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Atlas-based white matter analysis in individuals with velo-cardio-facial syndrome (22q11.2 deletion syndrome) and unaffected siblings

Atlas-based white matter analysis in individuals with velo-cardio-facial syndrome (22q11.2... Background: Velo-cardio-facial syndrome (VCFS, MIM#192430, 22q11.2 Deletion Syndrome) is a genetic disorder caused by a deletion of about 40 genes at the q11.2 band of one copy of chromosome 22. Individuals with VCFS present with deficits in cognition and social functioning, high risk of psychiatric disorders, volumetric reductions in gray and white matter (WM) and some alterations of the WM microstructure. The goal of the current study was to characterize the WM microstructural differences in individuals with VCFS and unaffected siblings, and the correlation of WM microstructure with neuropsychological performance. We hypothesized that individuals with VCFS would have decreased indices of WM microstructure (fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD)), particularly in WM tracts to the frontal lobe, and that these measures would be correlated with cognitive functioning. Methods: Thirty-three individuals with VCFS (21 female) and 16 unaffected siblings (8 female) participated in DTI scanning and neuropsychological testing. We performed an atlas-based analysis, extracted FA, AD, and RD measures for 54 WM tracts (27 in each hemisphere) for each participant, and used MANOVAs to compare individuals with VCFS to siblings. For WM tracts that were statistically significantly different between VCFS and siblings (p < 0.05), FDR we assessed the correlations between DTI and neuropsychological measures. Results: In VCFS individuals as compared to unaffected siblings, we found decreased FA in the uncinate fasciculus, and decreased AD in multiple WM tracts (bilateral superior and posterior corona radiata, dorsal cingulum, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, superior cerebellar peduncle, posterior thalamic radiation, and left anterior corona radiata, retrolenticular part of the internal capsule, external capsule, sagittal stratum). We also found significant correlations of AD with measures of executive function, IQ, working memory, and/or social cognition. Conclusions: Our results suggest that individuals with VCFS display abnormal WM connectivity in a widespread cerebro-anatomical network, involving tracts from/to all cerebral lobes and the cerebellum. Future studies could focus on the WM developmental trajectory in VCFS, the association of WM alterations with psychiatric disorders, and the effects of candidate 22q11.2 genes on WM anomalies. Keywords: VCFS, 22q11.2 deletion, DTI, White matter, LDDMM * Correspondence: katesw@upstate.edu Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA Program in Neuroscience, SUNY Upstate Medical University, Syracuse, NY, USA Full list of author information is available at the end of the article © 2012 Radoeva et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Radoeva et al. Behavioral and Brain Functions 2012, 8:38 Page 2 of 11 http://www.behavioralandbrainfunctions.com/content/8/1/38 Background between alterations in FA and neuropsychological/ Velo-cardio-facial syndrome (VCFS; MIM#192430) is a psychiatric function in VCFS have also been reported genetic disorder caused by a microdeletion of a portion for schizotypy [26], arithmetic abilities [24] and (along of the 11.2 band (spanning approximately 40 genes in with AD alterations) spatial attention [23]. most cases) of one copy of chromosome 22. The pheno- While these studies are important initial steps in the typic spectrum of VCFS includes cardiac malformations, study of white matter microstructure in VCFS and brain- palatal anomalies with speech impairment, endocrine and cognition correlations, several were limited, to some ex- immune problems [1]. Notably, individuals with VCFS tent, by small sample sizes [26], wide age ranges [25] and often have cognitive deficits in attention, working mem- a primary focus on FA [24-26]. As noted above, analyses ory, executive function, visuospatial perception, math of associations between DTI measures and neuropsycho- abilities, and reading comprehension [2,3]. In addition to logical data were also limited, in that many cognitive cognitive deficits, individuals with VCFS present with functions that are impaired in VCFS (e.g., memory, ex- emotion dysregulation [2,4,5], modestly difficult temper- ecutive functioning, social cognition) have not yet been ament [6], and social withdrawal [7,8]. High prevalence examined in relationship to white matter microstructure of psychiatric disorders [9] has been reported in VCFS in this disorder. A more detailed study, therefore, of add- across multiple studies, including autism spectrum dis- itional measures in multiple white matter tracts, in asso- order (ASD) [10,11], attention deficit hyperactivity dis- ciation with a wider range of cognitive functions, could order (ADHD) [9], schizophrenia/schizoaffective disorder better elucidate the underlying neuropathology of white [12,13], anxiety disorders [14], and mood disorders [9]. matter changes in VCFS. Neuroimaging studies of individuals with VCFS have In our current study, therefore, we utilized a novel DTI found volumetric reductions, including reduction in sub- analysis method— atlas-based whole brain white matter regions of the frontal lobe, decreased volumes of the gray analysis [27], to assess the microstructure (including FA, and white matter in the parietal, temporal, and occipital AD and RD measures) of a large number of white matter lobes, smaller hippocampus (bilaterally), and smaller tracts in 33 individuals with VCFS and their unaffected cerebellum (for meta-analysis see [15]). In addition to siblings. Our goals were (1) to increase the power to de- volumetric reductions, specific structural abnormalities tect microstructural WM alterations in VCFS by using a have been described in both the gray and white matter of larger sample size of individuals with VCFS; (2) to inves- individuals with VCFS, including white matter hyperin- tigate the relative contributions of AD and RD to WM tensities, cavum septum pellucidum/vergae, pachygyria, alterations in VCFS; (3) to evaluate the correlations of polymicrogyria, cortical dysgenesis or dysplasia, and WM microstructure with a wide variety of neuropsycho- Arnold-Chiari malformation [16-19]; for review, see [1]. logical standardized tests, including attention, working Diffusion tensor imaging (DTI) has also been used to memory, executive functioning, social cognition, and psy- evaluate the microstructure of WM in VCFS. Several mea- chiatric measures. Based on the previous VCFS literature, sures can be derived from DTI scans, including fractional we hypothesized that relative to their siblings, individuals anisotropy (FA), axial diffusivity (AD) and radial diffusivity with VCFS would display alterations in FA, RD and AD (RD). In general, decreases in FA are associated with vari- which would be distributed in frontal, parietal and tem- ousWMneuropathologies,includingdemyelination, ische- poral areas and the internal capsule. We further hypothe- mia, and inflammation. While FA is a sensitive measure sized that psychiatric measures would correlate with DTI of WM microstructural changes, it is not very specific as measures in the internal capsule. Studies of WM micro- to the type/cause of WM alteration [20]. Additional DTI structural underpinnings of cognitive function in the measures, including axial diffusivity and radial diffusivity, non-VCFS population led us to further hypothesize the can better characterize the specific types of WM micro- following associations: executive function with cortico- subcortical tracts [28], superior longitudinal fasciculus structural changes, and it has been argued that such measures should be routinely included in DTI studies (SLF), and superior corona radiata (SCR) [29]; working [20]. Increases in RD, for example, have been associated memory with SLF [30], SCR, and posterior corona radiata (PCR) [29]; and social cognition/socialization with un- with demyelination [21], while decreases in AD have been correlated with increased axonal damage [21,22]. cinate fasciculus (UNC) [31], SLF, posterior limb of the in- With the exception of one report [23], all previously ternal capsule (PLIC), anterior limb of the internal capsule (ALIC) and anterior thalamic radiation (ATR) [32]. published DTI studies of individuals with VCFS have fo- cused exclusively on FA. Alterations in FA have been re- ported in VCFS-affected individuals in frontal, temporal Materials and methods and parietal areas, including anomalous tracts between Participants frontal-temporal and frontal-parietal lobes [24,25], and the In this paper, we are reporting on the data collected on posterior limb of the internal capsule [26]. Associations 49 individuals, who are participants in a longitudinal Radoeva et al. Behavioral and Brain Functions 2012, 8:38 Page 3 of 11 http://www.behavioralandbrainfunctions.com/content/8/1/38 study of VCFS [33,34]. The study was approved by the DTI processing and data analysis IRB at SUNY Upstate Medical University, and informed The data were downloaded from the scanner, transferred consent was obtained from the participants and/or their and processed using DTIStudio 3.0.2, DiffeoMap 1.7.1, parents. We included data from all individuals who par- and ROI Editor 1.4.2 (https://www.mristudio.org/, [37]) ticipated in the study between December, 2008 and Feb- on a 64-bit Dell PC, running Windows 7 operating sys- ruary, 2011 on whom we collected DTI as well as tem. First, by utilizing a mutual information algorithm neuropsychological data. DTI data from four additional [38], all diffusion weighted images from a study (the four individuals with VCFS were excluded due to poor image repeats) were coregistered to the same reference volume, quality or severe motion/scanning artifacts (see Section the b0 volume of the first repeat. Axial slices with severe DTI processing and data analysis). The VCFS diagnosis scanning and motion artifacts were excluded via auto- was confirmed with fluorescence in situ hybridization matic outlier slice rejection in DTIStudio (with relative (FISH). This sample includes 33 individuals with VCFS error > 3%), and through visual inspection. The diffusion (12 male), and 16 unaffected siblings (8 male) , with weighted images (for each diffusion direction) were then average age for the VCFS group 17.7 (SD = 1.8) and for averaged, and the average set was used for further the sibling group 18.0 (SD = 1.7) (Table 1 and Table 2). analysis. Although all of the unaffected siblings who participated Tensor estimation was then performed, and Fractional in the larger longitudinal study had a matching brother Anisotropy (FA), Axial Diffusivity (AD), Radial Diffusivity or sister with VCFS, four of the siblings reported here (RD), and b0 maps were computed and saved (while ap- did not, because imaging data from his/her counterpart plying a skull-stripped mask generated in ROI Editor for with VCFS could not be acquired/used due to braces the b0 image of each participant). The FA and b0 maps (n = 1), claustrophobia (n = 1), severe scoliosis (n = 1) or of each participant were then used for Large Deform- severe motion/scanning artifacts (n = 1). All of the parti- ation Diffeomorphic Metric Mapping (LDDMM) [27], cipants were Caucasian except one participant with and regions of interest (ROIs) were generated for each VCFS and one sibling who were Asian. The average full- participant as follows. The b0 and FA maps of each par- scale IQ was 73 (SD = 12.9, ranging between 44 and 98) ticipant were first transformed linearly (using affine for the individuals with VCFS and 113 (SD = 11.5, ran- Automated Image Registration (AIR) transformation, ging between 98 and 141) for the siblings. with trilinear interpolation) and then non-linearly (using LDDMM, with cascading alpha of 0.01, 0.005, and 0.002), in order to match as well as possible the correspond- DTI acquisition ing Johns Hopkins University MNI-space single partici- The DTI scans were acquired on a 1.5 T Philips Interra pant skull-stripped templates (JHU_MNI_SS_b0_ss and scanner (release 11) equipped with a Sense Head coil to JHU_MNI_SS_FA_ss). A detailed atlas of the white improve the signal strength and the signal-to-noise ratio. matter tracts and gray matter ROIs had been previ- A multi-slice, single-shot EPI (SENSE factor = 2.0), spin ously constructed by [27] based on the data from the echo sequence (TR/TE = 8197/76 ms) was used to obtain participant used in the Johns Hopkins University MNI- 70 axial slices with no slice gap and 2.5 mm nominal iso- space single participant skull-stripped templates. Next, tropic resolution (FOV = 240 × 240, data matrix = 96 × 96, the inverse transformation algorithms (inverse LDDMM zero-filled and reconstructed to 256 × 256). Diffusion and then inverse AIR) were applied to the ROI atlas weighting was applied along 15 directions [36] with a b (JHU_MNI_SS_WMPM_TypeII), in order to obtain ROIs factor = 800 s/mm . One minimally weighted volume that are within each participant's original brain space. (b0) was acquired within each DTI dataset. The total To ensure the proper execution of the algorithms, the scan time to acquire one DTI dataset (15 DW and 1 b0 ROIs generated were visually inspected for accuracy. images) was 2 min 11 s. The total time, including image The mean FA, AD, and RD values for the ROIs were reconstruction, to acquire 4 DTI datasets in a scan ses- then extracted in ROI Editor. For further analyses, we sion (for each participant) was approximately 9 minutes. focused on the measures FA, AD, and RD of all available white matter tract ROIs (27 tracts in each hemisphere; Table 1 Demographics of the participants for a complete list see the list of Abbreviations at the end of the paper). Sample ROIs are shown in Figure 1. VCFS Siblings P-value (N = 33) (N = 16) Neuropsychological Testing Gender (N, % female) 21 (64%) 8 (50%) N.S. As part of the larger longitudinal study, the participants Race (Caucasian/Asian) 32/1 15/1 N.S. were tested with a wide array of neuropsychological tests. Age, in years (+/− SD) 17.7 (1.8) 18.0 (1.7) N.S. The Wechsler Intelligence Scale for Children— Third FSIQ (+/− SD) 73 (12.9) 113 (11.5) < 0.001 Edition (WISC-III) [39] was administered to participants Radoeva et al. Behavioral and Brain Functions 2012, 8:38 Page 4 of 11 http://www.behavioralandbrainfunctions.com/content/8/1/38 Table 2 Number (and percent) of participants with psychiatric diagnoses in the current study based on the Schedule for Affective Disorders and Schizophrenia for School-Age Children—Present and Lifetime Version (K-SADS-PL) [35] Psychiatric Diagnoses VCFS (N = 33) Siblings (N = 16) N (%) N (%) Schizophrenia 1 (3.0) 0 (0) Major depressive disorder (includes NOS) 6 (18.2) 0 (0) Bipolar disorder 1 (3.0) 0 (0) Anxiety disorder (includes generalized, overanxious, separation and panic) 7 (21.2) 0 (0) Simple or social phobia 11 (33.3) 3 (18.75) ADHD 10 (30.3) 1 (6.25) Enuresis 1 (3.0) 0 (0) Chronic motor or vocal tic disorder 2 (6.1) 0 (0) Oppositional defiant disorder 3 (9.1) 0 (0) Any disorder listed above 20 (60.6) 3 (18.75) under 17 years of age, and the Wechsler Adult Intel- CVLT (California Verbal Learning Test) [42]: All parti- ligence Scale (WAIS-III) [40] to participants 17 years of cipants completed the CVLT, which evaluated verbal age or older. learning and memory. The CVLT (1) T-scores for List A, trials 1–5; and (2) standard score for List A, trial 5 Attention, Memory and Executive Functioning Measures [33] were used for further analyses. Digit Span was evaluated as part of WISC-III or WAIS- Wisconsin Card Sorting Test (WCST) [43]: Each par- III. Forward and Backward z-scores were used for fur- ticipant completed the WCST as part of evaluation of ther analyses. executive functioning and, more specifically, cognitive Visual Span Test [41]: In this computerized instru- flexibility. The Perseverative Error Standard Score and ment, each participant was asked to reproduce an in- the Non-Perseverative Error Standard Score of WCST creasing number of patterns of squares displayed on a were used for further analyses. computer screen [10]. This test evaluates spatial/non- BRIEF (Behavior Rating Inventory of Executive Func- verbal working memory, and the Forward and Backward tioning) [44]: Parents completed the BRIEF or BRIEF-A Visual Span Z-Scores were used. questionnaires. The T-scores of the (1) Metacognition Index (assessing initiation, organization, planning, moni- toring, and working memory); and (2) the Behavioral Regulation Index (evaluating inhibition, shift, and cogni- CGC ACR tive control); were included for further analyses. GCC CGC SCR ALIC BCC Fx SFO Social Cognition/Skills Measures EC PLIC Fx The following instruments were used: RLIC Emotional Recognition Test [45]: In this computerized PLIC IFO test, each participant was asked to discriminate between PTR SCC happy, sad and neutral faces. The total number of cor- CGH rect responses was used for further analysis. BASC-2 (Behavior Assessment System for Children, Second Edition): Parents completed the BASC-2 [46], Figure 1 White matter tracts analyzed in the current report represented on the FA map of one individual with VCFS. which contains 150 items that are rated on a 4-point Abbreviations: ACR: Anterior corona radiata; ALIC: Anterior limb of scale. Scores were then derived for a variety of domains the internal capsule; BCC: Body of the corpus callosum; CGC: such as social skills, withdrawal, conduct problems. The Cingulum (cingulate gyrus); CGH: Cingulum (hippocampus); EC: T-scores of the BASC-2 social skills domain, atypicality, External capsule; Fx: Fornix (column and body of the fornix); GCC: and anxiety were used for analysis in this report. Genu of the corpus callosum; IFO: Inferior fronto-occipital fasciculus; PLIC: Posterior limb of the internal capsule; PTR: Posterior thalamic Vineland-II (Vineland Adaptive Behavior Scales, Sec- radiation; SCR: Superior corona radiata; SS: Sagittal stratum; RLIC: ond Edition): Parents were interviewed with Vineland-II Retrolenticular part of the internal capsule. For the full list of WM [47], evaluating various aspects of the child's behavior, tracts analyzed in the current study, see the List of Abbreviations. including social skills (socialization subdomain). Radoeva et al. Behavioral and Brain Functions 2012, 8:38 Page 5 of 11 http://www.behavioralandbrainfunctions.com/content/8/1/38 SRS (Social Responsiveness Scale): Parents completed a widely distributed network of tracts showed signifi- the SRS, which consists of 65 items [48,49], and mea- cantly lower AD in individuals with VCFS as compared sures aspects of social awareness, social cognition, social to siblings (p < 0.05) (see Figure 3), including tracts FDR communication, social motivation, and autistic manner- terminating in the parietal/occipital (posterior thalamic isms, and provides a total score. The items are slightly radiation, PTR; posterior corona radiata, PCR; retrolenti- different (but comparable) for children aged 18 or cular part of the internal capsule, RLIC; sagittal stratum, younger vs. adults (19 or older). Since norms, T-scores, SS), and/or frontal cortices (superior corona radiata, and domain classification are provided only for the SCR; anterior corona radiata, ACR); as well as fronto- child/adolescent scale (but not for the adult version), the parietal/occipital (inferior fronto-occipital fasciculus, total raw score was used for further analysis for all IFO; superior longitudinal fasciculus, SLF; external cap- participants. sule, EC); fronto-temporal (cingulum, CGC); and cer- CGAS (Children's Global Assessment Scale) [50]: A ebellar connections (superior cerebelar peduncle, SCP). clinician evaluated the global functioning of each partici- For reasons described below, both the uncorrected and pant (based on an interview with the parent and the FDR-corrected P-values from the MANOVAs are in- child), and completed the CGAS. cluded in Appendix 1. The majority of the WM mea- sures had normal distributions in both the VCFS and the Statistical Analysis control groups. However, some of the distributions were The Shapiro – Wilk Test of Normality was used to inves- not normal, and there were outliers for some of the tigate the distribution of all data (see results, below). tracts. Therefore, as a follow-up, we conducted non- Three MANOVAs were conducted with dependent var- parametric analysis (Mann–Whitney U tests), which is iables mean FA (or AD or RD) values (in each of the less sensitive to outliers and can appropriately be used tracts) and independent variable Group (VCFS vs. sib- for non-normally distributed data, and compared the lings), using SPSS 18 (http://www.spss.com/). FDR (false DTI measures of the tracts (for VCFS vs. controls), and discovery rate) correction for multiple comparisons was corrected the p-values using FDR. All the tracts sum- applied in the program R (http://www.r-project.org/) on marized in Figures 2 and 3 remained significant with this the p-values from each of the three MANOVAs [51]. For non-parametric analysis. RD in the right posterior cor- tracts that showed significant differences between the par- ona radiata (PCR) was not significant in this analysis, ticipants with VCFS and controls (p < 0.05), Pearson's and was dropped from further analyses. In addition, sev- FDR correlations were performed (in SPSS) between the DTI eral tracts that had non-normal distributions showed measures of the tracts, and each of the neuropsychological significant differences between patients and controls: measures (described above), across all of the study parti- namely, the AD of the left and right ML, left UNC, right cipants. Since multiple correlations were performed, the MCP, and right RLIC (data not shown). p-values of the correlations were also FDR-corrected. AD values were significantly correlated with several As noted in the background, individuals with VCFS neuropsychological and psychiatric measures across all have a higher prevalence of certain brain abnormalities, participants (Tables 3 and 4). AD values in fronto-parietal/ including cavum septum pellucidum/vergae. Four VCFS occipital circuits (SLF, IFO) correlated with measures of participants in our current sample have this variant as working memory, executive functioning, and social cogni- evaluated by a neuroradiologist. The presence of cavum tion. In addition measures of executive functioning cor- septum pellucidum/vergae seems to be associated with related with AD in PCR and PTR bilaterally. Overall an alteration of the anatomy of the fornix, such that the columns and body of the fornix do not join in the mid- 0.60 line and seem to run separately within the left and right VCFS 0.50 hemispheres between the cavum septum pellucidum and Siblings the lateral ventricles [52]. Thus, the automated fornix 0.40 measures in the current study might not be valid for 0.30 individuals with cavum septum pellucidum/vergae,so we 0.20 excluded these four individuals from the analyses only of 0.10 the fornix measures. 0.00 Left Left UNC UNC Right Right U UNC NC Results Figure 2 Significant Differences in Fractional Anisotropy The MANOVAs demonstrated that the FA in the left and (p < 0.05) in individuals with VCFS vs. siblings in the left and FDR right uncinate fasciculi (see Figure 2), and RD in the right right uncinate fasciculi (UNC, L and UNC, R respectively). posterior corona radiata (PCR) differed between parti- Error bars show SE. cipants with VCFS and siblings (p < 0.05). Furthermore, FDR Fractional Anisotropy Radoeva et al. Behavioral and Brain Functions 2012, 8:38 Page 6 of 11 http://www.behavioralandbrainfunctions.com/content/8/1/38 (A) (B) 0.0025 0.0025 VCFS 0.0020 0.0020 Siblings 0.0015 0.0015 0.0010 0.0010 0.0005 0.0005 0.0000 0.0000 SCP PTR ACR SCR PCR CGC SLF IFO SS EC RLIC SCP PTR SCR PCR CGC SLF IFO Figure 3 Significant Differences in Axial Diffusivity (p < 0.05) in individuals with VCFS (black) vs. siblings (grey) in the (A) left; or (B) FDR right sides of the brain. Error bars show SE. Abbreviations: SCP: Superior cerebellar peduncle; PTR: Posterior thalamic radiation; ACR: Anterior corona radiata; SCR: Superior corona radiata; PCR: Posterior corona radiata; CGC: Cingulum (cingulate gyrus); SLF: Superior longitudinal fasciculus; IFO: Inferior fronto-occipital fasciculus; SS: Sagittal stratum; EC: External capsule; RLIC: Retrolenticular part of the internal capsule. measures of cognitive skills (intelligence,VIQ and PIQ) cor- Discussion related with the majority of the studied tracts, which may Differences between individuals with VCFS and siblings be expected, since IQ is a composite assessment of mul- Our current findings are partially consistent with some tiple domains including attention, working memory, ver- of the data reported previously, and further suggest that bal comprehension, and processing speed (Tables 3 and 4). a more widely distributed set of tracts, including Table 3 Correlations between neuropsychological measures and the Axial Diffusivity of white matter tracts in the Left Hemisphere across all study participants Domain Measure Left Hemisphere Frontal/Temp Parietal/Occipital A/P Long Tracts Cer CGC SCR RLIC EC PTR PCR SLF IFO SS SCP Memory & Attention Digit Span FW 0.19 0.15 0.13 0.29 0.19 0.07 0.14 0.22 0.19 0.35 Digit Span BW 0.15 0.15 0.17 0.08 0.37 0.20 0.23 0.20 0.21 0.34 * ** * Visual Span FW 0.33 0.28 0.31 0.25 0.36 0.47 0.40 0.28 0.29 0.25 * ** ** ** * * Visual Span BW 0.34 0.28 0.43 0.29 0.52 0.48 0.47 0.40 0.38 0.27 CVLT_List A, Trials 1–5 0.07 0.18 0.08 0.09 0.30 0.35 0.37 0.14 0.16 0.21 ** * ** Executive Function WCST Perseverative Error 0.18 0.30 0.33 0.21 0.45 0.43 0.50 0.27 0.33 0.34 BRIEF Behavioral Regulation 0.00 −0.18 −0.17 −0.24 −0.42 −0.28 −0.30 −0.23 −0.16 −0.30 ** BRIEF Metacognition −0.15 −0.15 −0.22 −0.26 −0.51 −0.31 −0.34 −0.32 −0.18 −0.27 Social Cognition BASC Social Skills 0.08 0.16 0.11 0.23 0.24 0.28 0.29 0.17 0.21 0.26 ** * * Socialization Vineland Soc Skills 0.01 0.19 0.21 0.28 0.45 0.37 0.40 0.27 0.33 0.29 ** * * SRS −0.08 −0.25 −0.26 −0.27 −0.49 −0.42 −0.42 −0.30 −0.25 −0.33 Emotion Emotion Recognition 0.17 0.24 0.33 0.20 0.30 0.27 0.33 0.20 0.10 0.22 Psychiatric BASC Anxiety −0.06 −0.21 −0.08 −0.07 −0.31 −0.28 −0.27 −0.11 −0.19 −0.34 * * Symptoms BASC Atypicality −0.01 −0.30 −0.25 −0.24 −0.37 −0.35 −0.36 −0.27 −0.15 −0.30 * * CGAS 0.07 0.24 0.06 0.12 0.39 0.33 0.37 0.21 0.16 0.26 ** * ** ** ** * * * Overall Verbal IQ 0.32 0.34 0.47 0.35 0.52 0.54 0.55 0.36 0.43 0.43 * * ** * *** ** ** * * * Cognition Performance IQ 0.39 0.38 0.50 0.35 0.62 0.55 0.54 0.38 0.45 0.42 The subset of WM tracts included in this table had significantly different AD between individuals with VCFS and unaffected siblings, p <0.05. The R values for FDR the correlations are given, and corresponding FDR-corrected P-values are indicated with a superscript according to the legend below the table. No significance was found for the Non-Perseverative Error Standard Score of WCST, the standard score for List A, trial 5, and AD of the ACR tract in the left hemisphere: thus, these measures were not included in this table. Abbreviations BW: Backward; FW: Forward; CVLT: California Verbal Learning Test; WCST: Wisconsin Card Sorting Test; BRIEF: Behavior Rating Inventory of Executive Functioning; SRS: Social Responsiveness Scale; BASC: Behavior Assessment System for Children; CGAS: Children's Global Assessment Scale; IQ: Intelligence Quotient. Abbreviations for the white matter tracts are given in the list of Abbreviations at the end of the paper. A/P Long Tracts: Anterior-Poster Long Tracts; Cer: cerebellum. * p < 0.05. FDR ** p < 0.01. FDR *** p < 0.001. FDR Axial Diffusivity Radoeva et al. Behavioral and Brain Functions 2012, 8:38 Page 7 of 11 http://www.behavioralandbrainfunctions.com/content/8/1/38 Table 4 Correlations between neuropsychological measures and Axial Diffusivity of white matter tracts in the Right Hemisphere across all study participants Domain Measure Right Hemisphere Frontal/Temp Parietal/Occipital A/P Long Tracts Cer CGC SCR PTR PCR SLF IFO SCP Memory & Attention Digit Span FW 0.23 0.20 0.25 0.17 0.16 0.25 0.36 * * * Digit Span BW 0.24 0.12 0.38 0.26 0.30 0.36 0.44 * * ** ** ** Visual Span FW 0.42 0.38 0.29 0.48 0.47 0.48 0.25 * ** *** Visual Span BW 0.38 0.24 0.25 0.51 0.57 0.61 0.29 * * CVLT_List A, , Trials 1–5 0.18 0.17 0.29 0.36 0.38 0.25 0.26 * ** ** ** Executive Function WCST Perseverative Error 0.29 0.29 0.37 0.48 0.58 0.48 0.32 * ** BRIEF Behavioral Regulation −0.17 −0.31 −0.28 −0.40 −0.48 −0.34 −0.17 * ** ** * BRIEF Metacognition −0.22 −0.36 −0.30 −0.45 −0.53 −0.41 −0.18 Social Cognition BASC Social Skills 0.14 0.14 0.23 0.29 0.43 0.24 0.22 * ** * Socialization Vineland Soc Skills 0.17 0.22 0.27 0.38 0.54 0.41 0.31 ** * * SRS −0.24 −0.34 −0.27 −0.49 0.41 −0.44 −0.27 * * Emotion Emotion Recognition 0.24 0.15 0.17 0.28 0.38 0.41 0.23 Psychiatric BASC Anxiety −0.13 −0.23 −0.19 −0.34 −0.39 −0.22 −0.31 * * ** * Symptoms BASC Atypicality −0.16 −0.38 −0.26 −0.44 −0.48 −0.35 −0.23 * ** * CGAS 0.11 0.29 0.31 0.44 0.57 0.39 0.33 * ** ** *** ** ** Overall Verbal IQ 0.44 0.24 0.46 0.48 0.60 0.52 0.47 ** * ** ** *** *** ** Cognition Performance IQ 0.49 0.37 0.45 0.58 0.63 0.62 0.47 p < 0.05. FDR ** p < 0.01. FDR *** p < 0.001. FDR The subset of WM tracts included in this table had significantly different AD between individuals with VCFS and unaffected siblings (p < 0.05). For abbreviations FDR and further details, see the legend of Table 3. cortico-cortical and cortico-subcortical tracts, may show differences in our results relative to previous DTI find- abnormalities in VCFS than previously reported. Differ- ings in VCFS may be related to age effects. For example, ences in individuals with VCFS and controls have been the VCFS sample of [23] included a younger age group-- reported previously, for FA putatively in the SLF and ILF children aged 7 to 14. Here, we found fewer alterations [23,25], pre- and post-central gyri (likely reflecting in RD than Simon and colleagues (2008) [23], and it is cortico-spinal tract alterations) [25], radial diffusivity possible that changes in myelination as the brain ma- likely in SLF and the fasciculus occipito-frontalis and tures may account for some of these effects. axial diffusivity possibly in SCR, PCR, and RLIC/PLIC Interestingly, our findings of lower AD in multiple WM (according to Figure 3 in [23]). Our findings of group tracts (in contrast to RD differences) in VCFS relative to differences in a greater number of tracts than previous controls may suggest axonal damage/loss, or axonal fiber studies may be related to increased statistical power due maldevelopment in VCFS, rather than demyelination [22] to larger sample size and novel data analysis method. as a neuropathological correlate of the WM alterations in Our study had 33 participants with VCFS while the pre- VCFS individuals. Several 22q11.2 genes (COMT, PRODH, vious DTI studies have included between 11 and 19 indi- ZDHHC8, DGCR6) are involved in at least 3 major neu- viduals with VCFS [23-26]. Furthermore, the atlas-based rotransmitter systems (dopaminergic, glutamatergic and analysis (ABA) that we utilized has higher statistical GABAergic) [53-56]. Thus, it is likely that haploinsuffi- power than VBM (which has been used in previous DTI ciency, SNPs on the remaining copy of these genes, and/or studies of VCFS), because fewer comparisons are con- gene-gene interactions can result in changes of synaptic ducted in ABA than in VBM (i.e., 27 tracts per hemi- functioning, axonal maldevelopment or loss, and could sphere vs. thousands of voxels across the brain), and ultimately underlie the AD decreases observed in the ABA does not need to utilize spatial, isotropic blurring, current study. Several myelin-related genes, including which is often applied in VBM and can potentially ob- PIK4CA, SNAP29, and RTN4R [57-60] are also located scure differences and introduce noise within WM tracts in the 22q11.2 region and, therefore, could affect myelina- of close spatial proximity [27]. Furthermore, some of the tion, and possibly the RD and FA measures. Accordingly, Radoeva et al. Behavioral and Brain Functions 2012, 8:38 Page 8 of 11 http://www.behavioralandbrainfunctions.com/content/8/1/38 haploinsufficiency of one or more of those genes could its accuracy could be decreased in the presence of cer- account for our current findings. Future genetics studies tain brain abnormalities. For example, individuals with (e.g., focused on SNPs on the remaining copy of 22q11.2 VCFS often have enlarged ventricles, and we observed genes in VCFS individuals) would be crucial in elucidat- that the AIR and LDDMM transformations did not al- ing the roles of specific genes in the WM microstructural ways sufficiently warp the brain maps (especially for par- deficits observed in VCFS. ticipants with very large ventricles) to match the JHU Furthermore, we found that there was a somewhat lar- template, and thus, the corpus callosum ROIs sometimes ger number of WM tracts with significantly lower AD in included a portion of the lateral ventricles (esp. the sple- individuals with VCFS (as compared to controls) in the num of the corpus callosum). This artifact could result left hemisphere (11 tracts) vs. the right hemisphere (7 in relatively noisy measurements of the corpus callosum tracts) (see Figure 3), particularly in tracts to the frontal, ROIs, and, thus, loss of power. Indeed, in the current and parietal lobes (ACR, SS, EC, RLIC). These results study, we did not find significant differences for the cor- may be relevant to the findings of reduced laterality pre- pus callosum ROIs between individuals with VCFS and ference in VCFS [61], although we cannot directly ad- siblings. Another brain abnormality found more fre- dress this relationship in our current study since we do quently in VCFS is cavum septum pellucidum/vergae, not have detailed laterality preference/handedness mea- and 4 participants with VCFS in our current sample have sures on the VCFS and control participants. this finding. As mentioned in the methods, a cavum septum pellucidum can significantly alter the anatomical DTI correlates of neuropsychological performance location of the fornix. In order to avoid possible noise in Several studies have reported working memory and execu- the automated fornix delineation (in ABA), we have tive functioning deficits in VCFS [62-64]. Neuroanatomical excluded the individuals with cavum septum pelluci- correlates of working memory in typically developing chil- dum/vergae from our analyses of the fornix. dren (as rated by their parents) include frontal gray matter A relative strength (as well as potential weakness) of (GM) volume [65], as well as neural activation in frontal our study is that we correlated a large number of white and/or parietal areas in VCFS (as evaluated by fMRI) matter tracts with neuropsychological measures. There- [66,67]. Our current results demonstrate that working fore, we had to perform corrections for multiple compari- memory (and executive functioning) is associated with WM sons in order to avoid Type 1 error. Yet, by lowering the microstructure in PTR and PCR (i.e., abnormal connec- p-value level for significance (by using FDR-correction), tions to the parietal/occipital cortex), as well as SLF and we might have missed some true correlations that would IFO (abnormal frontal-occipital/parietal connectivity). have been otherwise significant (if they were reported on A wide variety of brain regions have been shown to sub- their own/separately). While our current study is the lar- serve social cognition (for review, see [68]). These struc- gest DTI study individuals withVCFS so far, larger samples tures include (but are not limited to) the prefrontal cortex, could result in higher statistical power and allow for the limbic structures (e.g., amygdala, cingulate gyrus, orbito- examination of the effects of the presence of psychiatric frontal cortex), as well as white matter tracts connecting disorders or the use of medication on the DTI measures. the cortical and subcortical regions. Damage to these structures can result in impairments in social behavior, Conclusions and Future Directions recognition of emotions, empathy, judgment, decision- Our results suggest abnormalities in the structural con- making. Consistent with these results, in our current study, nectivity in a widespread cerebro-anatomical network, we found correlations between social cognition measures involving WM tracts in all cerebral lobes as well as the (e.g., VINESOC) and AD in the PCR (which is a continu- cerebellum (mostly evidenced by alterations in AD) in ation of the fiber tracts that pass through the posterior individuals with VCFS (relative to unaffected siblings), limb of the internal capsule), as well as in fronto-parietal/ and correlations of WM microstructural measures to occipital connections (SLF, IFO). Notably, lower FA values working memory, executive function, social cognition in the posterior limb of the internal capsule had been impairments, and/or IQ. These correlations may account previously associated with schizotypy in VCFS [26] (and for some of the major phenotypic features reported in increased schizotypy implies more social difficulties). VCFS. Future studies could focus on tractography of specific white matter tracts, genetic correlates (e.g., indi- Limitations vidual candidate genes in the 22q11.2 region) of WM While the atlas-based whole brain white matter analysis alterations in VCFS, and the characterization of white method is extremely valuable in automatically delineat- matter abnormalities in individuals with VCFS and spe- ing ROIs, and it has been shown to have comparable re- cific psychiatric diagnoses, including autism spectrum liability to manual tracing of ROIs, there are some disorder (ASD). Last, longitudinal studies of individuals limitations when using this method. More specifically, with VCFS in our current sample could explore whether Radoeva et al. Behavioral and Brain Functions 2012, 8:38 Page 9 of 11 http://www.behavioralandbrainfunctions.com/content/8/1/38 the current DTI results (for individual participants) may Abbreviations CST: Corticospinal tract; ICP: Inferior cerebellar peduncle; ML: Medial have predictive power, as to who might later on develop lemniscus; SCP: Superior cerebellar peduncle; CP: Cerebral peduncle; schizophrenia/schizoaffective disorder. ALIC: Anterior limb of the internal capsule; PLIC: Posterior limb of the internal capsule; PTR: Posterior thalamic radiation (include optic radiation); Endnotes ACR: Anterior corona radiata; SCR: Superior corona radiata; PCR: Posterior corona radiata; CGC: Cingulum (cingulate gyrus); CGH: Cingulum A subset of the participants in this report has been (hippocampus); Fx/ST: Fornix (cres)/Stria terminalis (can not be resolved with included in an abstract for the 2011 Meeting of the current resolution); SLF: Superior longitudinal fasciculus; SFO: Superior fronto- Organization for Human Brain Mapping [69] and a pres- occipital fasciculus (could be a part of anterior internal capsule); IFO: Inferior fronto-occipital fasciculus; SS: Sagittal stratum (include inferior longitudinal entation at the 2011 International Congress of Schizo- fasciculus and inferior fronto-occipital fasciculus); EC: External capsule; phrenia Research. All of the current participants have UNC: Uncinate fasciculus; PCT: Pontine crossing tract (a part of MCP); been included in an abstract presented at the 2011 Soci- MCP: Middle cerebellar peduncle; Fx: Fornix (column and body of the fornix); GCC: Genu of the corpus callosum; BCC: Body of the corpus callosum; ety for Neuroscience Meeting [70]. SCC: Splenium of the corpus callosum; RLIC: Retrolenticular part of the internal capsule; ABA: Atlas-based analysis; AD: Axial diffusivity; A/P Long Appendix Tracts: Anterior-Poster Long Tracts; ASD: Autism spectrum disorder; nd Appendix 1 Table with original P-values (Orig P, not BASC-2: Behavior Assessment System for Children 2 ed; BRIEF: Behavior Rating Inventory of Executive Functioning; CGAS: Children's Global corrected for multiple comparisons), and FDR-corrected Assessment Scale; CVLT: California verbal learning test; DTI: Diffusion tensor p-values (FDR P) from the MANOVAs on FA, AD and imaging; FA: Fractional anisotropy; RD: Radial diffusivity; SRS: Social RD (in VCFS individuals vs. controls): Responsiveness Scale; VBM: Voxel-based morphometry; VCFS: Velo-cardio-facial syndrome; WCST: Wisconsin card sorting test; WM: White matter. AD AD RD RD FA FA Tract Competing interests Orig P FDR P Orig P FDR P Orig P FDR P The authors declare that they have no competing interests. ACR_L 0.012 0.039 N.S. N.S. N.S. N.S. CGC_L 0.011 0.037 N.S. N.S. N.S. N.S. Authors’ contributions PR participated in data analysis and wrote the first draft of the manuscript. CGC_R 0.001 0.003 0.018 N.S. N.S. N.S. KA and WF conducted the neuropsychological and psychiatric assessments of the participants, and KA contributed to the draft of the manuscript. IC CP_L N.S. N.S. N.S. N.S. 0.014 N.S. participated in the design of the study and in data analysis, and contributed EC_L 3.4E-04 0.002 N.S. N.S. 0.022 N.S. to the draft of the manuscript. CS and AK participated in data analysis. DW assisted with statistical analysis. RS participated in the overall Fx_R 0.021 N.S. 0.019 N.S. 0.048 N.S. conceptualization of the study, and contributed to the draft of the Fx_L N.S. N.S. 0.037 N.S. N.S. N.S. manuscript. WK conceived of the study design, participated in data analysis, and helped to draft the manuscript. All authors read and approved the final Fx/ST_L N.S. N.S. N.S. N.S. 0.013 N.S. manuscript. IFO_L 2.0E-04 0.001 N.S. N.S. N.S. N.S. Acknowledgements IFO_R 5.6E-06 <0.001 N.S. N.S. 0.029 N.S. The funding sources for the study included grants from the National Institute PCR_L 1.8E-08 <0.001 0.004 N.S. N.S. N.S. of Mental Health (R01 MH64824, R01 MH65481 to WRK), and the Dennis Weatherstone Pre-Doctoral Fellowship from Autism Speaks (#7076 to PDR). PCR_R 9.2E-07 <0.001 0.001 0.038 N.S. N.S. Special thanks to Anne Marie Higgins and Jo-Anna Botti for coordination of PLIC_R N.S. N.S. 0.048 N.S. N.S. N.S. the longitudinal study, and Gwen Tillapaugh-Fay and Kelly Wallace for assistance with scanning. PTR_L 3.0E-08 <0.001 0.018 N.S. N.S. N.S. Author details PTR_R 0.001 0.005 0.013 N.S. N.S. N.S. Department of Neuroscience and Physiology, SUNY Upstate Medical RLIC_L 7.2E-05 0.001 N.S. N.S. N.S. N.S. 2 University, Syracuse, NY, USA. Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA. Department RLIC_R N.S. N.S. 0.024 N.S. N.S. N.S. of Public Health and Preventive Medicine, SUNY Upstate Medical University, SCP_L 3.5E-04 0.002 N.S. N.S. N.S. N.S. Syracuse, NY, USA. The Virtual Center for Velo-Cardio-Facial Syndrome, www.vcfscenter.com, Manlius, NY, USA. Program in Neuroscience, SUNY SCP_R 3.4E-04 0.002 N.S. N.S. 0.045 N.S. Upstate Medical University, Syracuse, NY, USA. Department of Psychiatry and SCR_L 0.003 0.009 0.048 N.S. N.S. N.S. Behavioral Sciences, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA. SCR_R 0.015 0.046 0.003 N.S. N.S. N.S. SFO_L N.S. N.S. N.S. N.S. 0.025 N.S. Received: 18 January 2012 Accepted: 11 July 2012 Published: 1 August 2012 SLF_L 3.3E-06 <0.001 0.020 N.S. N.S. N.S. SLF_R 5.2E-09 <0.001 0.024 N.S. N.S. N.S. References 1. Shprintzen RJ, Golding-Kushner KJ: Velo-Cardio-Facial Syndrome, Volume I SS_L 2.6E-04 0.002 N.S. N.S. N.S. N.S. (Genetic Syndromes and Communication Disorders). Plural Publishing Inc; SS_R 0.038 N.S. N.S. N.S. 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Atlas-based white matter analysis in individuals with velo-cardio-facial syndrome (22q11.2 deletion syndrome) and unaffected siblings

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Springer Journals
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Copyright © 2012 by Radoeva 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: Velo-cardio-facial syndrome (VCFS, MIM#192430, 22q11.2 Deletion Syndrome) is a genetic disorder caused by a deletion of about 40 genes at the q11.2 band of one copy of chromosome 22. Individuals with VCFS present with deficits in cognition and social functioning, high risk of psychiatric disorders, volumetric reductions in gray and white matter (WM) and some alterations of the WM microstructure. The goal of the current study was to characterize the WM microstructural differences in individuals with VCFS and unaffected siblings, and the correlation of WM microstructure with neuropsychological performance. We hypothesized that individuals with VCFS would have decreased indices of WM microstructure (fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD)), particularly in WM tracts to the frontal lobe, and that these measures would be correlated with cognitive functioning. Methods: Thirty-three individuals with VCFS (21 female) and 16 unaffected siblings (8 female) participated in DTI scanning and neuropsychological testing. We performed an atlas-based analysis, extracted FA, AD, and RD measures for 54 WM tracts (27 in each hemisphere) for each participant, and used MANOVAs to compare individuals with VCFS to siblings. For WM tracts that were statistically significantly different between VCFS and siblings (p < 0.05), FDR we assessed the correlations between DTI and neuropsychological measures. Results: In VCFS individuals as compared to unaffected siblings, we found decreased FA in the uncinate fasciculus, and decreased AD in multiple WM tracts (bilateral superior and posterior corona radiata, dorsal cingulum, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, superior cerebellar peduncle, posterior thalamic radiation, and left anterior corona radiata, retrolenticular part of the internal capsule, external capsule, sagittal stratum). We also found significant correlations of AD with measures of executive function, IQ, working memory, and/or social cognition. Conclusions: Our results suggest that individuals with VCFS display abnormal WM connectivity in a widespread cerebro-anatomical network, involving tracts from/to all cerebral lobes and the cerebellum. Future studies could focus on the WM developmental trajectory in VCFS, the association of WM alterations with psychiatric disorders, and the effects of candidate 22q11.2 genes on WM anomalies. Keywords: VCFS, 22q11.2 deletion, DTI, White matter, LDDMM * Correspondence: katesw@upstate.edu Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA Program in Neuroscience, SUNY Upstate Medical University, Syracuse, NY, USA Full list of author information is available at the end of the article © 2012 Radoeva et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Radoeva et al. Behavioral and Brain Functions 2012, 8:38 Page 2 of 11 http://www.behavioralandbrainfunctions.com/content/8/1/38 Background between alterations in FA and neuropsychological/ Velo-cardio-facial syndrome (VCFS; MIM#192430) is a psychiatric function in VCFS have also been reported genetic disorder caused by a microdeletion of a portion for schizotypy [26], arithmetic abilities [24] and (along of the 11.2 band (spanning approximately 40 genes in with AD alterations) spatial attention [23]. most cases) of one copy of chromosome 22. The pheno- While these studies are important initial steps in the typic spectrum of VCFS includes cardiac malformations, study of white matter microstructure in VCFS and brain- palatal anomalies with speech impairment, endocrine and cognition correlations, several were limited, to some ex- immune problems [1]. Notably, individuals with VCFS tent, by small sample sizes [26], wide age ranges [25] and often have cognitive deficits in attention, working mem- a primary focus on FA [24-26]. As noted above, analyses ory, executive function, visuospatial perception, math of associations between DTI measures and neuropsycho- abilities, and reading comprehension [2,3]. In addition to logical data were also limited, in that many cognitive cognitive deficits, individuals with VCFS present with functions that are impaired in VCFS (e.g., memory, ex- emotion dysregulation [2,4,5], modestly difficult temper- ecutive functioning, social cognition) have not yet been ament [6], and social withdrawal [7,8]. High prevalence examined in relationship to white matter microstructure of psychiatric disorders [9] has been reported in VCFS in this disorder. A more detailed study, therefore, of add- across multiple studies, including autism spectrum dis- itional measures in multiple white matter tracts, in asso- order (ASD) [10,11], attention deficit hyperactivity dis- ciation with a wider range of cognitive functions, could order (ADHD) [9], schizophrenia/schizoaffective disorder better elucidate the underlying neuropathology of white [12,13], anxiety disorders [14], and mood disorders [9]. matter changes in VCFS. Neuroimaging studies of individuals with VCFS have In our current study, therefore, we utilized a novel DTI found volumetric reductions, including reduction in sub- analysis method— atlas-based whole brain white matter regions of the frontal lobe, decreased volumes of the gray analysis [27], to assess the microstructure (including FA, and white matter in the parietal, temporal, and occipital AD and RD measures) of a large number of white matter lobes, smaller hippocampus (bilaterally), and smaller tracts in 33 individuals with VCFS and their unaffected cerebellum (for meta-analysis see [15]). In addition to siblings. Our goals were (1) to increase the power to de- volumetric reductions, specific structural abnormalities tect microstructural WM alterations in VCFS by using a have been described in both the gray and white matter of larger sample size of individuals with VCFS; (2) to inves- individuals with VCFS, including white matter hyperin- tigate the relative contributions of AD and RD to WM tensities, cavum septum pellucidum/vergae, pachygyria, alterations in VCFS; (3) to evaluate the correlations of polymicrogyria, cortical dysgenesis or dysplasia, and WM microstructure with a wide variety of neuropsycho- Arnold-Chiari malformation [16-19]; for review, see [1]. logical standardized tests, including attention, working Diffusion tensor imaging (DTI) has also been used to memory, executive functioning, social cognition, and psy- evaluate the microstructure of WM in VCFS. Several mea- chiatric measures. Based on the previous VCFS literature, sures can be derived from DTI scans, including fractional we hypothesized that relative to their siblings, individuals anisotropy (FA), axial diffusivity (AD) and radial diffusivity with VCFS would display alterations in FA, RD and AD (RD). In general, decreases in FA are associated with vari- which would be distributed in frontal, parietal and tem- ousWMneuropathologies,includingdemyelination, ische- poral areas and the internal capsule. We further hypothe- mia, and inflammation. While FA is a sensitive measure sized that psychiatric measures would correlate with DTI of WM microstructural changes, it is not very specific as measures in the internal capsule. Studies of WM micro- to the type/cause of WM alteration [20]. Additional DTI structural underpinnings of cognitive function in the measures, including axial diffusivity and radial diffusivity, non-VCFS population led us to further hypothesize the can better characterize the specific types of WM micro- following associations: executive function with cortico- subcortical tracts [28], superior longitudinal fasciculus structural changes, and it has been argued that such measures should be routinely included in DTI studies (SLF), and superior corona radiata (SCR) [29]; working [20]. Increases in RD, for example, have been associated memory with SLF [30], SCR, and posterior corona radiata (PCR) [29]; and social cognition/socialization with un- with demyelination [21], while decreases in AD have been correlated with increased axonal damage [21,22]. cinate fasciculus (UNC) [31], SLF, posterior limb of the in- With the exception of one report [23], all previously ternal capsule (PLIC), anterior limb of the internal capsule (ALIC) and anterior thalamic radiation (ATR) [32]. published DTI studies of individuals with VCFS have fo- cused exclusively on FA. Alterations in FA have been re- ported in VCFS-affected individuals in frontal, temporal Materials and methods and parietal areas, including anomalous tracts between Participants frontal-temporal and frontal-parietal lobes [24,25], and the In this paper, we are reporting on the data collected on posterior limb of the internal capsule [26]. Associations 49 individuals, who are participants in a longitudinal Radoeva et al. Behavioral and Brain Functions 2012, 8:38 Page 3 of 11 http://www.behavioralandbrainfunctions.com/content/8/1/38 study of VCFS [33,34]. The study was approved by the DTI processing and data analysis IRB at SUNY Upstate Medical University, and informed The data were downloaded from the scanner, transferred consent was obtained from the participants and/or their and processed using DTIStudio 3.0.2, DiffeoMap 1.7.1, parents. We included data from all individuals who par- and ROI Editor 1.4.2 (https://www.mristudio.org/, [37]) ticipated in the study between December, 2008 and Feb- on a 64-bit Dell PC, running Windows 7 operating sys- ruary, 2011 on whom we collected DTI as well as tem. First, by utilizing a mutual information algorithm neuropsychological data. DTI data from four additional [38], all diffusion weighted images from a study (the four individuals with VCFS were excluded due to poor image repeats) were coregistered to the same reference volume, quality or severe motion/scanning artifacts (see Section the b0 volume of the first repeat. Axial slices with severe DTI processing and data analysis). The VCFS diagnosis scanning and motion artifacts were excluded via auto- was confirmed with fluorescence in situ hybridization matic outlier slice rejection in DTIStudio (with relative (FISH). This sample includes 33 individuals with VCFS error > 3%), and through visual inspection. The diffusion (12 male), and 16 unaffected siblings (8 male) , with weighted images (for each diffusion direction) were then average age for the VCFS group 17.7 (SD = 1.8) and for averaged, and the average set was used for further the sibling group 18.0 (SD = 1.7) (Table 1 and Table 2). analysis. Although all of the unaffected siblings who participated Tensor estimation was then performed, and Fractional in the larger longitudinal study had a matching brother Anisotropy (FA), Axial Diffusivity (AD), Radial Diffusivity or sister with VCFS, four of the siblings reported here (RD), and b0 maps were computed and saved (while ap- did not, because imaging data from his/her counterpart plying a skull-stripped mask generated in ROI Editor for with VCFS could not be acquired/used due to braces the b0 image of each participant). The FA and b0 maps (n = 1), claustrophobia (n = 1), severe scoliosis (n = 1) or of each participant were then used for Large Deform- severe motion/scanning artifacts (n = 1). All of the parti- ation Diffeomorphic Metric Mapping (LDDMM) [27], cipants were Caucasian except one participant with and regions of interest (ROIs) were generated for each VCFS and one sibling who were Asian. The average full- participant as follows. The b0 and FA maps of each par- scale IQ was 73 (SD = 12.9, ranging between 44 and 98) ticipant were first transformed linearly (using affine for the individuals with VCFS and 113 (SD = 11.5, ran- Automated Image Registration (AIR) transformation, ging between 98 and 141) for the siblings. with trilinear interpolation) and then non-linearly (using LDDMM, with cascading alpha of 0.01, 0.005, and 0.002), in order to match as well as possible the correspond- DTI acquisition ing Johns Hopkins University MNI-space single partici- The DTI scans were acquired on a 1.5 T Philips Interra pant skull-stripped templates (JHU_MNI_SS_b0_ss and scanner (release 11) equipped with a Sense Head coil to JHU_MNI_SS_FA_ss). A detailed atlas of the white improve the signal strength and the signal-to-noise ratio. matter tracts and gray matter ROIs had been previ- A multi-slice, single-shot EPI (SENSE factor = 2.0), spin ously constructed by [27] based on the data from the echo sequence (TR/TE = 8197/76 ms) was used to obtain participant used in the Johns Hopkins University MNI- 70 axial slices with no slice gap and 2.5 mm nominal iso- space single participant skull-stripped templates. Next, tropic resolution (FOV = 240 × 240, data matrix = 96 × 96, the inverse transformation algorithms (inverse LDDMM zero-filled and reconstructed to 256 × 256). Diffusion and then inverse AIR) were applied to the ROI atlas weighting was applied along 15 directions [36] with a b (JHU_MNI_SS_WMPM_TypeII), in order to obtain ROIs factor = 800 s/mm . One minimally weighted volume that are within each participant's original brain space. (b0) was acquired within each DTI dataset. The total To ensure the proper execution of the algorithms, the scan time to acquire one DTI dataset (15 DW and 1 b0 ROIs generated were visually inspected for accuracy. images) was 2 min 11 s. The total time, including image The mean FA, AD, and RD values for the ROIs were reconstruction, to acquire 4 DTI datasets in a scan ses- then extracted in ROI Editor. For further analyses, we sion (for each participant) was approximately 9 minutes. focused on the measures FA, AD, and RD of all available white matter tract ROIs (27 tracts in each hemisphere; Table 1 Demographics of the participants for a complete list see the list of Abbreviations at the end of the paper). Sample ROIs are shown in Figure 1. VCFS Siblings P-value (N = 33) (N = 16) Neuropsychological Testing Gender (N, % female) 21 (64%) 8 (50%) N.S. As part of the larger longitudinal study, the participants Race (Caucasian/Asian) 32/1 15/1 N.S. were tested with a wide array of neuropsychological tests. Age, in years (+/− SD) 17.7 (1.8) 18.0 (1.7) N.S. The Wechsler Intelligence Scale for Children— Third FSIQ (+/− SD) 73 (12.9) 113 (11.5) < 0.001 Edition (WISC-III) [39] was administered to participants Radoeva et al. Behavioral and Brain Functions 2012, 8:38 Page 4 of 11 http://www.behavioralandbrainfunctions.com/content/8/1/38 Table 2 Number (and percent) of participants with psychiatric diagnoses in the current study based on the Schedule for Affective Disorders and Schizophrenia for School-Age Children—Present and Lifetime Version (K-SADS-PL) [35] Psychiatric Diagnoses VCFS (N = 33) Siblings (N = 16) N (%) N (%) Schizophrenia 1 (3.0) 0 (0) Major depressive disorder (includes NOS) 6 (18.2) 0 (0) Bipolar disorder 1 (3.0) 0 (0) Anxiety disorder (includes generalized, overanxious, separation and panic) 7 (21.2) 0 (0) Simple or social phobia 11 (33.3) 3 (18.75) ADHD 10 (30.3) 1 (6.25) Enuresis 1 (3.0) 0 (0) Chronic motor or vocal tic disorder 2 (6.1) 0 (0) Oppositional defiant disorder 3 (9.1) 0 (0) Any disorder listed above 20 (60.6) 3 (18.75) under 17 years of age, and the Wechsler Adult Intel- CVLT (California Verbal Learning Test) [42]: All parti- ligence Scale (WAIS-III) [40] to participants 17 years of cipants completed the CVLT, which evaluated verbal age or older. learning and memory. The CVLT (1) T-scores for List A, trials 1–5; and (2) standard score for List A, trial 5 Attention, Memory and Executive Functioning Measures [33] were used for further analyses. Digit Span was evaluated as part of WISC-III or WAIS- Wisconsin Card Sorting Test (WCST) [43]: Each par- III. Forward and Backward z-scores were used for fur- ticipant completed the WCST as part of evaluation of ther analyses. executive functioning and, more specifically, cognitive Visual Span Test [41]: In this computerized instru- flexibility. The Perseverative Error Standard Score and ment, each participant was asked to reproduce an in- the Non-Perseverative Error Standard Score of WCST creasing number of patterns of squares displayed on a were used for further analyses. computer screen [10]. This test evaluates spatial/non- BRIEF (Behavior Rating Inventory of Executive Func- verbal working memory, and the Forward and Backward tioning) [44]: Parents completed the BRIEF or BRIEF-A Visual Span Z-Scores were used. questionnaires. The T-scores of the (1) Metacognition Index (assessing initiation, organization, planning, moni- toring, and working memory); and (2) the Behavioral Regulation Index (evaluating inhibition, shift, and cogni- CGC ACR tive control); were included for further analyses. GCC CGC SCR ALIC BCC Fx SFO Social Cognition/Skills Measures EC PLIC Fx The following instruments were used: RLIC Emotional Recognition Test [45]: In this computerized PLIC IFO test, each participant was asked to discriminate between PTR SCC happy, sad and neutral faces. The total number of cor- CGH rect responses was used for further analysis. BASC-2 (Behavior Assessment System for Children, Second Edition): Parents completed the BASC-2 [46], Figure 1 White matter tracts analyzed in the current report represented on the FA map of one individual with VCFS. which contains 150 items that are rated on a 4-point Abbreviations: ACR: Anterior corona radiata; ALIC: Anterior limb of scale. Scores were then derived for a variety of domains the internal capsule; BCC: Body of the corpus callosum; CGC: such as social skills, withdrawal, conduct problems. The Cingulum (cingulate gyrus); CGH: Cingulum (hippocampus); EC: T-scores of the BASC-2 social skills domain, atypicality, External capsule; Fx: Fornix (column and body of the fornix); GCC: and anxiety were used for analysis in this report. Genu of the corpus callosum; IFO: Inferior fronto-occipital fasciculus; PLIC: Posterior limb of the internal capsule; PTR: Posterior thalamic Vineland-II (Vineland Adaptive Behavior Scales, Sec- radiation; SCR: Superior corona radiata; SS: Sagittal stratum; RLIC: ond Edition): Parents were interviewed with Vineland-II Retrolenticular part of the internal capsule. For the full list of WM [47], evaluating various aspects of the child's behavior, tracts analyzed in the current study, see the List of Abbreviations. including social skills (socialization subdomain). Radoeva et al. Behavioral and Brain Functions 2012, 8:38 Page 5 of 11 http://www.behavioralandbrainfunctions.com/content/8/1/38 SRS (Social Responsiveness Scale): Parents completed a widely distributed network of tracts showed signifi- the SRS, which consists of 65 items [48,49], and mea- cantly lower AD in individuals with VCFS as compared sures aspects of social awareness, social cognition, social to siblings (p < 0.05) (see Figure 3), including tracts FDR communication, social motivation, and autistic manner- terminating in the parietal/occipital (posterior thalamic isms, and provides a total score. The items are slightly radiation, PTR; posterior corona radiata, PCR; retrolenti- different (but comparable) for children aged 18 or cular part of the internal capsule, RLIC; sagittal stratum, younger vs. adults (19 or older). Since norms, T-scores, SS), and/or frontal cortices (superior corona radiata, and domain classification are provided only for the SCR; anterior corona radiata, ACR); as well as fronto- child/adolescent scale (but not for the adult version), the parietal/occipital (inferior fronto-occipital fasciculus, total raw score was used for further analysis for all IFO; superior longitudinal fasciculus, SLF; external cap- participants. sule, EC); fronto-temporal (cingulum, CGC); and cer- CGAS (Children's Global Assessment Scale) [50]: A ebellar connections (superior cerebelar peduncle, SCP). clinician evaluated the global functioning of each partici- For reasons described below, both the uncorrected and pant (based on an interview with the parent and the FDR-corrected P-values from the MANOVAs are in- child), and completed the CGAS. cluded in Appendix 1. The majority of the WM mea- sures had normal distributions in both the VCFS and the Statistical Analysis control groups. However, some of the distributions were The Shapiro – Wilk Test of Normality was used to inves- not normal, and there were outliers for some of the tigate the distribution of all data (see results, below). tracts. Therefore, as a follow-up, we conducted non- Three MANOVAs were conducted with dependent var- parametric analysis (Mann–Whitney U tests), which is iables mean FA (or AD or RD) values (in each of the less sensitive to outliers and can appropriately be used tracts) and independent variable Group (VCFS vs. sib- for non-normally distributed data, and compared the lings), using SPSS 18 (http://www.spss.com/). FDR (false DTI measures of the tracts (for VCFS vs. controls), and discovery rate) correction for multiple comparisons was corrected the p-values using FDR. All the tracts sum- applied in the program R (http://www.r-project.org/) on marized in Figures 2 and 3 remained significant with this the p-values from each of the three MANOVAs [51]. For non-parametric analysis. RD in the right posterior cor- tracts that showed significant differences between the par- ona radiata (PCR) was not significant in this analysis, ticipants with VCFS and controls (p < 0.05), Pearson's and was dropped from further analyses. In addition, sev- FDR correlations were performed (in SPSS) between the DTI eral tracts that had non-normal distributions showed measures of the tracts, and each of the neuropsychological significant differences between patients and controls: measures (described above), across all of the study parti- namely, the AD of the left and right ML, left UNC, right cipants. Since multiple correlations were performed, the MCP, and right RLIC (data not shown). p-values of the correlations were also FDR-corrected. AD values were significantly correlated with several As noted in the background, individuals with VCFS neuropsychological and psychiatric measures across all have a higher prevalence of certain brain abnormalities, participants (Tables 3 and 4). AD values in fronto-parietal/ including cavum septum pellucidum/vergae. Four VCFS occipital circuits (SLF, IFO) correlated with measures of participants in our current sample have this variant as working memory, executive functioning, and social cogni- evaluated by a neuroradiologist. The presence of cavum tion. In addition measures of executive functioning cor- septum pellucidum/vergae seems to be associated with related with AD in PCR and PTR bilaterally. Overall an alteration of the anatomy of the fornix, such that the columns and body of the fornix do not join in the mid- 0.60 line and seem to run separately within the left and right VCFS 0.50 hemispheres between the cavum septum pellucidum and Siblings the lateral ventricles [52]. Thus, the automated fornix 0.40 measures in the current study might not be valid for 0.30 individuals with cavum septum pellucidum/vergae,so we 0.20 excluded these four individuals from the analyses only of 0.10 the fornix measures. 0.00 Left Left UNC UNC Right Right U UNC NC Results Figure 2 Significant Differences in Fractional Anisotropy The MANOVAs demonstrated that the FA in the left and (p < 0.05) in individuals with VCFS vs. siblings in the left and FDR right uncinate fasciculi (see Figure 2), and RD in the right right uncinate fasciculi (UNC, L and UNC, R respectively). posterior corona radiata (PCR) differed between parti- Error bars show SE. cipants with VCFS and siblings (p < 0.05). Furthermore, FDR Fractional Anisotropy Radoeva et al. Behavioral and Brain Functions 2012, 8:38 Page 6 of 11 http://www.behavioralandbrainfunctions.com/content/8/1/38 (A) (B) 0.0025 0.0025 VCFS 0.0020 0.0020 Siblings 0.0015 0.0015 0.0010 0.0010 0.0005 0.0005 0.0000 0.0000 SCP PTR ACR SCR PCR CGC SLF IFO SS EC RLIC SCP PTR SCR PCR CGC SLF IFO Figure 3 Significant Differences in Axial Diffusivity (p < 0.05) in individuals with VCFS (black) vs. siblings (grey) in the (A) left; or (B) FDR right sides of the brain. Error bars show SE. Abbreviations: SCP: Superior cerebellar peduncle; PTR: Posterior thalamic radiation; ACR: Anterior corona radiata; SCR: Superior corona radiata; PCR: Posterior corona radiata; CGC: Cingulum (cingulate gyrus); SLF: Superior longitudinal fasciculus; IFO: Inferior fronto-occipital fasciculus; SS: Sagittal stratum; EC: External capsule; RLIC: Retrolenticular part of the internal capsule. measures of cognitive skills (intelligence,VIQ and PIQ) cor- Discussion related with the majority of the studied tracts, which may Differences between individuals with VCFS and siblings be expected, since IQ is a composite assessment of mul- Our current findings are partially consistent with some tiple domains including attention, working memory, ver- of the data reported previously, and further suggest that bal comprehension, and processing speed (Tables 3 and 4). a more widely distributed set of tracts, including Table 3 Correlations between neuropsychological measures and the Axial Diffusivity of white matter tracts in the Left Hemisphere across all study participants Domain Measure Left Hemisphere Frontal/Temp Parietal/Occipital A/P Long Tracts Cer CGC SCR RLIC EC PTR PCR SLF IFO SS SCP Memory & Attention Digit Span FW 0.19 0.15 0.13 0.29 0.19 0.07 0.14 0.22 0.19 0.35 Digit Span BW 0.15 0.15 0.17 0.08 0.37 0.20 0.23 0.20 0.21 0.34 * ** * Visual Span FW 0.33 0.28 0.31 0.25 0.36 0.47 0.40 0.28 0.29 0.25 * ** ** ** * * Visual Span BW 0.34 0.28 0.43 0.29 0.52 0.48 0.47 0.40 0.38 0.27 CVLT_List A, Trials 1–5 0.07 0.18 0.08 0.09 0.30 0.35 0.37 0.14 0.16 0.21 ** * ** Executive Function WCST Perseverative Error 0.18 0.30 0.33 0.21 0.45 0.43 0.50 0.27 0.33 0.34 BRIEF Behavioral Regulation 0.00 −0.18 −0.17 −0.24 −0.42 −0.28 −0.30 −0.23 −0.16 −0.30 ** BRIEF Metacognition −0.15 −0.15 −0.22 −0.26 −0.51 −0.31 −0.34 −0.32 −0.18 −0.27 Social Cognition BASC Social Skills 0.08 0.16 0.11 0.23 0.24 0.28 0.29 0.17 0.21 0.26 ** * * Socialization Vineland Soc Skills 0.01 0.19 0.21 0.28 0.45 0.37 0.40 0.27 0.33 0.29 ** * * SRS −0.08 −0.25 −0.26 −0.27 −0.49 −0.42 −0.42 −0.30 −0.25 −0.33 Emotion Emotion Recognition 0.17 0.24 0.33 0.20 0.30 0.27 0.33 0.20 0.10 0.22 Psychiatric BASC Anxiety −0.06 −0.21 −0.08 −0.07 −0.31 −0.28 −0.27 −0.11 −0.19 −0.34 * * Symptoms BASC Atypicality −0.01 −0.30 −0.25 −0.24 −0.37 −0.35 −0.36 −0.27 −0.15 −0.30 * * CGAS 0.07 0.24 0.06 0.12 0.39 0.33 0.37 0.21 0.16 0.26 ** * ** ** ** * * * Overall Verbal IQ 0.32 0.34 0.47 0.35 0.52 0.54 0.55 0.36 0.43 0.43 * * ** * *** ** ** * * * Cognition Performance IQ 0.39 0.38 0.50 0.35 0.62 0.55 0.54 0.38 0.45 0.42 The subset of WM tracts included in this table had significantly different AD between individuals with VCFS and unaffected siblings, p <0.05. The R values for FDR the correlations are given, and corresponding FDR-corrected P-values are indicated with a superscript according to the legend below the table. No significance was found for the Non-Perseverative Error Standard Score of WCST, the standard score for List A, trial 5, and AD of the ACR tract in the left hemisphere: thus, these measures were not included in this table. Abbreviations BW: Backward; FW: Forward; CVLT: California Verbal Learning Test; WCST: Wisconsin Card Sorting Test; BRIEF: Behavior Rating Inventory of Executive Functioning; SRS: Social Responsiveness Scale; BASC: Behavior Assessment System for Children; CGAS: Children's Global Assessment Scale; IQ: Intelligence Quotient. Abbreviations for the white matter tracts are given in the list of Abbreviations at the end of the paper. A/P Long Tracts: Anterior-Poster Long Tracts; Cer: cerebellum. * p < 0.05. FDR ** p < 0.01. FDR *** p < 0.001. FDR Axial Diffusivity Radoeva et al. Behavioral and Brain Functions 2012, 8:38 Page 7 of 11 http://www.behavioralandbrainfunctions.com/content/8/1/38 Table 4 Correlations between neuropsychological measures and Axial Diffusivity of white matter tracts in the Right Hemisphere across all study participants Domain Measure Right Hemisphere Frontal/Temp Parietal/Occipital A/P Long Tracts Cer CGC SCR PTR PCR SLF IFO SCP Memory & Attention Digit Span FW 0.23 0.20 0.25 0.17 0.16 0.25 0.36 * * * Digit Span BW 0.24 0.12 0.38 0.26 0.30 0.36 0.44 * * ** ** ** Visual Span FW 0.42 0.38 0.29 0.48 0.47 0.48 0.25 * ** *** Visual Span BW 0.38 0.24 0.25 0.51 0.57 0.61 0.29 * * CVLT_List A, , Trials 1–5 0.18 0.17 0.29 0.36 0.38 0.25 0.26 * ** ** ** Executive Function WCST Perseverative Error 0.29 0.29 0.37 0.48 0.58 0.48 0.32 * ** BRIEF Behavioral Regulation −0.17 −0.31 −0.28 −0.40 −0.48 −0.34 −0.17 * ** ** * BRIEF Metacognition −0.22 −0.36 −0.30 −0.45 −0.53 −0.41 −0.18 Social Cognition BASC Social Skills 0.14 0.14 0.23 0.29 0.43 0.24 0.22 * ** * Socialization Vineland Soc Skills 0.17 0.22 0.27 0.38 0.54 0.41 0.31 ** * * SRS −0.24 −0.34 −0.27 −0.49 0.41 −0.44 −0.27 * * Emotion Emotion Recognition 0.24 0.15 0.17 0.28 0.38 0.41 0.23 Psychiatric BASC Anxiety −0.13 −0.23 −0.19 −0.34 −0.39 −0.22 −0.31 * * ** * Symptoms BASC Atypicality −0.16 −0.38 −0.26 −0.44 −0.48 −0.35 −0.23 * ** * CGAS 0.11 0.29 0.31 0.44 0.57 0.39 0.33 * ** ** *** ** ** Overall Verbal IQ 0.44 0.24 0.46 0.48 0.60 0.52 0.47 ** * ** ** *** *** ** Cognition Performance IQ 0.49 0.37 0.45 0.58 0.63 0.62 0.47 p < 0.05. FDR ** p < 0.01. FDR *** p < 0.001. FDR The subset of WM tracts included in this table had significantly different AD between individuals with VCFS and unaffected siblings (p < 0.05). For abbreviations FDR and further details, see the legend of Table 3. cortico-cortical and cortico-subcortical tracts, may show differences in our results relative to previous DTI find- abnormalities in VCFS than previously reported. Differ- ings in VCFS may be related to age effects. For example, ences in individuals with VCFS and controls have been the VCFS sample of [23] included a younger age group-- reported previously, for FA putatively in the SLF and ILF children aged 7 to 14. Here, we found fewer alterations [23,25], pre- and post-central gyri (likely reflecting in RD than Simon and colleagues (2008) [23], and it is cortico-spinal tract alterations) [25], radial diffusivity possible that changes in myelination as the brain ma- likely in SLF and the fasciculus occipito-frontalis and tures may account for some of these effects. axial diffusivity possibly in SCR, PCR, and RLIC/PLIC Interestingly, our findings of lower AD in multiple WM (according to Figure 3 in [23]). Our findings of group tracts (in contrast to RD differences) in VCFS relative to differences in a greater number of tracts than previous controls may suggest axonal damage/loss, or axonal fiber studies may be related to increased statistical power due maldevelopment in VCFS, rather than demyelination [22] to larger sample size and novel data analysis method. as a neuropathological correlate of the WM alterations in Our study had 33 participants with VCFS while the pre- VCFS individuals. Several 22q11.2 genes (COMT, PRODH, vious DTI studies have included between 11 and 19 indi- ZDHHC8, DGCR6) are involved in at least 3 major neu- viduals with VCFS [23-26]. Furthermore, the atlas-based rotransmitter systems (dopaminergic, glutamatergic and analysis (ABA) that we utilized has higher statistical GABAergic) [53-56]. Thus, it is likely that haploinsuffi- power than VBM (which has been used in previous DTI ciency, SNPs on the remaining copy of these genes, and/or studies of VCFS), because fewer comparisons are con- gene-gene interactions can result in changes of synaptic ducted in ABA than in VBM (i.e., 27 tracts per hemi- functioning, axonal maldevelopment or loss, and could sphere vs. thousands of voxels across the brain), and ultimately underlie the AD decreases observed in the ABA does not need to utilize spatial, isotropic blurring, current study. Several myelin-related genes, including which is often applied in VBM and can potentially ob- PIK4CA, SNAP29, and RTN4R [57-60] are also located scure differences and introduce noise within WM tracts in the 22q11.2 region and, therefore, could affect myelina- of close spatial proximity [27]. Furthermore, some of the tion, and possibly the RD and FA measures. Accordingly, Radoeva et al. Behavioral and Brain Functions 2012, 8:38 Page 8 of 11 http://www.behavioralandbrainfunctions.com/content/8/1/38 haploinsufficiency of one or more of those genes could its accuracy could be decreased in the presence of cer- account for our current findings. Future genetics studies tain brain abnormalities. For example, individuals with (e.g., focused on SNPs on the remaining copy of 22q11.2 VCFS often have enlarged ventricles, and we observed genes in VCFS individuals) would be crucial in elucidat- that the AIR and LDDMM transformations did not al- ing the roles of specific genes in the WM microstructural ways sufficiently warp the brain maps (especially for par- deficits observed in VCFS. ticipants with very large ventricles) to match the JHU Furthermore, we found that there was a somewhat lar- template, and thus, the corpus callosum ROIs sometimes ger number of WM tracts with significantly lower AD in included a portion of the lateral ventricles (esp. the sple- individuals with VCFS (as compared to controls) in the num of the corpus callosum). This artifact could result left hemisphere (11 tracts) vs. the right hemisphere (7 in relatively noisy measurements of the corpus callosum tracts) (see Figure 3), particularly in tracts to the frontal, ROIs, and, thus, loss of power. Indeed, in the current and parietal lobes (ACR, SS, EC, RLIC). These results study, we did not find significant differences for the cor- may be relevant to the findings of reduced laterality pre- pus callosum ROIs between individuals with VCFS and ference in VCFS [61], although we cannot directly ad- siblings. Another brain abnormality found more fre- dress this relationship in our current study since we do quently in VCFS is cavum septum pellucidum/vergae, not have detailed laterality preference/handedness mea- and 4 participants with VCFS in our current sample have sures on the VCFS and control participants. this finding. As mentioned in the methods, a cavum septum pellucidum can significantly alter the anatomical DTI correlates of neuropsychological performance location of the fornix. In order to avoid possible noise in Several studies have reported working memory and execu- the automated fornix delineation (in ABA), we have tive functioning deficits in VCFS [62-64]. Neuroanatomical excluded the individuals with cavum septum pelluci- correlates of working memory in typically developing chil- dum/vergae from our analyses of the fornix. dren (as rated by their parents) include frontal gray matter A relative strength (as well as potential weakness) of (GM) volume [65], as well as neural activation in frontal our study is that we correlated a large number of white and/or parietal areas in VCFS (as evaluated by fMRI) matter tracts with neuropsychological measures. There- [66,67]. Our current results demonstrate that working fore, we had to perform corrections for multiple compari- memory (and executive functioning) is associated with WM sons in order to avoid Type 1 error. Yet, by lowering the microstructure in PTR and PCR (i.e., abnormal connec- p-value level for significance (by using FDR-correction), tions to the parietal/occipital cortex), as well as SLF and we might have missed some true correlations that would IFO (abnormal frontal-occipital/parietal connectivity). have been otherwise significant (if they were reported on A wide variety of brain regions have been shown to sub- their own/separately). While our current study is the lar- serve social cognition (for review, see [68]). These struc- gest DTI study individuals withVCFS so far, larger samples tures include (but are not limited to) the prefrontal cortex, could result in higher statistical power and allow for the limbic structures (e.g., amygdala, cingulate gyrus, orbito- examination of the effects of the presence of psychiatric frontal cortex), as well as white matter tracts connecting disorders or the use of medication on the DTI measures. the cortical and subcortical regions. Damage to these structures can result in impairments in social behavior, Conclusions and Future Directions recognition of emotions, empathy, judgment, decision- Our results suggest abnormalities in the structural con- making. Consistent with these results, in our current study, nectivity in a widespread cerebro-anatomical network, we found correlations between social cognition measures involving WM tracts in all cerebral lobes as well as the (e.g., VINESOC) and AD in the PCR (which is a continu- cerebellum (mostly evidenced by alterations in AD) in ation of the fiber tracts that pass through the posterior individuals with VCFS (relative to unaffected siblings), limb of the internal capsule), as well as in fronto-parietal/ and correlations of WM microstructural measures to occipital connections (SLF, IFO). Notably, lower FA values working memory, executive function, social cognition in the posterior limb of the internal capsule had been impairments, and/or IQ. These correlations may account previously associated with schizotypy in VCFS [26] (and for some of the major phenotypic features reported in increased schizotypy implies more social difficulties). VCFS. Future studies could focus on tractography of specific white matter tracts, genetic correlates (e.g., indi- Limitations vidual candidate genes in the 22q11.2 region) of WM While the atlas-based whole brain white matter analysis alterations in VCFS, and the characterization of white method is extremely valuable in automatically delineat- matter abnormalities in individuals with VCFS and spe- ing ROIs, and it has been shown to have comparable re- cific psychiatric diagnoses, including autism spectrum liability to manual tracing of ROIs, there are some disorder (ASD). Last, longitudinal studies of individuals limitations when using this method. More specifically, with VCFS in our current sample could explore whether Radoeva et al. Behavioral and Brain Functions 2012, 8:38 Page 9 of 11 http://www.behavioralandbrainfunctions.com/content/8/1/38 the current DTI results (for individual participants) may Abbreviations CST: Corticospinal tract; ICP: Inferior cerebellar peduncle; ML: Medial have predictive power, as to who might later on develop lemniscus; SCP: Superior cerebellar peduncle; CP: Cerebral peduncle; schizophrenia/schizoaffective disorder. ALIC: Anterior limb of the internal capsule; PLIC: Posterior limb of the internal capsule; PTR: Posterior thalamic radiation (include optic radiation); Endnotes ACR: Anterior corona radiata; SCR: Superior corona radiata; PCR: Posterior corona radiata; CGC: Cingulum (cingulate gyrus); CGH: Cingulum A subset of the participants in this report has been (hippocampus); Fx/ST: Fornix (cres)/Stria terminalis (can not be resolved with included in an abstract for the 2011 Meeting of the current resolution); SLF: Superior longitudinal fasciculus; SFO: Superior fronto- Organization for Human Brain Mapping [69] and a pres- occipital fasciculus (could be a part of anterior internal capsule); IFO: Inferior fronto-occipital fasciculus; SS: Sagittal stratum (include inferior longitudinal entation at the 2011 International Congress of Schizo- fasciculus and inferior fronto-occipital fasciculus); EC: External capsule; phrenia Research. All of the current participants have UNC: Uncinate fasciculus; PCT: Pontine crossing tract (a part of MCP); been included in an abstract presented at the 2011 Soci- MCP: Middle cerebellar peduncle; Fx: Fornix (column and body of the fornix); GCC: Genu of the corpus callosum; BCC: Body of the corpus callosum; ety for Neuroscience Meeting [70]. SCC: Splenium of the corpus callosum; RLIC: Retrolenticular part of the internal capsule; ABA: Atlas-based analysis; AD: Axial diffusivity; A/P Long Appendix Tracts: Anterior-Poster Long Tracts; ASD: Autism spectrum disorder; nd Appendix 1 Table with original P-values (Orig P, not BASC-2: Behavior Assessment System for Children 2 ed; BRIEF: Behavior Rating Inventory of Executive Functioning; CGAS: Children's Global corrected for multiple comparisons), and FDR-corrected Assessment Scale; CVLT: California verbal learning test; DTI: Diffusion tensor p-values (FDR P) from the MANOVAs on FA, AD and imaging; FA: Fractional anisotropy; RD: Radial diffusivity; SRS: Social RD (in VCFS individuals vs. controls): Responsiveness Scale; VBM: Voxel-based morphometry; VCFS: Velo-cardio-facial syndrome; WCST: Wisconsin card sorting test; WM: White matter. AD AD RD RD FA FA Tract Competing interests Orig P FDR P Orig P FDR P Orig P FDR P The authors declare that they have no competing interests. ACR_L 0.012 0.039 N.S. N.S. N.S. N.S. CGC_L 0.011 0.037 N.S. N.S. N.S. N.S. Authors’ contributions PR participated in data analysis and wrote the first draft of the manuscript. CGC_R 0.001 0.003 0.018 N.S. N.S. N.S. KA and WF conducted the neuropsychological and psychiatric assessments of the participants, and KA contributed to the draft of the manuscript. IC CP_L N.S. N.S. N.S. N.S. 0.014 N.S. participated in the design of the study and in data analysis, and contributed EC_L 3.4E-04 0.002 N.S. N.S. 0.022 N.S. to the draft of the manuscript. CS and AK participated in data analysis. DW assisted with statistical analysis. RS participated in the overall Fx_R 0.021 N.S. 0.019 N.S. 0.048 N.S. conceptualization of the study, and contributed to the draft of the Fx_L N.S. N.S. 0.037 N.S. N.S. N.S. manuscript. WK conceived of the study design, participated in data analysis, and helped to draft the manuscript. All authors read and approved the final Fx/ST_L N.S. N.S. N.S. N.S. 0.013 N.S. manuscript. IFO_L 2.0E-04 0.001 N.S. N.S. N.S. N.S. Acknowledgements IFO_R 5.6E-06 <0.001 N.S. N.S. 0.029 N.S. The funding sources for the study included grants from the National Institute PCR_L 1.8E-08 <0.001 0.004 N.S. N.S. N.S. of Mental Health (R01 MH64824, R01 MH65481 to WRK), and the Dennis Weatherstone Pre-Doctoral Fellowship from Autism Speaks (#7076 to PDR). PCR_R 9.2E-07 <0.001 0.001 0.038 N.S. N.S. Special thanks to Anne Marie Higgins and Jo-Anna Botti for coordination of PLIC_R N.S. N.S. 0.048 N.S. N.S. N.S. the longitudinal study, and Gwen Tillapaugh-Fay and Kelly Wallace for assistance with scanning. PTR_L 3.0E-08 <0.001 0.018 N.S. N.S. N.S. Author details PTR_R 0.001 0.005 0.013 N.S. N.S. N.S. Department of Neuroscience and Physiology, SUNY Upstate Medical RLIC_L 7.2E-05 0.001 N.S. N.S. N.S. N.S. 2 University, Syracuse, NY, USA. Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA. Department RLIC_R N.S. N.S. 0.024 N.S. N.S. N.S. of Public Health and Preventive Medicine, SUNY Upstate Medical University, SCP_L 3.5E-04 0.002 N.S. N.S. N.S. N.S. Syracuse, NY, USA. The Virtual Center for Velo-Cardio-Facial Syndrome, www.vcfscenter.com, Manlius, NY, USA. Program in Neuroscience, SUNY SCP_R 3.4E-04 0.002 N.S. N.S. 0.045 N.S. Upstate Medical University, Syracuse, NY, USA. Department of Psychiatry and SCR_L 0.003 0.009 0.048 N.S. N.S. N.S. Behavioral Sciences, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA. SCR_R 0.015 0.046 0.003 N.S. N.S. N.S. SFO_L N.S. N.S. N.S. N.S. 0.025 N.S. Received: 18 January 2012 Accepted: 11 July 2012 Published: 1 August 2012 SLF_L 3.3E-06 <0.001 0.020 N.S. N.S. N.S. SLF_R 5.2E-09 <0.001 0.024 N.S. N.S. N.S. References 1. Shprintzen RJ, Golding-Kushner KJ: Velo-Cardio-Facial Syndrome, Volume I SS_L 2.6E-04 0.002 N.S. N.S. N.S. N.S. (Genetic Syndromes and Communication Disorders). Plural Publishing Inc; SS_R 0.038 N.S. N.S. N.S. 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