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Hippocampal volume reduction in children with chromosome 22q11.2 deletion syndrome is associated with cognitive impairment

Hippocampal volume reduction in children with chromosome 22q11.2 deletion syndrome is associated... Background: Previous investigations of individuals with chromosome 22q11.2 deletion syndrome (DS22q11.2) have reported alterations in both brain anatomy and cognitive function. Neuroanatomical studies have reported multiple abnormalities including changes in both gray and white matter in the temporal lobe, including the amygdala and hippocampus. Separate investigations of cognitive abilities have established the prevalence of general intellectual impairment, although the actual extent to which a single individual is affected varies greatly within the population. The present study was designed to examine structures within the temporal lobe and assess their functional significance in terms of cognition in children with DS22q11.2. Method: A total of 72 children (ages 7–14 years) participated in the investigation: 36 children (19 female, 17 male) tested FISH positive for chromosome 22q11.2 deletion (Mean age = 10 years 9 months, ± 2 yr 4 mo) and 36 were age-matched typically developing controls (13 female, 23 male; Mean age = 10 years 6 months, ± 1 yr 11 mo). For each subject, a three-dimensional high-resolution (1 mm isotropic) T1-weighted structural MRI was acquired. Neuroanatomical guidelines were used to define borders of the amygdala and hippocampus bilaterally and volumes were calculated based on manual tracings of the regions. The Wechsler Intelligence Scale for Children (WISC) was also administered. Results: Volumetric reductions in total gray matter, white matter, and both the amygdala and hippocampus bilaterally were observed in children with DS22q11.2. Reductions in the left hippocampus were disproportionate to decreases in gray matter after statistically controlling for group differences in total gray matter, age, and data collection site. This specific reduction in hippocampal volume was significantly correlated with performance on standardized measures of intelligence, whereas the other neuroanatomical measures were not (gray/white matter, CSF, and amygdala). Conclusion: Results from this study not only contribute to the understanding of the neuroanatomical variation in DS22q11.2, but also provide insight into the nature and source of the cognitive impairments associated with the syndrome. Specifically, we report that decreases in hippocampal volume may serve as an index of severity for cognitive impairments in children with DS22q11.2. Page 1 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:54 http://www.behavioralandbrainfunctions.com/content/3/1/54 tions emerging in the presence of marked psychopathol- Background Chromosome 22q11.2 deletion syndrome (DS22q11.2) ogy [18,23]. is a congenital condition known to affect brain develop- ment and cognition that occurs in 1–2 out of every 4,000 Although the number of studies examining individual live births [1]. The syndrome results from a microdeletion structures (i.e., amygdala and hippocampus) in the tem- nd on the long arm (q) of the 22 chromosome and has poral lobes is increasing, findings to date have been vari- been identified as the molecular cause for several symp- able (cf. [22,24-26]). Some of this heterogeneity can be tom-based medical diagnoses [2]. Medical characteristics attributed to small sample sizes, differences in the ages, associated with the syndrome typically include palatal cognitive abilities, and psychiatric symptoms of those abnormalities and/or velopharyngeal insufficiency, tested, the control groups chosen for comparison, the immune deficiency, congenital cardiac defects, neonatal methods used to determine anatomical boundaries, and hypocalcemia, and facial dysmorphisms [3,4]. Individu- the covariates used in analyses. For example, dispropor- als with DS22q11.2 are also at an increased risk for devel- tionate decreases in hippocampal volume have not typi- oping psychiatric disorders such as ADHD [5], obsessive- cally been reported when total brain volume is used as a compulsive disorder [6], affective disorders [7], autism covariate (e.g., [22,26]), but have been reported when [5], and schizophrenia [8]. Significant intellectual impair- total gray matter is used (e.g., [24,25]). Moreover, these ments are often observed as well [9]. However, at present, findings are difficult to compare directly given the wide far less is known about the cognitive characteristics than range of ages and cognitive abilities of the participants, as for the medical indications. well as variations in the tracing methods used for volu- metric analyses (cf.; [27,28]). Impairment in general intellectual functioning is one of the most consistently reported features in DS22q11.2 [9]. Thus, although some progress has been made in charac- IQ scores typically fall in the range of 70–85, one full terizing the neuroanatomical differences within this pop- standard deviation or more below the population mean. ulation, the implications for neurocognitive outcomes Empirical investigations have demonstrated that low per- remain poorly understood. Bearden and colleagues [17] formance on IQ assessments are not the result of the phys- have begun to address this issue by relating regional brain ical or medical characteristics [10,11], nor the associated abnormalities with cognitive ability and behavioral phe- behavioral problems that commonly accompany the syn- notype in a sample of 13 children with DS22q11.2. drome [12]. Studies of academic achievement have Results of this investigation indicated that only temporal attempted to further clarify these cognitive difficulties and lobe volume (both gray and white matter) significantly report that children with DS22q11.2 perform better at predicted overall cognitive performance in children with reading and spelling than arithmetic [13]. This specific DS22q11.2 [17]. Specifically, temporal lobe volume was a pattern of cognitive strengths and weaknesses has lead to significant positive predictor of Full Scale and Verbal IQ, the hypothesis that the cognitive difficulties are the cas- but not Performance IQ (as measured by WISC-III). In caded effects of core deficits in visuospatial processing addition, Bearden et al. [17] report a negative correlation and attention, both of which are primarily mediated by between Thought Problems as assessed by the Child cortical networks in the parietal and temporal lobes [14- Behavior Checklist (CBCL; [29]) and temporal lobe gray 16]. matter volume. At least some of the genetic material in the deleted seg- Within the temporal lobe are two structures on which ment (30–40 genes) appears to be related to typical brain much empirical research has been conducted: the amy- development, as anomalous brain structure is consistently gdala (implicated in emotion and social behavior) and reported [17,18]. Thus far, characterization of the expres- the hippocampus (well-known for its role in memory and sion of DS22q11.2 in terms of neurodevelopment has spatial cognition). Investigation of these individual struc- come from studies using structural and function magnetic tures may provide more detail regarding regionally spe- resonance imaging and diffusor tensor imaging in chil- cific changes within the temporal lobe network. While the dren, adolescents, and adults with the syndrome [18-21]. hippocampus has been measured volumetrically in The most reliable neuroanatomical finding thus far is an DS22q11.2 and has been hypothesized to be related to overall reduction in total brain volume ranging from 8.5– risk for psychopathology [22] and memory impairments 11% that appears more concentrated in the posterior and [25], to our knowledge, no evidence exists to date regard- inferior regions of the brain [19-21]. During childhood, ing the functional significance resulting from these volumetric reductions in the temporal lobe have been observed abnormalities. Studies with typically developing reported as the result of decreases in both gray and white children have suggested that the hippocampus is corre- matter [22]. Similarly, studies in adulthood also report lated with both IQ [30] and memory (see [31] for review). reductions in temporal lobe volume, with greatest reduc- Also relevant for studies of children with DS22q11.2, Page 2 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:54 http://www.behavioralandbrainfunctions.com/content/3/1/54 there is evidence of associations between reductions in 256, slice thickness = 1.0 mm, yielding 160 axial slices hippocampus volume in schizophrenia (see [32] for with an in-plane resolution of 1 × 1 mm, 3T Siemens Mag- review), which may make assessment of this structure netom Trio, TR = 1620 ms, TE = 3.87 ms, 15 degree flip important for risk assessment and prediction of out- angle, matrix size = 256 × 192, slice thickness = 1.0 mm, comes. 160 axial slices with in-plane resolution of 0.98 × 0.98 mm. Although data collection site was not significantly In short, the purpose of present investigation was to correlated with any of the volumetric measurements it expand on previous research examining neuroanatomical was entered as a covariate in all analyses. differences in children with DS22q11.2 and link these findings to resulting cognitive outcomes. The ultimate In addition to the structural MRI procedure, the Wechsler goal of this line of research is to gain further insight into Intelligence Scale for Children (WISC-III/IV) was also complex gene-brain-behavior relations associated with administered to 41 participants (20 control, 21 this syndrome and improve outcome predictions. Volu- Ds22q11.2). In order to equate WISC versions IIII and IV metric measurements of regions within the temporal lobe, Verbal Comprehension Factor/Perceptual Organization namely the hippocampus and amygdala, were measured (nonverbal) Factor (VC/PO) were used from WISC-III and bilaterally from structural MRIs in 72 children and adoles- Verbal Comprehension Index/Perceptual Reasoning cents with and without DS22q11.2. Associations with Index (VCI/PRI) were used from WISC-IV. The remaining intellectual ability were assessed. children were either unable to return for clinical evalua- tion or received an abbreviated version of the intelligence assessment which was not compatible with the WISCII-IV. Methods Participants Neuroanatomical findings for this subgroup of 41 chil- A total of 72 children (ages 7–14 years) participated in dren comparing amygdala and hippocampal volume were this investigation: 36 children (19 female, 17 male) diag- identical to that of the entire sample. nosed with chromosome 22q11.2 deletion syndrome (Mean age = 10 years 9 months, ± 2 yr 4 mo) and 36 age- Data analysis/processing matched typically developing controls (13 female, 23 Overall brain volume measurements for each tissue type (gray matter, white matter, and cerebrospinal fluid or male; Mean age = 10 years 6 months, ± 1 yr 11 mo). Informed asset and consent was obtained from all partic- CSF) were calculated using the segmentation algorithms ipants and their guardians prior to participation. Diagno- in SPM2 (Wellcome Department of Cognitive Neurology, sis of chromosome 22q11.2 deletion was confirmed using London, UK, [33]). All MRI scans were spatially normal- fluorescent in situ hybridization (FISH). The experimental ized through registration to a template before the segmen- protocol followed guidelines set forth in the Helsinki Dec- tation was preformed. For the spatial normalization, a laration for the ethical treatment of human research par- pediatric brain template (CCHMC2 template, Cincinnati ticipants and was approved by the governing Institutional Children's Hospital Medical Center, Cincinnati, OH) was Review Boards of the data collection sites (Children's Hos- used instead of the default ICBM's adult template in SPM2 pital of Philadelphia, Hospital of the University of Penn- as we wanted to minimize the amount of deformation sylvania, and the University of California, Davis Medical during the non-linear spatial normalization for our child Center). participants [34]. The CCHMC2 template was generated from 200 healthy children, 98 boys and 102 girls, ranging Procedure in age from 5 to 18 years (mean age was 11.43 F 3.59 MRI data were acquired using a 1.5T Siemens Vision and years) at the date of the MR-exam. The registration two 3T Siemens Trios (Siemens Medical Solutions, Welan- between individual subjects and the template was per- gen, Germany). For each subject, a three-dimensional formed by minimizing the residual sum of squared differ- high-resolution (1 mm isotropic voxels) structural MRI ence with a 12-parameter affine transformation followed was acquired using a T1-weighted MP-RAGE sequence. by a non-linear transformation comprising a linear com- Before MRI scanning, children received head motion sup- bination of 7 × 8 × 7 smooth spatial basis function. The pression training in the laboratory and in a mock MRI spatially normalized images were then resliced to a reso- scanner. Scanner parameters were as follows: 1.5T Sie- lution with voxel size of 2 × 2 × 2 mm. mens Magnetom Vision scanner (Siemens Medical Solu- tions, Erlangen, Germany), TR = 9.7 ms, TE = 4 ms, 12 Tissue probability values for gray matter, white matter, degree flip angle, number of excitations = 1, matrix size, and CSF were generated using SPM's segmentation algo- 256 × 256, slice thickness = 1.0 mm, yielding 160 sagittal rithm. Voxelwise Bayesian classification based on individ- slices with an in-plane resolution of 1 × 1 mm, 3T Siemens ual image intensity and prior probability maps (i.e., Magnetom Trio, TR = 1820 ms, TE = 2.93 ms, 12 degree CCHMC2 maps) was iteratively computed followed by flip angle, number of excitations = 1, matrix size, 256 × bias correction. After segmentation, some non-brain vox- Page 3 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:54 http://www.behavioralandbrainfunctions.com/content/3/1/54 els, such as scalp, skull and venous sinuses, and odd vox- Images were reoriented so that the horizontal axis was els on tissue edges were cleaned from the segmented parallel to a line from the rostral to the caudal pole of the images by using a series of fully automated morphological hippocampus. Coronal sections were viewed perpendicu- operations [35]. The segmented tissue maps were modu- lar to the horizontal axis. On each coronal image, neuro- lated by the Jacobian determinants derived from the spa- anatomical guidelines were used to define borders of the tial deformation field to preserve the total brain volume. amygdala and hippocampus bilaterally and volumes were Total volumes for gray matter, white matter and CSF were calculated based on manual tracings of the regions in then obtained by summing the voxel values in the modu- native space, see Figure 1 (complete details of the proce- lated images. dure can be found in [37]). For manual tracings of the amygdala and hippocampus, After establishing inter-rater reliability of greater than .90 non-normalized T1-weighted images were imported into on 10 training cases, raters who were blind to group status Analyze 5.0 (Biomedical Imaging Resource, Rochester, manually traced the amygdala and hippocampus. Approx- MN; [36]) and converted to cubic voxel dimensions of imately 10% of the cases included in this investigation 0.469 mm (using a cubic spline interpolation algorithm). were then re-traced by all raters to ensure equality Orthogonal views for segmenting th Figure 1 e amygdala and hippocampus on MRI sections Orthogonal views for segmenting the amygdala and hippocampus on MRI sections. A three dimensional reconstruction of images (a) in which lines indicate the position of the horizontal plane (b), sagittal plane (c), and coronal plane (d) is shown. The arrow in b indicates the best-fit line along the white matter separating the amygdala from the putamen; the arrow in c repre- sents the white matter that forms the ventral border of the rostral amygdala. A, Amygdala; EC, entorhinal cortex; H, hippoc- ampus; PU, putamen; TLV, temporal horn of the lateral ventricle; WM, subamygdaloid white matter. Figure reproduced with permission from [37]. Copyright 2004 by the Society for Neuroscience. Page 4 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:54 http://www.behavioralandbrainfunctions.com/content/3/1/54 Table 1: Mean IQ (SD) for DS22q11.2 and control groups between tracings. Inter-rater reliability for the left and right amygdala was: .952 and .949; inter-rater reliability Controls (n = 20) DS22q11.2 (n = 21) One-way ANOVA for the left and right hippocampus was: .953 and .923. VC/VCI 111 (11) 81 (14) F(1, 39) = 61.01, p < .001 PO/PRI 112 (11) 78 (13) F(1, 39) = 82.99, p < .001 Results FSIQ 110 (11) 77 (12) F(1, 39) = 88.70, p < .001 Multivariate ANCOVAs were used to assess group differ- ences in gray and white matter and CSF, with age and data collection site entered as covariates. Multivariate ANCO- VAs were also used to assess group differences in both 3.11) compared to controls (M = 2.56 cm , SD = 3.73), right and left amygdala and hippocampus volumes, with F(1, 65) = 7.29, p <.01. However, right hippocampal vol- age, data collection site, and gray matter volume entered ume did not differ between the DS22q11.2 group (M = as covariates. Analyses regarding bilateral volume of the 2.46, SD = 3.24) and controls (M = 2.57 cm , SD = 3.45), amygdala and hippocampus were rerun using total brain F(1,65) = .28, p = .60. Results for the cognitive assessment volume as a covariate in place of gray matter volume. indicated that, as a group, DS22q11.2 scored significantly Results did not differ with regards to the specific covariate below controls on all IQ indices, see Table 1. used, thus only the former are reported. Data points from two outliers were removed from the analyses of the hip- In order to determine if differences in neuroanatomical pocampus and amygdala to ensure volumetric data met measurements were related to differences in cognition, the necessary criteria for employing parametric statistics correlational analyses were conducted between IQ (as (i.e., assumption of normality and homogeneity of vari- measured by WISCIII/IV) and tissue volumes. The pattern ance between groups). of results was identical when z-score transformations were used in place of tissue volumes. Thus, for the sake of brev- Results indicated that, after statistically controlling for ity, only the results from the non-transformed dataset are possible differences due to data collection site and age, the presented. Hippocampal volume was significantly corre- DS22q11.2 group had significantly less gray (M = 710.58 lated with performance on standardized measures of 3 3 cm , SD = 67.97) and white (M = 356.51 cm , SD = 51.10) intelligence; however, other cortical measures (gray/white matter compared to controls (M = 763.63 cm , SD = 72.48 matter, CSF, and left and right amygdala) were not. Table and M = 388.46 cm , SD = 46.32), Fs(1, 68) = 10.12, 8.6 2 presents the results of the bivariate correlations and an respectively, ps < .01. However, CSF volume did not differ illustration of association between hippocampus and between the groups (DS22q11.2 M = 188.36 cm , SD = FSIQ is presented in Figure 2. 50.16, control M = 198.56 cm , SD = 37.22, F(1, 68) = .66, p = .49). After statistically controlling for differences in All correlations between IQ and hippocampal volume gray matter, age, and data collection site, there were no remained statistically significant after entering age, gray significant differences in bilateral volumes of the amy- matter, and data collection site as covariates (left hemi- gdala between DS22q11.2 (left hemisphere: M = 1.76 sphere VC/VCI r(36) = .61, p < .001, PO/PRI r(36) = .61, 3 3 cm , SD = 2.78, right hemisphere: M = 1.77 cm , SD = p < .001, FSIQ r(36) = .61, p < .001, right hemisphere VC/ 2.56) and control (left hemisphere M = 1.90 cm , SD = VCI r(36) = .45, p < .01, PO/PRI r(36) = .45, p < .01, FSIQ 2.50, right hemisphere: M = 1.90 cm , SD = 2.50) groups, r(36) = .42, p < .01). Partial correlations for each group are Fs(1, 65) = 2.08, 0.66, ps = .15, .24 respectively. After con- presented in Table 3. In order to determine if a specific trolling for differences in gray matter, age, and data collec- subtest of the IQ assessments contributed more than the tion site, left hippocampal volume was significantly others to the reported effects, partial correlations were reduced in children with DS22q11.2 (M = 2.31 cm , SD = computed on four common subtests (Similarities, Vocab- Table 2: Two-tailed bivariate correlations of neuroanatomical and IQ measures across both DS22q11.2 and control groups Gray Matter White Matter CSF Amygdala Hippocampus Left Right Left Right VC/VCI Pearson's r 0.19 0.19 -0.12 0.24 0.17 .62*** .50*** PO/PRI Pearson's r 0.17 0.18 0.02 0.25 0.21 .58*** .47*** FSIQ Pearson's r 0.11 0.08 -0.19 0.16 0.13 .56*** .39** **p ≤ .01 *** p ≤ .001 Page 5 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:54 http://www.behavioralandbrainfunctions.com/content/3/1/54 Table 4: Two-tailed partial correlations of hippocampus and IQ subtests for DS22q11.2 and control groups combined Left Right Similarities Pearson's r .47*** 0.29† Vocabulary Pearson's r .54*** .40* Block Design Pearson's r .53** .39* Comprehension Pearson's r .51** .50** † p < .10 * p < .05 ** p ≤ .01 *** p < .001 were not significant when groups were analyzed sepa- rately. This finding suggests that performance on one indi- vidual subtest was not solely responsible for the overall result of associations between hippocampal volume and IQ. In sum, within the DS22q11.2 group we report significant reductions in hippocampal volume that, in the left hemi- sphere, were disproportionate to decreases in total gray matter. These volumetric differences were significantly 2 3 respectively) Figure 2 Lin (b) positively correlates wi e hippoca ar regression scatterplot sh mpal volume measur th Full Sca ed in cu owing le IQ (r that left ( bic = .32 an millimeters a) a d .15 nd rig (mm ht ) related performance on standardized assessments of intel- Linear regression scatterplot showing that left (a) and right ligence, including tests of both verbal and non-verbal (i.e., (b) hippocampal volume measured in cubic millimeters (mm ) performance) skills. The specific pattern of association positively correlates with Full Scale IQ (r = .32 and .15 differed between the DS22q11.2 and control groups, with respectively) verbal IQ indices more strongly correlated in the DS22q11.2 group and performance IQ indices more strongly correlated in the control group. These findings ulary, Block Design, and Comprehension). Results of the are discussed, in turn, in the following section. bivariate correlational analyses are presented in Table 4. Subtest scores for 6 individuals could not be obtained Discussion from the clinic with which we were collaborating and thus Children with DS22q11.2 exhibited a disproportionate were not included in the follow-up analysis. Across decrease in left hippocampal volume compared to age groups, performance on all four subtests was correlated matched controls, even after statistically controlling for with hippocampal volume. However, these correlations group differences in overall gray matter, age, and data col- lection site. Children with DS22q11.2 also exhibited smaller volumes of the right hippocampus, and amygdala Table 3: Two-tailed partial correlations of hippocampus and IQ measures for both DS22q11.2 and control groups bilaterally, but these reductions were not disproportion- ate to reductions in gray matter. Consistent with previous Controls (n = 20) DS22q11.2 (n = 21) reports, children with DS22q11.2 also scored significantly Left Right Left Right lower than age-matched controls on all indices of the cog- nitive assessments. VC/VCI Pearson's r 0.30 0.37 .49* .62** PO/PRI Although previous studies have suggested an association Pearson's r .60** .57* 0.25 0.42† between decreased hippocampal volume and neuropsy- FSIQ chological and behavioral characteristics [25] in children Pearson's r 0.38 0.31 .48* .58* with DS22q11.2, this hypothesis has not been examined empirically. This study is the first to show associations † p < .10 between decreased hippocampal volume and intelligence * p < .05 in children with DS22q11.2. Specifically, significant cor- ** p ≤ .01 Page 6 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:54 http://www.behavioralandbrainfunctions.com/content/3/1/54 relations were observed between hippocampal volume control group but not for the DS22q11.2 group. The com- and IQ, even after controlling for group differences in gray plex development of connectivity between regions in the matter, age, and data collection site. Importantly, these medial temporal lobe, such as the hippocampus and differences did not differ as a function of the covariates other cortical regions, is a source of current investigation utilized (gray matter vs. total brain volume). In contrast, in typically developing children [38]. It is our hope that amygdalar volumes were not related to cognitive meas- future investigations will continue to explore not only ures (cf. [26]). Similar to findings of regional reduction in how this connectivity is altered within DS22q11.2 popu- temporal lobe volume in children DS22q11.2 [17], signif- lation but also associate these changes with cognitive out- icant associations were found between hippocampal vol- comes. ume and Verbal IQ (as indexed by VC/VCI) but not Performance IQ (as indexed by PO/PRI) in the Finally, there are two aspects of the present investigation DS22q11.2 subgroup. Previous research has suggested that limit interpretation of the results. First, multiple scan- that hippocampal volume is strongly related to intellec- ner sites were used in order to obtain data. Although scan- tual function during typical development (e.g., [30,31]). ner site was used as a covariate in all analyses to In our investigation this association held for the statistically control for potential effects, future investiga- DS22q11.2 group in the verbal domain, which is a relative tions should limit data collection to one site. A second strength in this population. However, this relation did not limitation is that, although calculation of both hippocam- hold in the nonverbal domain, which is known to be sig- pal and amygdalar volumes were derived from native nificantly impaired in individuals with DS22q11.2, espe- space, whole brains were spatially transformed to a com- cially in area of spatial cognition [14]. mon anatomical template before gray matter, white mat- ter, and CSF volumes were calculated. Based on previous The cognitive skills subserved by the hippocampus and research, it is very likely that the two groups had different associated cortical regions undergo significant develop- global brain volumes before, as well as after, the transfor- mental changes during middle childhood and adoles- mation. The fact that those differences might have caused cence. Not only are the effects of genetics important to the template normalization to behave differently in the consider but hormonal and environmental effects are as two groups cannot be ruled out. Although this issue does well. Results in the control group presented in the current not directly impact volumetric calculations of the primary paper varied slightly from previous published investiga- regions of interest (hippocampus and amygdala), the tions, which report significant associations between hip- indirect effects on the covariates are unknown. pocampal volume and Verbal IQ and not between hippocampal volume and Performance IQ. We propose Conclusion that this disparity may be attributable to differences in the Chromosome 22q11.2 deletion syndrome provides a use- ages and genders included in the analyses and possibly the ful model to explore specific genetic influences on brain specific IQ measurement used, as the single existing previ- development and resulting cognitive outcomes [17]. The ous report included older children, was restricted to male findings reported here indicate that decreased hippocam- participants only, and used a different IQ assessment [30]. pal volume is associated with cognitive performance. Not only do these findings contribute to the understanding of Additionally, at present, we can only speculate as to why the neuroanatomical variation in DS22q11.2, but they the pattern of correlations between hippocampal volume provide insight into the nature and possible source of the and IQ differed between children in the DS22q11.2 and cognitive impairments associated with the syndrome. control groups. It is possible that within the DS22q11.2 Given the known association between intellectual impair- group the developmental trajectory of the hippocampus ment, risk for psychosis, and reduced hippocampal vol- was altered early during neurodevelopment as either a ume [39,40] careful characterization of hippocampal direct result of the genetic deletion or as a downstream morphology and associations with cognition in the same effect. This variation may have affected gray matter within participants is essential for predicting outcomes in individ- the hippocampus (as measured in the present report) as uals with this syndrome and for the understanding of this well as wider connectivity between the hippocampus and neurodevelopmental disorder. other cortical regions. These alterations to neurodevelop- ment could have provided an opportunity for functional List of Abbreviations reorganization and/or compensatory mechanisms to DS22q11.2: Chromosome 22q11.2 deletion syndrome emerge. The resulting outcome of these changes may have had a stronger effect on nonverbal cognitive domains, VC/VCI : Verbal Comprehension Factor/Verbal Compre- which are more impaired in this population compared to hension Index (VCI) Wechsler Intelligence Scale for Chil- verbal domains, thus resulting in a significant correlation dren (WISC-III/IV) between Performance IQ (as indexed by PO/PCI) for the Page 7 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:54 http://www.behavioralandbrainfunctions.com/content/3/1/54 syndrome. Am J Med Genet B Neuropsychiatr Genet 2004, PO/PCI: Perceptual Organization (nonverbal) Factor/Per- 126(1):99-105. ceptual Reasoning Index (PRI) Wechsler Intelligence Scale 7. 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K, Fryns JP: Neuropsychological, learning and psychosocial profile of primary school aged children with the velo-cardio- Authors' contributions facial syndrome (22q11 deletion): evidence for a nonverbal learning disability? Child Neuropsychol 1999, 5(4):230-241. TD drafted the manuscript and supervised all manage- 14. Simon TJ, Bish JP, Bearden CE, Ding L, Ferrante S, Nguyen V, Gee JC, ment, analysis, and interpretation of the data. ZW contrib- McDonald-McGinn DM, Zackai EH, Emannuel BS: A multiple levels uted to data analysis and helped to draft the manuscript. analysis of cognitive dysfunction and psychopathology asso- ciated with chromosome 22q11.2 deletion syndrome in chil- AL provided quality assurance of volumetric MRI data and dren. Dev Psychopathol 2005, 17:753-784. assisted with data management. TJS conceived of the 15. Bearden CE, Woodin MF, Wang PP, Moss E, McDonald-McGinn D, Zackai E, Emannuel B, Cannon TD: The neurocognitive pheno- study, secured funding, was responsible for its design and type of the 22q11.2 deletion syndrome: selective deficit in coordination, and helped to draft the manuscript. All visual-spatial memory. J Clin Exp Neuropsychol 2001, authors read and approved the final manuscript. 23(4):447-464. 16. Simon TJ, Bearden CE, McDonald-McGinn DM, Zackai E: Visuospa- tial and numerical cognitive deficits in children with chromo- Acknowledgements some 22q11.2 deletion syndrome. Cortex 2005, 41(2):145-155. This research was supported by NIH R01HD46159 and R01HD42974 to 17. Bearden CE, Erp TGM, Monterosso JR, Simon TJ, Glahn DC, Saleh PA, Hill NM, McDonald-McGinn DM, Zackai E, Emanuel BS, Cannon TJS, as well as the Autism Research Training Grant T32-MH073124. 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Genet Med Amelsvoort T, Chitnis X, Cutter W, Murphy DG, Murphy KC: Brain 2001, 3(1):79-84. and behaviour in children with 22q11.2 deletion syndrome: a 6. Gothelf D, Presburger G, Zohar AH, Burg M, Nahmani A, Frydman volumetric and voxel-based morphometry MRI study. Brain M, Shohat M, Inbar D, Aviram-Goldring A, Yeshaya J, Steinberg T, Fin- 2006, 129(Pt 5):1218-1228. kelstein Y, Frisch A, Weizman A, Apter A: Obsessive-compulsive disorder in patients with velocardiofacial (22q11 deletion) Page 8 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:54 http://www.behavioralandbrainfunctions.com/content/3/1/54 25. Debbane M, Schaer M, Farhoumand R, Glaser B, Eliez S: Hippocam- pal volume reduction in 22q11.2 deletion syndrome. Neu- ropsychologia 2006, 44:2360-2365. 26. 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Schumann CM, Hamstra J, Goodlin-Jones BL, Lotspeich LJ, Kwon H, Buonocore MH, Lammers CR, Reiss AL, Amaral DG: The amygdala is enlarged in children but not adolescents with autism; the hippocampus is enlarged at all ages. J Neurosci 2004, 24(28):6392-6401. 38. Menon V, Boyett-Anderson JM, Reiss AL: Maturation of medial temporal lobe response and connectivity during memory encoding. Brain Res Cogn Brain Res 2005, 25:379-385. 39. Lawrie SM, Whalley HC, Abukmeil SS, Kestelman JN, Miller P, Best JJK, Owens DGC, Johnstone EC: Temporal lobe volume changes in people at high risk of schizophrenia with psychotic symp- toms. Br J Psychiatry 2002, 181:138-143. 40. Wood SSJ, Pantelis CC, Proffitt TT, Phillips LLJ, Stuart GGW, Bucha- nan JJA, Mahony KK, Brewer WW, Smith DDJ, McGorry PPD: Spa- tial working memory ability is a marker of risk-for-psychosis. Psychol Med 2003, 33(7):1239-1247. Publish with Bio Med Central and every scientist can read your work free of charge "BioMed Central will be the most significant development for disseminating the results of biomedical researc h in our lifetime." Sir Paul Nurse, Cancer Research UK Your research papers will be: available free of charge to the entire biomedical community peer reviewed and published immediately upon acceptance cited in PubMed and archived on PubMed Central yours — you keep the copyright BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 9 of 9 (page number not for citation purposes) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Behavioral and Brain Functions Springer Journals

Hippocampal volume reduction in children with chromosome 22q11.2 deletion syndrome is associated with cognitive impairment

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Springer Journals
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Copyright © 2007 by DeBoer et al; licensee BioMed Central Ltd.
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Biomedicine; Neurosciences; Neurology; Behavioral Therapy; Psychiatry
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1744-9081
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Abstract

Background: Previous investigations of individuals with chromosome 22q11.2 deletion syndrome (DS22q11.2) have reported alterations in both brain anatomy and cognitive function. Neuroanatomical studies have reported multiple abnormalities including changes in both gray and white matter in the temporal lobe, including the amygdala and hippocampus. Separate investigations of cognitive abilities have established the prevalence of general intellectual impairment, although the actual extent to which a single individual is affected varies greatly within the population. The present study was designed to examine structures within the temporal lobe and assess their functional significance in terms of cognition in children with DS22q11.2. Method: A total of 72 children (ages 7–14 years) participated in the investigation: 36 children (19 female, 17 male) tested FISH positive for chromosome 22q11.2 deletion (Mean age = 10 years 9 months, ± 2 yr 4 mo) and 36 were age-matched typically developing controls (13 female, 23 male; Mean age = 10 years 6 months, ± 1 yr 11 mo). For each subject, a three-dimensional high-resolution (1 mm isotropic) T1-weighted structural MRI was acquired. Neuroanatomical guidelines were used to define borders of the amygdala and hippocampus bilaterally and volumes were calculated based on manual tracings of the regions. The Wechsler Intelligence Scale for Children (WISC) was also administered. Results: Volumetric reductions in total gray matter, white matter, and both the amygdala and hippocampus bilaterally were observed in children with DS22q11.2. Reductions in the left hippocampus were disproportionate to decreases in gray matter after statistically controlling for group differences in total gray matter, age, and data collection site. This specific reduction in hippocampal volume was significantly correlated with performance on standardized measures of intelligence, whereas the other neuroanatomical measures were not (gray/white matter, CSF, and amygdala). Conclusion: Results from this study not only contribute to the understanding of the neuroanatomical variation in DS22q11.2, but also provide insight into the nature and source of the cognitive impairments associated with the syndrome. Specifically, we report that decreases in hippocampal volume may serve as an index of severity for cognitive impairments in children with DS22q11.2. Page 1 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:54 http://www.behavioralandbrainfunctions.com/content/3/1/54 tions emerging in the presence of marked psychopathol- Background Chromosome 22q11.2 deletion syndrome (DS22q11.2) ogy [18,23]. is a congenital condition known to affect brain develop- ment and cognition that occurs in 1–2 out of every 4,000 Although the number of studies examining individual live births [1]. The syndrome results from a microdeletion structures (i.e., amygdala and hippocampus) in the tem- nd on the long arm (q) of the 22 chromosome and has poral lobes is increasing, findings to date have been vari- been identified as the molecular cause for several symp- able (cf. [22,24-26]). Some of this heterogeneity can be tom-based medical diagnoses [2]. Medical characteristics attributed to small sample sizes, differences in the ages, associated with the syndrome typically include palatal cognitive abilities, and psychiatric symptoms of those abnormalities and/or velopharyngeal insufficiency, tested, the control groups chosen for comparison, the immune deficiency, congenital cardiac defects, neonatal methods used to determine anatomical boundaries, and hypocalcemia, and facial dysmorphisms [3,4]. Individu- the covariates used in analyses. For example, dispropor- als with DS22q11.2 are also at an increased risk for devel- tionate decreases in hippocampal volume have not typi- oping psychiatric disorders such as ADHD [5], obsessive- cally been reported when total brain volume is used as a compulsive disorder [6], affective disorders [7], autism covariate (e.g., [22,26]), but have been reported when [5], and schizophrenia [8]. Significant intellectual impair- total gray matter is used (e.g., [24,25]). Moreover, these ments are often observed as well [9]. However, at present, findings are difficult to compare directly given the wide far less is known about the cognitive characteristics than range of ages and cognitive abilities of the participants, as for the medical indications. well as variations in the tracing methods used for volu- metric analyses (cf.; [27,28]). Impairment in general intellectual functioning is one of the most consistently reported features in DS22q11.2 [9]. Thus, although some progress has been made in charac- IQ scores typically fall in the range of 70–85, one full terizing the neuroanatomical differences within this pop- standard deviation or more below the population mean. ulation, the implications for neurocognitive outcomes Empirical investigations have demonstrated that low per- remain poorly understood. Bearden and colleagues [17] formance on IQ assessments are not the result of the phys- have begun to address this issue by relating regional brain ical or medical characteristics [10,11], nor the associated abnormalities with cognitive ability and behavioral phe- behavioral problems that commonly accompany the syn- notype in a sample of 13 children with DS22q11.2. drome [12]. Studies of academic achievement have Results of this investigation indicated that only temporal attempted to further clarify these cognitive difficulties and lobe volume (both gray and white matter) significantly report that children with DS22q11.2 perform better at predicted overall cognitive performance in children with reading and spelling than arithmetic [13]. This specific DS22q11.2 [17]. Specifically, temporal lobe volume was a pattern of cognitive strengths and weaknesses has lead to significant positive predictor of Full Scale and Verbal IQ, the hypothesis that the cognitive difficulties are the cas- but not Performance IQ (as measured by WISC-III). In caded effects of core deficits in visuospatial processing addition, Bearden et al. [17] report a negative correlation and attention, both of which are primarily mediated by between Thought Problems as assessed by the Child cortical networks in the parietal and temporal lobes [14- Behavior Checklist (CBCL; [29]) and temporal lobe gray 16]. matter volume. At least some of the genetic material in the deleted seg- Within the temporal lobe are two structures on which ment (30–40 genes) appears to be related to typical brain much empirical research has been conducted: the amy- development, as anomalous brain structure is consistently gdala (implicated in emotion and social behavior) and reported [17,18]. Thus far, characterization of the expres- the hippocampus (well-known for its role in memory and sion of DS22q11.2 in terms of neurodevelopment has spatial cognition). Investigation of these individual struc- come from studies using structural and function magnetic tures may provide more detail regarding regionally spe- resonance imaging and diffusor tensor imaging in chil- cific changes within the temporal lobe network. While the dren, adolescents, and adults with the syndrome [18-21]. hippocampus has been measured volumetrically in The most reliable neuroanatomical finding thus far is an DS22q11.2 and has been hypothesized to be related to overall reduction in total brain volume ranging from 8.5– risk for psychopathology [22] and memory impairments 11% that appears more concentrated in the posterior and [25], to our knowledge, no evidence exists to date regard- inferior regions of the brain [19-21]. During childhood, ing the functional significance resulting from these volumetric reductions in the temporal lobe have been observed abnormalities. Studies with typically developing reported as the result of decreases in both gray and white children have suggested that the hippocampus is corre- matter [22]. Similarly, studies in adulthood also report lated with both IQ [30] and memory (see [31] for review). reductions in temporal lobe volume, with greatest reduc- Also relevant for studies of children with DS22q11.2, Page 2 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:54 http://www.behavioralandbrainfunctions.com/content/3/1/54 there is evidence of associations between reductions in 256, slice thickness = 1.0 mm, yielding 160 axial slices hippocampus volume in schizophrenia (see [32] for with an in-plane resolution of 1 × 1 mm, 3T Siemens Mag- review), which may make assessment of this structure netom Trio, TR = 1620 ms, TE = 3.87 ms, 15 degree flip important for risk assessment and prediction of out- angle, matrix size = 256 × 192, slice thickness = 1.0 mm, comes. 160 axial slices with in-plane resolution of 0.98 × 0.98 mm. Although data collection site was not significantly In short, the purpose of present investigation was to correlated with any of the volumetric measurements it expand on previous research examining neuroanatomical was entered as a covariate in all analyses. differences in children with DS22q11.2 and link these findings to resulting cognitive outcomes. The ultimate In addition to the structural MRI procedure, the Wechsler goal of this line of research is to gain further insight into Intelligence Scale for Children (WISC-III/IV) was also complex gene-brain-behavior relations associated with administered to 41 participants (20 control, 21 this syndrome and improve outcome predictions. Volu- Ds22q11.2). In order to equate WISC versions IIII and IV metric measurements of regions within the temporal lobe, Verbal Comprehension Factor/Perceptual Organization namely the hippocampus and amygdala, were measured (nonverbal) Factor (VC/PO) were used from WISC-III and bilaterally from structural MRIs in 72 children and adoles- Verbal Comprehension Index/Perceptual Reasoning cents with and without DS22q11.2. Associations with Index (VCI/PRI) were used from WISC-IV. The remaining intellectual ability were assessed. children were either unable to return for clinical evalua- tion or received an abbreviated version of the intelligence assessment which was not compatible with the WISCII-IV. Methods Participants Neuroanatomical findings for this subgroup of 41 chil- A total of 72 children (ages 7–14 years) participated in dren comparing amygdala and hippocampal volume were this investigation: 36 children (19 female, 17 male) diag- identical to that of the entire sample. nosed with chromosome 22q11.2 deletion syndrome (Mean age = 10 years 9 months, ± 2 yr 4 mo) and 36 age- Data analysis/processing matched typically developing controls (13 female, 23 Overall brain volume measurements for each tissue type (gray matter, white matter, and cerebrospinal fluid or male; Mean age = 10 years 6 months, ± 1 yr 11 mo). Informed asset and consent was obtained from all partic- CSF) were calculated using the segmentation algorithms ipants and their guardians prior to participation. Diagno- in SPM2 (Wellcome Department of Cognitive Neurology, sis of chromosome 22q11.2 deletion was confirmed using London, UK, [33]). All MRI scans were spatially normal- fluorescent in situ hybridization (FISH). The experimental ized through registration to a template before the segmen- protocol followed guidelines set forth in the Helsinki Dec- tation was preformed. For the spatial normalization, a laration for the ethical treatment of human research par- pediatric brain template (CCHMC2 template, Cincinnati ticipants and was approved by the governing Institutional Children's Hospital Medical Center, Cincinnati, OH) was Review Boards of the data collection sites (Children's Hos- used instead of the default ICBM's adult template in SPM2 pital of Philadelphia, Hospital of the University of Penn- as we wanted to minimize the amount of deformation sylvania, and the University of California, Davis Medical during the non-linear spatial normalization for our child Center). participants [34]. The CCHMC2 template was generated from 200 healthy children, 98 boys and 102 girls, ranging Procedure in age from 5 to 18 years (mean age was 11.43 F 3.59 MRI data were acquired using a 1.5T Siemens Vision and years) at the date of the MR-exam. The registration two 3T Siemens Trios (Siemens Medical Solutions, Welan- between individual subjects and the template was per- gen, Germany). For each subject, a three-dimensional formed by minimizing the residual sum of squared differ- high-resolution (1 mm isotropic voxels) structural MRI ence with a 12-parameter affine transformation followed was acquired using a T1-weighted MP-RAGE sequence. by a non-linear transformation comprising a linear com- Before MRI scanning, children received head motion sup- bination of 7 × 8 × 7 smooth spatial basis function. The pression training in the laboratory and in a mock MRI spatially normalized images were then resliced to a reso- scanner. Scanner parameters were as follows: 1.5T Sie- lution with voxel size of 2 × 2 × 2 mm. mens Magnetom Vision scanner (Siemens Medical Solu- tions, Erlangen, Germany), TR = 9.7 ms, TE = 4 ms, 12 Tissue probability values for gray matter, white matter, degree flip angle, number of excitations = 1, matrix size, and CSF were generated using SPM's segmentation algo- 256 × 256, slice thickness = 1.0 mm, yielding 160 sagittal rithm. Voxelwise Bayesian classification based on individ- slices with an in-plane resolution of 1 × 1 mm, 3T Siemens ual image intensity and prior probability maps (i.e., Magnetom Trio, TR = 1820 ms, TE = 2.93 ms, 12 degree CCHMC2 maps) was iteratively computed followed by flip angle, number of excitations = 1, matrix size, 256 × bias correction. After segmentation, some non-brain vox- Page 3 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:54 http://www.behavioralandbrainfunctions.com/content/3/1/54 els, such as scalp, skull and venous sinuses, and odd vox- Images were reoriented so that the horizontal axis was els on tissue edges were cleaned from the segmented parallel to a line from the rostral to the caudal pole of the images by using a series of fully automated morphological hippocampus. Coronal sections were viewed perpendicu- operations [35]. The segmented tissue maps were modu- lar to the horizontal axis. On each coronal image, neuro- lated by the Jacobian determinants derived from the spa- anatomical guidelines were used to define borders of the tial deformation field to preserve the total brain volume. amygdala and hippocampus bilaterally and volumes were Total volumes for gray matter, white matter and CSF were calculated based on manual tracings of the regions in then obtained by summing the voxel values in the modu- native space, see Figure 1 (complete details of the proce- lated images. dure can be found in [37]). For manual tracings of the amygdala and hippocampus, After establishing inter-rater reliability of greater than .90 non-normalized T1-weighted images were imported into on 10 training cases, raters who were blind to group status Analyze 5.0 (Biomedical Imaging Resource, Rochester, manually traced the amygdala and hippocampus. Approx- MN; [36]) and converted to cubic voxel dimensions of imately 10% of the cases included in this investigation 0.469 mm (using a cubic spline interpolation algorithm). were then re-traced by all raters to ensure equality Orthogonal views for segmenting th Figure 1 e amygdala and hippocampus on MRI sections Orthogonal views for segmenting the amygdala and hippocampus on MRI sections. A three dimensional reconstruction of images (a) in which lines indicate the position of the horizontal plane (b), sagittal plane (c), and coronal plane (d) is shown. The arrow in b indicates the best-fit line along the white matter separating the amygdala from the putamen; the arrow in c repre- sents the white matter that forms the ventral border of the rostral amygdala. A, Amygdala; EC, entorhinal cortex; H, hippoc- ampus; PU, putamen; TLV, temporal horn of the lateral ventricle; WM, subamygdaloid white matter. Figure reproduced with permission from [37]. Copyright 2004 by the Society for Neuroscience. Page 4 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:54 http://www.behavioralandbrainfunctions.com/content/3/1/54 Table 1: Mean IQ (SD) for DS22q11.2 and control groups between tracings. Inter-rater reliability for the left and right amygdala was: .952 and .949; inter-rater reliability Controls (n = 20) DS22q11.2 (n = 21) One-way ANOVA for the left and right hippocampus was: .953 and .923. VC/VCI 111 (11) 81 (14) F(1, 39) = 61.01, p < .001 PO/PRI 112 (11) 78 (13) F(1, 39) = 82.99, p < .001 Results FSIQ 110 (11) 77 (12) F(1, 39) = 88.70, p < .001 Multivariate ANCOVAs were used to assess group differ- ences in gray and white matter and CSF, with age and data collection site entered as covariates. Multivariate ANCO- VAs were also used to assess group differences in both 3.11) compared to controls (M = 2.56 cm , SD = 3.73), right and left amygdala and hippocampus volumes, with F(1, 65) = 7.29, p <.01. However, right hippocampal vol- age, data collection site, and gray matter volume entered ume did not differ between the DS22q11.2 group (M = as covariates. Analyses regarding bilateral volume of the 2.46, SD = 3.24) and controls (M = 2.57 cm , SD = 3.45), amygdala and hippocampus were rerun using total brain F(1,65) = .28, p = .60. Results for the cognitive assessment volume as a covariate in place of gray matter volume. indicated that, as a group, DS22q11.2 scored significantly Results did not differ with regards to the specific covariate below controls on all IQ indices, see Table 1. used, thus only the former are reported. Data points from two outliers were removed from the analyses of the hip- In order to determine if differences in neuroanatomical pocampus and amygdala to ensure volumetric data met measurements were related to differences in cognition, the necessary criteria for employing parametric statistics correlational analyses were conducted between IQ (as (i.e., assumption of normality and homogeneity of vari- measured by WISCIII/IV) and tissue volumes. The pattern ance between groups). of results was identical when z-score transformations were used in place of tissue volumes. Thus, for the sake of brev- Results indicated that, after statistically controlling for ity, only the results from the non-transformed dataset are possible differences due to data collection site and age, the presented. Hippocampal volume was significantly corre- DS22q11.2 group had significantly less gray (M = 710.58 lated with performance on standardized measures of 3 3 cm , SD = 67.97) and white (M = 356.51 cm , SD = 51.10) intelligence; however, other cortical measures (gray/white matter compared to controls (M = 763.63 cm , SD = 72.48 matter, CSF, and left and right amygdala) were not. Table and M = 388.46 cm , SD = 46.32), Fs(1, 68) = 10.12, 8.6 2 presents the results of the bivariate correlations and an respectively, ps < .01. However, CSF volume did not differ illustration of association between hippocampus and between the groups (DS22q11.2 M = 188.36 cm , SD = FSIQ is presented in Figure 2. 50.16, control M = 198.56 cm , SD = 37.22, F(1, 68) = .66, p = .49). After statistically controlling for differences in All correlations between IQ and hippocampal volume gray matter, age, and data collection site, there were no remained statistically significant after entering age, gray significant differences in bilateral volumes of the amy- matter, and data collection site as covariates (left hemi- gdala between DS22q11.2 (left hemisphere: M = 1.76 sphere VC/VCI r(36) = .61, p < .001, PO/PRI r(36) = .61, 3 3 cm , SD = 2.78, right hemisphere: M = 1.77 cm , SD = p < .001, FSIQ r(36) = .61, p < .001, right hemisphere VC/ 2.56) and control (left hemisphere M = 1.90 cm , SD = VCI r(36) = .45, p < .01, PO/PRI r(36) = .45, p < .01, FSIQ 2.50, right hemisphere: M = 1.90 cm , SD = 2.50) groups, r(36) = .42, p < .01). Partial correlations for each group are Fs(1, 65) = 2.08, 0.66, ps = .15, .24 respectively. After con- presented in Table 3. In order to determine if a specific trolling for differences in gray matter, age, and data collec- subtest of the IQ assessments contributed more than the tion site, left hippocampal volume was significantly others to the reported effects, partial correlations were reduced in children with DS22q11.2 (M = 2.31 cm , SD = computed on four common subtests (Similarities, Vocab- Table 2: Two-tailed bivariate correlations of neuroanatomical and IQ measures across both DS22q11.2 and control groups Gray Matter White Matter CSF Amygdala Hippocampus Left Right Left Right VC/VCI Pearson's r 0.19 0.19 -0.12 0.24 0.17 .62*** .50*** PO/PRI Pearson's r 0.17 0.18 0.02 0.25 0.21 .58*** .47*** FSIQ Pearson's r 0.11 0.08 -0.19 0.16 0.13 .56*** .39** **p ≤ .01 *** p ≤ .001 Page 5 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:54 http://www.behavioralandbrainfunctions.com/content/3/1/54 Table 4: Two-tailed partial correlations of hippocampus and IQ subtests for DS22q11.2 and control groups combined Left Right Similarities Pearson's r .47*** 0.29† Vocabulary Pearson's r .54*** .40* Block Design Pearson's r .53** .39* Comprehension Pearson's r .51** .50** † p < .10 * p < .05 ** p ≤ .01 *** p < .001 were not significant when groups were analyzed sepa- rately. This finding suggests that performance on one indi- vidual subtest was not solely responsible for the overall result of associations between hippocampal volume and IQ. In sum, within the DS22q11.2 group we report significant reductions in hippocampal volume that, in the left hemi- sphere, were disproportionate to decreases in total gray matter. These volumetric differences were significantly 2 3 respectively) Figure 2 Lin (b) positively correlates wi e hippoca ar regression scatterplot sh mpal volume measur th Full Sca ed in cu owing le IQ (r that left ( bic = .32 an millimeters a) a d .15 nd rig (mm ht ) related performance on standardized assessments of intel- Linear regression scatterplot showing that left (a) and right ligence, including tests of both verbal and non-verbal (i.e., (b) hippocampal volume measured in cubic millimeters (mm ) performance) skills. The specific pattern of association positively correlates with Full Scale IQ (r = .32 and .15 differed between the DS22q11.2 and control groups, with respectively) verbal IQ indices more strongly correlated in the DS22q11.2 group and performance IQ indices more strongly correlated in the control group. These findings ulary, Block Design, and Comprehension). Results of the are discussed, in turn, in the following section. bivariate correlational analyses are presented in Table 4. Subtest scores for 6 individuals could not be obtained Discussion from the clinic with which we were collaborating and thus Children with DS22q11.2 exhibited a disproportionate were not included in the follow-up analysis. Across decrease in left hippocampal volume compared to age groups, performance on all four subtests was correlated matched controls, even after statistically controlling for with hippocampal volume. However, these correlations group differences in overall gray matter, age, and data col- lection site. Children with DS22q11.2 also exhibited smaller volumes of the right hippocampus, and amygdala Table 3: Two-tailed partial correlations of hippocampus and IQ measures for both DS22q11.2 and control groups bilaterally, but these reductions were not disproportion- ate to reductions in gray matter. Consistent with previous Controls (n = 20) DS22q11.2 (n = 21) reports, children with DS22q11.2 also scored significantly Left Right Left Right lower than age-matched controls on all indices of the cog- nitive assessments. VC/VCI Pearson's r 0.30 0.37 .49* .62** PO/PRI Although previous studies have suggested an association Pearson's r .60** .57* 0.25 0.42† between decreased hippocampal volume and neuropsy- FSIQ chological and behavioral characteristics [25] in children Pearson's r 0.38 0.31 .48* .58* with DS22q11.2, this hypothesis has not been examined empirically. This study is the first to show associations † p < .10 between decreased hippocampal volume and intelligence * p < .05 in children with DS22q11.2. Specifically, significant cor- ** p ≤ .01 Page 6 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:54 http://www.behavioralandbrainfunctions.com/content/3/1/54 relations were observed between hippocampal volume control group but not for the DS22q11.2 group. The com- and IQ, even after controlling for group differences in gray plex development of connectivity between regions in the matter, age, and data collection site. Importantly, these medial temporal lobe, such as the hippocampus and differences did not differ as a function of the covariates other cortical regions, is a source of current investigation utilized (gray matter vs. total brain volume). In contrast, in typically developing children [38]. It is our hope that amygdalar volumes were not related to cognitive meas- future investigations will continue to explore not only ures (cf. [26]). Similar to findings of regional reduction in how this connectivity is altered within DS22q11.2 popu- temporal lobe volume in children DS22q11.2 [17], signif- lation but also associate these changes with cognitive out- icant associations were found between hippocampal vol- comes. ume and Verbal IQ (as indexed by VC/VCI) but not Performance IQ (as indexed by PO/PRI) in the Finally, there are two aspects of the present investigation DS22q11.2 subgroup. Previous research has suggested that limit interpretation of the results. First, multiple scan- that hippocampal volume is strongly related to intellec- ner sites were used in order to obtain data. Although scan- tual function during typical development (e.g., [30,31]). ner site was used as a covariate in all analyses to In our investigation this association held for the statistically control for potential effects, future investiga- DS22q11.2 group in the verbal domain, which is a relative tions should limit data collection to one site. A second strength in this population. However, this relation did not limitation is that, although calculation of both hippocam- hold in the nonverbal domain, which is known to be sig- pal and amygdalar volumes were derived from native nificantly impaired in individuals with DS22q11.2, espe- space, whole brains were spatially transformed to a com- cially in area of spatial cognition [14]. mon anatomical template before gray matter, white mat- ter, and CSF volumes were calculated. Based on previous The cognitive skills subserved by the hippocampus and research, it is very likely that the two groups had different associated cortical regions undergo significant develop- global brain volumes before, as well as after, the transfor- mental changes during middle childhood and adoles- mation. The fact that those differences might have caused cence. Not only are the effects of genetics important to the template normalization to behave differently in the consider but hormonal and environmental effects are as two groups cannot be ruled out. Although this issue does well. Results in the control group presented in the current not directly impact volumetric calculations of the primary paper varied slightly from previous published investiga- regions of interest (hippocampus and amygdala), the tions, which report significant associations between hip- indirect effects on the covariates are unknown. pocampal volume and Verbal IQ and not between hippocampal volume and Performance IQ. We propose Conclusion that this disparity may be attributable to differences in the Chromosome 22q11.2 deletion syndrome provides a use- ages and genders included in the analyses and possibly the ful model to explore specific genetic influences on brain specific IQ measurement used, as the single existing previ- development and resulting cognitive outcomes [17]. The ous report included older children, was restricted to male findings reported here indicate that decreased hippocam- participants only, and used a different IQ assessment [30]. pal volume is associated with cognitive performance. Not only do these findings contribute to the understanding of Additionally, at present, we can only speculate as to why the neuroanatomical variation in DS22q11.2, but they the pattern of correlations between hippocampal volume provide insight into the nature and possible source of the and IQ differed between children in the DS22q11.2 and cognitive impairments associated with the syndrome. control groups. It is possible that within the DS22q11.2 Given the known association between intellectual impair- group the developmental trajectory of the hippocampus ment, risk for psychosis, and reduced hippocampal vol- was altered early during neurodevelopment as either a ume [39,40] careful characterization of hippocampal direct result of the genetic deletion or as a downstream morphology and associations with cognition in the same effect. This variation may have affected gray matter within participants is essential for predicting outcomes in individ- the hippocampus (as measured in the present report) as uals with this syndrome and for the understanding of this well as wider connectivity between the hippocampus and neurodevelopmental disorder. other cortical regions. These alterations to neurodevelop- ment could have provided an opportunity for functional List of Abbreviations reorganization and/or compensatory mechanisms to DS22q11.2: Chromosome 22q11.2 deletion syndrome emerge. The resulting outcome of these changes may have had a stronger effect on nonverbal cognitive domains, VC/VCI : Verbal Comprehension Factor/Verbal Compre- which are more impaired in this population compared to hension Index (VCI) Wechsler Intelligence Scale for Chil- verbal domains, thus resulting in a significant correlation dren (WISC-III/IV) between Performance IQ (as indexed by PO/PCI) for the Page 7 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:54 http://www.behavioralandbrainfunctions.com/content/3/1/54 syndrome. Am J Med Genet B Neuropsychiatr Genet 2004, PO/PCI: Perceptual Organization (nonverbal) Factor/Per- 126(1):99-105. ceptual Reasoning Index (PRI) Wechsler Intelligence Scale 7. 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Gerdes M, Solot CB, Wang PP, Moss EM, LaRossa D, Randall P, Gold- muntz E, Clark BJ, Driscoll DA, Jawad A, Emmanuel BS, McDonald- McGinn DM, Batshaw ML, Zackai EH: Cognitive and behavior CSF: Cerebrospinal fluid profile of preschool children with chromosome 22q11.2 dele- tion. Am J Med Genet 1999, 85:127-133. 11. Gerdes M, Solot C, Wang PP, McDonald-McGinn DM, Zackai EH: WISC-III/IV: Wechsler Intelligence Scale for Children ver- Taking advantage of early diagnosis: preschool children with sion III/IV the 22q11.2 deletion. Genet Med 2001, 3(1):40-44. 12. Jansen PW, Duijff SN, Beemer FA, Vorstman JAS, Klaassen PWJ, Mor- cus MEJ, Boer JAH: Behavioral problems in relation to intelli- Competing interests gence in children with 22q11.2 deletion syndrome: a The author(s) declare that they have no competing inter- matched control study. Am J Med Genet A 2007, 143(6):574-580. 13. Swillen A, Vandeputte L, Cracco J, Maes B, Ghesquiere P, Devriendt ests. K, Fryns JP: Neuropsychological, learning and psychosocial profile of primary school aged children with the velo-cardio- Authors' contributions facial syndrome (22q11 deletion): evidence for a nonverbal learning disability? Child Neuropsychol 1999, 5(4):230-241. TD drafted the manuscript and supervised all manage- 14. Simon TJ, Bish JP, Bearden CE, Ding L, Ferrante S, Nguyen V, Gee JC, ment, analysis, and interpretation of the data. ZW contrib- McDonald-McGinn DM, Zackai EH, Emannuel BS: A multiple levels uted to data analysis and helped to draft the manuscript. analysis of cognitive dysfunction and psychopathology asso- ciated with chromosome 22q11.2 deletion syndrome in chil- AL provided quality assurance of volumetric MRI data and dren. Dev Psychopathol 2005, 17:753-784. assisted with data management. TJS conceived of the 15. Bearden CE, Woodin MF, Wang PP, Moss E, McDonald-McGinn D, Zackai E, Emannuel B, Cannon TD: The neurocognitive pheno- study, secured funding, was responsible for its design and type of the 22q11.2 deletion syndrome: selective deficit in coordination, and helped to draft the manuscript. All visual-spatial memory. J Clin Exp Neuropsychol 2001, authors read and approved the final manuscript. 23(4):447-464. 16. Simon TJ, Bearden CE, McDonald-McGinn DM, Zackai E: Visuospa- tial and numerical cognitive deficits in children with chromo- Acknowledgements some 22q11.2 deletion syndrome. Cortex 2005, 41(2):145-155. This research was supported by NIH R01HD46159 and R01HD42974 to 17. Bearden CE, Erp TGM, Monterosso JR, Simon TJ, Glahn DC, Saleh PA, Hill NM, McDonald-McGinn DM, Zackai E, Emanuel BS, Cannon TJS, as well as the Autism Research Training Grant T32-MH073124. 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