al. (1997)
consistently had disproportionate enlargement of the left Sylvian fissure compared with the right, suggesting lateralized effects of a gene or genes in the deleted region on the development of perisylvian cortex. Although specific genes known to be responsible for lateralization defects have not been yet mapped to the 22q11.2 region, the abnormal asymmetry of cortical thickness detected specifically in the parietooccipital region in 22q11DS patients suggests that certain of the deleted genes may directly contribute to lateralization processes in the normal human cortex (Sun et al. 2005
). Although here we detected significantly altered cortical asymmetry only in the parietooccipital ROI and not in frontal cortex, the observed cortical asymmetries in both regions warrant further investigation in future larger studies.
Although, to our knowledge, asymmetries of thickness have not previously been investigated across the cortical surface in normal children, Luders et al. (2006)
used these same methods to investigate hemispheric asymmetries of cortical thickness and the influence of gender in young, healthy adults (mean age ~25 years). They found a similar asymmetry profile in both sexes, with more pronounced leftward than rightward asymmetry in the anterior temporal lobe, the precentral gyrus, and middle frontal regions. We found a very similar pattern of increased rightward asymmetry in the IFG and the inferior posterior temporal lobe. Thus, whereas leftward asymmetries appeared more pronounced in the older sample studied by Luders et al. (2006)
, the specific regions in which asymmetry was detected were quite similar in our study, particularly in the RH. In addition, using volumetric measures in normal children and adolescents aged 5–17 years, Reiss et al. (1996)
previously reported a pattern of cerebral asymmetry involving rightward prominence of cortical GM, similar to the pattern we observed here using cortical thickness measures.
Notably, this cognitive profile of relative strengths in verbal memory, in contrast to marked deficits in visuospatial memory, bears striking similarity to that seen in another genetic deletion syndrome, Williams syndrome (WS; Bearden et al. 2002
). However, unlike WS, there is no evidence that patients with 22q11DS are hypersociable or show particular strengths in musical ability (Karmiloff-Smith et al. 2004
). Using identical methods to those reported here, a pattern of anatomically localized failure of cortical maturation was observed in patients with WS, involving a delimited zone of RH perisylvian cortex that was 5–10% thicker in WS than in matched controls, despite pervasive GM and WM deficits, but with corresponding deficits in adjacent dorsal stream regions including superior parietal areas (Thompson et al. 2005
; see Supplementary Fig. 4
). In addition, using functional brain imaging to assess task-related activation in WS,Meyer-Lindenberg et al. (2004)
identified a pattern of hypoactivation in the parietal portion of the dorsal stream, concomitant with GM volume reduction in the immediately adjacent parietooccipital/intraparietal sulcus. A similar pattern of localized neuroanatomical deficits may underlie the visuospatial cognitive impairments characteristic of both 22q11DS and WS.
Relationship to Psychiatric Disorders
These cortical anomalies do not closely resemble those seen in schizophrenia, where prefrontal and temporal regions show greatest GM deficits (Wright et al. 2000
). Developmental factors may play an important role in these differences. Using identical cortical pattern-matching methods to those reported here, Thompson et al. (2001)
mapped cortical changes over time in adolescents with childhood onset of schizophrenia. Early deficits in parietal brain regions progressed anteriorly into temporal lobes, engulfing sensorimotor and dorsolateral prefrontal cortices over a 5-year period. Only the latest changes included dorsolateral prefrontal cortex and superior temporal gyri, deficit regions found consistently in adult studies, suggesting that these structural changes occur later in the course of illness. In this sample of children and adolescents with the deletion, we did not find evidence for differences in patterns of cortical thickness between patients with and without psychiatric disorders. However, only one patient had a psychotic disorder diagnosis; the majority had anxiety disorder and attention deficit hyperactivity disorder diagnoses, which are likely to be associated with more subtle neuroanatomical alterations (Milham et al. 2005
) that may not result in detectable differences beyond those associated with the genetic deletion itself.
Effects of Development and IQ
Here we find a moderate inverse relationship between age and cortical thickness, in both patients with 22q11DS and healthy controls. After covarying for age, results of diagnosis remained significant. Thus, although developmental factors are clearly important, it does not appear that the slight, nonsignificant age difference between the groups accounts for the observed group differences in cortical thickness.
Consistent with the pattern seen in our healthy comparison subjects, O’Donnell et al. (2005)
specifically examined changes in cortical thickness in the frontopolar cortex (FPC) through late childhood and adolescence and found a linear decline in cortical thickness in the FPC and the dorsolateral prefrontal cortex between the ages of 8 and 19 years.
Although measures of cortical thickness are fairly novel, earlier studies have examined changes in GM density over the course of development (a measure which is highly correlated with cortical thickness; Thompson et al. 2005
). Studies of GM maturation indicate loss of cortical GM density over time, which is temporally associated with postmortem findings of increased synaptic pruning during adolescence and early adulthood (Sowell et al. 1999
). In a longitudinal study examining the sequence of cortical GM development between the age of 4 and 21 years, Gogtay et al. (2004)
found that primary sensorimotor cortices, along with frontal and occipital poles, mature first and the remainder of the cortex develops in a parietal-to-frontal (back-to-front) direction. Thus, alterations in either the degree or timing of basic maturational processes may at least partially underlie the pattern of cortical thickness deficit observed here.
Only one study has examined adults with 22q11DS using quantitative methods (van Amelsvoort et al. 2001
). Compared with IQ-matched controls, adult patients demonstrated diffuse WM deficits in frontal regions, the fasciculus longitudinalis and optic radiation, and regionally specific GM reductions in the left cerebellum, insula, and frontal and right temporal lobes, suggesting that cerebellar anomalies may be relatively stable but additional frontal and temporal GM reductions may emerge over the course of development (van Amelsvoort et al. 2004
). Although our findings are not entirely consistent with these results, this is not surprising given the differences in the age of the sample (children vs. adults) and study methodology (semiautomated voxel-based morphometry vs. cortical pattern matching).
In addition, consistent with the only existing large-scale study examining the relationship between IQ and cortical thickness (Shaw et al. 2006
), we found a nonsignificant linear correlation between mean cortical thickness and IQ in our sample overall. In a sample of 307 healthy children and adolescents, Shaw et al. (2006)
recently reported a complex relationship between development and cortical thickness; specifically, although there was an overall decline in cortical thickness throughout the age period studied, it was the trajectory of “ change” in cortical thickness, rather than the thickness of the cortex itself, that showed the closest relationship with the level of intelligence. Unfortunately, this sort of complex, nonlinear relationship could not be examined in this cross-sectional study. Longitudinal studies are clearly warranted to better understand the effects of development on cortical alterations in this syndrome.
Candidate Genes for Cortical Dysmorphology in 22q11DS
Cortical architecture in 22q11DS is highly likely to be affected by haploinsufficiency for particular genes in the deleted region, but it is also likely to be dynamic, and environmental influences may also play a role (e.g., Simon et al. 2005
). Although here we correlate a genetic mutation with anatomical change, direct causality cannot be determined; it is impossible to disentangle genetic and nongenetic influences as both may occur downstream of a genetic lesion. The observed cortical thinning may be shaped primarily by genetically programmed anomalous neurodevelopment that impairs parietal-occipital structure and function. Several genes that influence neurogenesis and neuronal migration, including CRKL, zinc finger protein 74, platelet glycoprotein Ib, and its precursor, human cell division cycle-related protein-1 (peanut-like 1), are housed in the deleted 22q11.2 chromosomal region (Maynard et al. 2003
), suggesting a possible genetic basis for the cortical dysmorphology observed here. In addition, the proline dehydrogenase (ProDH) gene, mapped to this region, regulates glutamate and γ-aminobutyrate (GABA) neurotransmission (Paterlini et al. 2005
). ProDH-deficient mice have reduced glutamate, GABA, and aspartate levels in the hypothalamus and reduced GABA and aspartate in the frontal cortex (Gogos et al. 1999
). Moreover, prepulse inhibition, a measure of sensorimotor gating, was decreased in these mice as compared with their littermates, a behavioral phenotype that has also been identified in children with 22q11DS (Sobin et al. 2005
) and is associated with genetic risk for schizophrenia (Berrettini 2005
). More recently, Mukai et al. (2004)
also reported a significant association between a single nucleotide polymorphism in another gene in the 22q11 region, ZDHHC8
, which is believed to be involved in palmitoylation, a process that modulates activity-dependent plasticity at glutamatergic synapses in the cortex and hippocampus (Jablensky 2004
The embryological basis of the 22q11DS phenotype is believed to be aberrant cephalic neural crest migration to the third and fourth branchial arches (Marusich and Weston 1991
) as many of the involved tissues (thymus, cardiac conotruncus, and parathyroid glands) are known to derive from the branchial arch/pharyngeal pouch system (Scambler 2000
). This mechanism has yet to be confirmed, but experiments that perturb neural crest function can produce the main phenotypic features of 22q11DS; moreover, mutations of genes associated with neural crest development can similarly result in malformations that resemble those of 22q11DS (Roberts et al. 1997
; Scambler 2000
). Although it is tempting to hypothesize that the observed cortical thickness deficits may reflect a failure of neuronal migration in these brain regions, this possibility remains purely speculative at present.
In this initial study, we did not attempt to recruit IQ-matched comparison subjects, resulting in a significant IQ difference between groups. The issue of appropriately matched comparison subjects is complex in developmentally delayed populations, given that individuals with comparable IQ to those with 22q11.2 deletions are likely to have intellectual disability of heterogeneous etiology, including undetected chromosomal abnormalities or unknown environmental exposures (e.g., lead exposure, fetal oxygen deprivation), which are likely to lead to a variety of cortical anomalies that are not well characterized. In addition, inclusion of children with familial low IQ and/or environmental exposures would likely lead to systematic “unmatching” on other demographic variables (i.e., parental education). As such, we adopted this more straightforward approach for our initial investigation but fully recognize that optimally designed future studies will include both normal as well as IQ-matched comparison groups.