Abstract
Children with chromosome 22q11.2 deletion syndrome (22q11.2DS) exhibit impaired ability to process and understand emotions in others. We measured structural connectivity in children and adolescents with 22q11.2DS (n = 28) and healthy controls (n = 29). Compared to controls, those with 22q11.2DS had poorer social skills and more difficulty recognizing facial emotions. Children with 22q11.2DS also had higher fractional anisotropic diffusion in right amygdala to fusiform gyrus white matter pathways. Right amygdala to fusiform gyrus fractional anisotropy values partially mediated the relationship between 22q11.2DS and social skills, as well as the relationship between 22q11.2DS and emotion recognition accuracy. These findings provide insight into the neural origins of social skills deficits seen in 22q11.2DS and may serve as a biomarker for risk of future psychiatric problems.
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Albohn, D. N., & Adams, R. B. (2016). Social vision: At the intersection of vision and person perception. Neuroimaging personality, social cognition, and character (pp. 159–186). Elsevier.
Andersson, F., Glaser, B., Spiridon, M., Debbané, M., Vuilleumier, P., & Eliez, S. (2008). Impaired activation of face processing networks revealed by functional magnetic resonance imaging in 22q11.2 deletion syndrome. Biological Psychiatry, 63(1), 49–57.
Angkustsiri, K., Goodlin-Jones, B., Deprey, L., Brahmbhatt, K., Harris, S., & Simon, T. J. (2014). Social impairments in chromosome 22q11.2 deletion syndrome (22q11. 2DS): Autism spectrum disorder or a different endophenotype? Journal of Autism and Developmental Disorders, 44, 739–746.
Baker, K. D., & Skuse, D. H. (2005). Adolescents and young adults with 22q11 deletion syndrome: Psychopathology in an at-risk group. The British Journal of Psychiatry, 186(2), 115–120.
Bassett, A. S., Chow, E. W., AbdelMalik, P., Gheorghiu, M., Husted, J., & Weksberg, R. (2014). The schizophrenia phenotype in 22q11 deletion syndrome. American Journal of Psychiatry, 160(9), 1580–1586.
Baxter, M. G., Parker, A., Lindner, C. C., Izquierdo, A. D., & Murray, E. A. (2000). Control of response selection by reinforcer value requires interaction of amygdala and orbital prefrontal cortex. Journal of Neuroscience, 20(11), 4311–4319.
Beaulieu, C. (2002). The basis of anisotropic water diffusion in the nervous system–a technical review. NMR in Biomedicine: An International Journal Devoted to the Development and Application of Magnetic Resonance in Vivo, 15(7–8), 435–455.
Boyatzis, C. J., Chazan, E., & Ting, C. Z. (1993). Preschool children’s decoding of facial emotions. The Journal of Genetic Psychology, 154(3), 375–382.
Buka, S. L., Tsuang, M. T., Torrey, E. F., Klebanoff, M. A., Wagner, R. L., & Yolken, R. H. (2001). Maternal cytokine levels during pregnancy and adult psychosis [Research Support, Non-U S Gov’t Research Support, U S Gov’t, Non-P H S]. Brain, Behavior, and Immunity, 15(4), 411–420.
Campbell, I. M., Sheppard, S. E., Crowley, T. B., McGinn, D. E., Bailey, A., McGinn, M. J., Unolt, M., Homans, J. F., Chen, E. Y., Salmons, H. I., Gaynor, J. W., & McDonald-McGinn, D. M. (2018). What is new with 22q? An update from the 22q and You Center at the Children’s Hospital of Philadelphia. American Journal of Medical Genetics. Part A, 176(10), 2058–2069.
Campbell, L. E., Azuma, R., Ambery, F., Stevens, A., Smith, A., Morris, R. G., & Murphy, K. C. (2010). Executive functions and memory abilities in children with 22q11.2 deletion syndrome [Research Support, Non-US Gov’t]. Australian and New Zealand Journal of Psychiatry, 44(4), 364–371. https://doi.org/10.3109/00048670903489882
Campbell, L. E., Stevens, A., Daly, E., Toal, F., Azuma, R., Karmiloff-Smith, A., & Murphy, K. C. (2009). A comparative study of cognition and brain anatomy between two neurodevelopmental disorders: 22q11.2 deletion syndrome and Williams syndrome [comparative study]. Neuropsychologia, 47(4), 1034–1044. https://doi.org/10.1016/j.neuropsychologia.2008.10.029
Campbell, L. E., Stevens, A. F., McCabe, K., Cruickshank, L., Morris, R. G., Murphy, D. G., & Murphy, K. C. (2011). Is theory of mind related to social dysfunction and emotional problems in 22q11.2 deletion syndrome (velo-cardio-facial syndrome)? Journal of Neurodevelopmental Disorders, 3(2), 152–161.
Cheung, V., Chiu, C. P. Y., Law, C. W., Cheung, C., Hui, C. L. M., Chan, K. K. S., Sham, P. C., Deng, M. Y., Tai, K. S., Khong, P. L., & McAlonan, G. M. (2011). Positive symptoms and white matter microstructure in never-medicated first episode schizophrenia. Psychological Medicine, 41(8), 1709–1719.
Constantino, J. N., & Gruber, C. P. (2012). Social responsiveness scale: SRS-2. Western Psychological Services Torrance.
Critchley, H. D., Mathias, C. J., & Dolan, R. J. (2002). Fear conditioning in humans: The influence of awareness and autonomic arousal on functional neuroanatomy. Neuron, 33(4), 653–663.
Dennis, M., Francis, D. J., Cirino, P. T., Schachar, R., Barnes, M. A., & Fletcher, J. M. (2009). Why IQ is not a covariate in cognitive studies of neurodevelopmental disorders. Journal of the International Neuropsychological Society, 15(3), 331–343. https://doi.org/10.1017/S1355617709090481
Desikan, R. S., Ségonne, F., Fischl, B., Quinn, B. T., Dickerson, B. C., Blacker, D., Buckner, R. L., Dale, A. M., Maguire, R. P., Hyman, B. T., & Albert, M. S. (2006). An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. NeuroImage, 31(3), 968–980.
Durand, K., Gallay, M., Seigneuric, A., Robichon, F., & Baudouin, J. Y. (2007). The development of facial emotion recognition: The role of configural information. Journal of Experimental Child Psychology, 97(1), 14–27.
Fairhall, S. L., & Ishai, A. (2007). Effective connectivity within the distributed cortical network for face perception. Cerebral Cortex, 17(10), 2400–2406.
Fischl, B., Salat, D. H., Busa, E., Albert, M., Dieterich, M., Haselgrove, C., Van Der Kouwe, A., Killiany, R., Kennedy, D., Klaveness, S., & Montillo, A. (2002). Whole brain segmentation: Automated labeling of neuroanatomical structures in the human brain. Neuron, 33(3), 341–355.
Fossati, P. (2012). Neural correlates of emotion processing: From emotional to social brain. European Neuropsychopharmacology, 22, S487–S491.
Fuerst, K. B., Dool, C. B., & Rourke, B. P. (1995). Syndrome of nonverbal learning disabilities: Neurodevelopmental manifestations. Past and future. The Guilford Press.
Gobbini, M. I., & Haxby, J. V. (2007). Neural systems for recognition of familiar faces. Neuropsychologia, 45(1), 32–41.
Goebel, R., Esposito, F., & Formisano, E. (2006). Analysis of functional image analysis contest (FIAC) data with brainvoyager QX: From single-subject to cortically aligned group general linear model analysis and self-organizing group independent component analysis. Human Brain Mapping, 27(5), 392–401.
Gur, R. E., McGrath, C., Chan, R. M., Schroeder, L., Turner, T., Turetsky, B. I., Ragland, J. D., et al. (2002). An fMRI study of facial emotion processing in patients with schizophrenia. American Journal of Psychiatry, 159(12), 1992–1999.
Haxby, J. V., Hoffman, E. A., & Gobbini, M. I. (2002). Human neural systems for face recognition and social communication. Biological Psychiatry, 51(1), 59–67.
Hoeft, F., Barnea-Goraly, N., Haas, B. W., Golarai, G., Ng, D., Mills, D., Korenberg, J., Bellugi, U., Galaburda, A., & Reiss, A. L. (2007). More is not always better: Increased fractional anisotropy of superior longitudinal fasciculus associated with poor visuospatial abilities in Williams syndrome. Journal of Neuroscience, 27(44), 11960–11965.
Howley, S. A., Prasad, S. E., Pender, N. P., & Murphy, K. C. (2012). Relationship between reaction time, fine motor control, and visual–spatial perception on vigilance and visual-motor tasks in 22q11.2 deletion syndrome. Research in Developmental Disabilities, 33(5), 1495–1502.
Jalbrzikowski, M., Carter, C., Senturk, D., Chow, C., Hopkins, J. M., Green, M. F., Galván, A., Cannon, T. D., & Bearden, C. E. (2012). Social cognition in 22q11.2 microdeletion syndrome: relevance to psychosis? Schizophrenia Research, 142(1–3), 99–107.
Jalbrzikowski, M., Jonas, R., Senturk, D., Patel, A., Chow, C., Green, M. F., & Bearden, C. E. (2013). Structural abnormalities in cortical volume, thickness, and surface area in 22q11.2 microdeletion syndrome: Relationship with psychotic symptoms. Neuroimage Clinical, 3, 405–415.
Jáni, M., & Kašpárek, T. (2018). Emotion recognition and theory of mind in schizophrenia: A meta-analysis of neuroimaging studies. The World Journal of Biological Psychiatry, 19(sup3), S86–S96.
Kanwisher, N., McDermott, J., & Chun, M. M. (1997). The fusiform face area: A module in human extrastriate cortex specialized for face perception. Journal of Neuroscience, 17(11), 4302–4311.
Karayiorgou, M., Simon, T. J., & Gogos, J. A. (2010). 22q11.2 microdeletions: linking DNA structural variation to brain dysfunction and schizophrenia. Nature Reviews Neuroscience, 11(6), 402.
Keuken, M. C., Hardie, A., Dorn, B. T., Dev, S., Paulus, M. P., Jonas, K. J., Van Den Wildenberg, W. P. M., & Pineda, J. A. (2011). The role of the left inferior frontal gyrus in social perception: An rTMS study. Brain Research, 1383, 196–205.
Kikinis, Z., Asami, T., Bouix, S., Finn, C. T., Ballinger, T., Tworog-Dube, E., & Kubicki, M. (2012). Reduced fractional anisotropy and axial diffusivity in white matter in 22q11.2 deletion syndrome: a pilot study [Multicenter Study Research Support, N I H, Extramural Research Support, Non-U S Gov’t Research Support, U S Gov’t, Non-P H S]. Schizophrenia Research, 141(1), 35–39.
LaBar, K. S., Gatenby, J. C., Gore, J. C., LeDoux, J. E., & Phelps, E. A. (1998). Human amygdala activation during conditioned fear acquisition and extinction: A mixed-trial fMRI study. Neuron, 20(5), 937–945.
Leleu, A., Saucourt, G., Rigard, C., Chesnoy, G., Baudouin, J. Y., Rossi, M., Edery, P., Franck, N., & Demily, C. (2016). Facial emotion perception by intensity in children and adolescents with 22q11.2 deletion syndrome. European Child & Adolescent Psychiatry, 25(3), 297–310.
Liang, X., Zebrowitz, L. A., & Aharon, I. (2009). Effective connectivity between amygdala and orbitofrontal cortex differentiates the perception of facial expressions. Social Neuroscience, 4(2), 185–196.
Loveland, K. A., Pearson, D. A., Tunali-Kotoski, B., Ortegon, J., & Gibbs, M. C. (2001). Judgments of social appropriateness by children and adolescents with autism. Journal of Autism and Developmental Disorders, 31(4), 367–376.
Marrazzo, G., Vaessen, M. J., & de Gelder, B. (2021). Decoding the difference between explicit and implicit body expression representation in high level visual, prefrontal and inferior parietal cortex. NeuroImage, 243, 118545.
Mattiaccio, L. M., Coman, I. L., Thompson, C. A., Fremont, W. P., Antshel, K. M., & Kates, W. R. (2018). Frontal dysconnectivity in 22q11.2 deletion syndrome: an atlas-based functional connectivity analysis. Behavioral and Brain Functions, 14(1), 2. https://doi.org/10.1186/s12993-018-0134-y
Maurer, D., Le Grand, R., & Mondloch, C. J. (2002). The many faces of configural processing. Trends in Cognitive Sciences, 6(6), 255–260.
McCabe, K., Rich, D., Loughland, C. M., Schall, U., & Campbell, L. E. (2011). Visual scanpath abnormalities in 22q11.2 deletion syndrome: is this a face specific deficit? Psychiatry Research, 189(2), 292–298.
McCabe, K. L., Melville, J. L., Rich, D., Strutt, P. A., Cooper, G., Loughland, C. M., Schall, U., & Campbell, L. E. (2013). Divergent patterns of social cognition performance in autism and 22q11.2 deletion syndrome (22q11DS). Journal of Autism and Developmental Disorders, 43(8), 1926–1934.
Miller, E. K., & Cohen, J. D. (2001). An integrative theory of prefrontal cortex function [research support, non-U S gov’t, research support, U S gov’t, P H S review]. Annual Review of Neuroscience, 24, 167–202.
Moss, E. M., Batshaw, M. L., Solot, C. B., Gerdes, M., McDonald-McGinn, D. M., Driscoll, D. A., Emanuel, B. S., Zackai, E. H., & Wang, P. P. (1999). Psychoeducational profile of the 22q11.2 microdeletion: a complex pattern. The Journal of Pediatrics, 134(2), 193–198.
Niklasson, L., Rasmussen, P., Óskarsdóttir, S., & Gillberg, C. (2001). Neuropsychiatric disorders in the 22q11 deletion syndrome. Genetics in Medicine, 3(1), 79–84.
Norkett, E. M., Lincoln, S. H., Gonzalez-Heydrich, J., & D’Angelo, E. J. (2017). Social cognitive impairment in 22q11 deletion syndrome: A review. Psychiatry Research, 253, 99–106.
Olszewski, A. K., Kikinis, Z., Gonzalez, C. S., Coman, I. L., Makris, N., Gong, X., & Kates, W. R. (2017). The social brain network in 22q11.2 deletion syndrome: a diffusion tensor imaging study. Behavioral and Brain Functions, 13(1), 4. https://doi.org/10.1186/s12993-017-0122-7
Ottet, M. C., Schaer, M., Debbané, M., Cammoun, L., Thiran, J. P., & Eliez, S. (2013). Graph theory reveals dysconnected hubs in 22q11DS and altered nodal efficiency in patients with hallucinations. Frontiers in Human Neuroscience, 7, 402.
Padula, M. C., Schaer, M., Scariati, E., Schneider, M., Van De Ville, D., Debbané, M., & Eliez, S. (2015). Structural and functional connectivity in the default mode network in 22q112 deletion syndrome. Journal of Neurodevelopmental Disorders, 7(1), 23. https://doi.org/10.1186/s11689-015-9120-y
Penn, D. L., Sanna, L. J., & Roberts, D. L. (2008). Social cognition in schizophrenia: An overview. Schizophrenia Bulletin, 34(3), 408–411.
Peterson, D. J., Ryan, M., Rimrodt, S. L., Cutting, L. E., Denckla, M. B., Kaufmann, W. E., & Mahone, E. M. (2011). Increased regional fractional anisotropy in highly screened attention-deficit hyperactivity disorder (ADHD). Journal of Child Neurology, 26(10), 1296–1302.
Philippi, C. L., Mehta, S., Grabowski, T., Adolphs, R., & Rudrauf, D. (2009). Damage to association fiber tracts impairs recognition of the facial expression of emotion. The Journal of Neuroscience, 29(48), 15089–15099. https://doi.org/10.1523/jneurosci.0796-09.2009
Phillips, M. L., Drevets, W. C., Rauch, S. L., & Lane, R. (2003). Neurobiology of emotion perception I: The neural basis of normal emotion perception. Biological Psychiatry, 54(5), 504–514.
Pitcher, D. (2014). Facial expression recognition takes longer in the posterior superior temporal sulcus than in the occipital face area. Journal of Neuroscience, 34(27), 9173–9177.
Popa, A. M., Cruz, J. R., Wong, L. M., Harvey, D. J., Angkustsiri, K., Leckliter, I. N., Perez-Edgar, K., & Simon, T. J. (2019). Seeing eye to eye with threat: Atypical threat bias in children with 22q11.2 deletion syndrome. American Journal on Intellectual and Developmental Disabilities, 124(6), 549–567.
R Development Core Team. (2020). R: A language and environment for statistical programming. In (Version 3.6.2) R Foundation for Statistical Programming. R Development Core Team.
Radoeva, P. D., Coman, I. L., Antshel, K. M., Fremont, W., McCarthy, C. S., Kotkar, A., & Kates, W. R. (2012). Atlas-based white matter analysis in individuals with velo-cardio-facial syndrome (22q11.2 deletion syndrome) and unaffected siblings [Research Support, N I H, Extramural Research Support, non-U S Gov’t]. Behavioral and Brain Functions, 8(38), 1744–9081.
Revelle, W. (2019). psychTools: Tools to accompany the ‘psych’ package for psychological research. R Package Version, 1, 12.
Reynolds, & Kamphaus. (2015). Behavior Assessment System for Children, Second Edition (BASC-2). Wiley. https://doi.org/10.1002/9781118625392.wbecp447
Rice, M. E., Okada, Y. C., & Nicholson, C. H. A. R. L. E. S. (1993). Anisotropic and heterogeneous diffusion in the turtle cerebellum: Implications for volume transmission. Journal of Neurophysiology, 70(5), 2035–2044.
Roy, A. K., Vasa, R. A., Bruck, M., Mogg, K., Bradley, B. P., Sweeney, M., Bergman, R. L., McClure-Tone, E. B., & Pine, D. S. (2008). Attention bias toward threat in pediatric anxiety disorders. Journal of the American Academy of Child & Adolescent Psychiatry, 47(10), 1189–1196.
Schneider, M., Debbané, M., Lagioia, A., Salomon, R., d’Argembeau, A., & Eliez, S. (2012). Comparing the neural bases of self-referential processing in typically developing and 22q11.2 adolescents. Developmental Cognitive Neuroscience, 2(2), 277–289.
Schneider, W., Eschman, A., & Zuccolotto, A. (2002). E-Prime: User's guide. Reference guide. Getting started guide. Psychology Software Tools, Incorporated.
Shapiro, H. M., Tassone, F., Choudhary, N. S., & Simon, T. J. (2014). The development of cognitive control in children with chromosome 22q11.2 deletion syndrome. Frontiers in Psychology, 5, 1–14. https://doi.org/10.3389/fpsyg.2014.00566
Simon, T. J., Bearden, C. E., Moss, E. M., McDonald-McGinn, D., Zackai, E., & Wang, P. P. (2002). Cognitive development in VCFS. Progress in Pediatric Cardiology, 15(2), 109–117.
Sing, T., Sander, O., Beerenwinkel, N., & Lengauer, T. (2005). ROCR: Visualizing classifier performance in R. Bioinformatics, 21(20), 3940–3941.
Sobin, C., Kiley-Brabeck, K., Daniels, S., Khuri, J., Taylor, L., Blundell, M., Anyane-Yeboa, K., & Karayiorgou, M. (2005). Neuropsychological characteristics of children with the 22q11 deletion syndrome: a descriptive analysis. Child Neuropsychology, 11(1), 39–53.
Stigler, K., & McDougle, C. (2013). Structural and functional MRI studies of autism spectrum disorders. Elsevier. https://doi.org/10.1016/B978-0-12-391924-3.00017-X
Swillen, A., Devriendt, K., Legius, E., Eyskens, B., Dumoulin, M., Gewillig, M., & Fryns, J.-P. (1997). Intelligence and psychosocial adjustment in velocardiofacial syndrome: A study of 37 children and adolescents with VCFS. Journal of Medical Genetics, 34(6), 453–458.
Szeszko, P. R., Robinson, D. G., Ashtari, M., Vogel, J., Betensky, J., Sevy, S., Ardekani, B. A., Lencz, T., Malhotra, A. K., McCormack, J., & Miller, R. (2008). Clinical and neuropsychological correlates of white matter abnormalities in recent onset schizophrenia. Neuropsychopharmacology, 33(5), 976–984.
Talairach, J., & Tournoux, P. (1988). Co-planar stereotaxic atlas of the human brain (Vol. 270, pp. 132). Theime.
Thaler, A. (2018). Structural and functional MRI in familial Parkinson’s disease. International Review of Neurobiology, 142, 261–287.
Thiele, C., & Hirschfeld, G. (2020). cutpointr: Improved estimation and validation of optimal cutpoints in R. https://arxiv.org/abs/2002.09209
Thomas, L. A., De Bellis, M. D., Graham, R., & LaBar, K. S. (2007). Development of emotional facial recognition in late childhood and adolescence. Developmental Science, 10(5), 547–558.
Tong, F., Nakayama, K., Moscovitch, M., Weinrib, O., & Kanwisher, N. (2000). Response properties of the human fusiform face area. Cognitive Neuropsychology, 17(1–3), 257–280.
Tuch, D. S., Salat, D. H., Wisco, J. J., Zaleta, A. K., Hevelone, N. D., & Rosas, H. D. (2005). Choice reaction time performance correlates with diffusion anisotropy in white matter pathways supporting visuospatial attention. Proceedings of the National Academy of Sciences, 102(34), 12212–12217.
Van, L., Heung, T., Graffi, J., Ng, E., Malecki, S., Van Mil, S., & Bassett, A. S. (2019). All-cause mortality and survival in adults with 22q11.2 deletion syndrome. Genetics in Medicine, 21(10), 2328–2335. https://doi.org/10.1038/s41436-019-0509-y
Van Amelsvoort, T., Schmitz, N., Daly, E., Deeley, Q., Critchley, H., Henry, J., Robertson, D., Owen, M., Murphy, K. C., & Murphy, D. G. (2006). Processing facial emotions in adults with velo-cardio-facial syndrome: Functional magnetic resonance imaging. The British Journal of Psychiatry, 189(6), 560–561.
Volker, M. A., Lopata, C., Smerbeck, A. M., Knoll, V. A., Thomeer, M. L., Toomey, J. A., & Rodgers, J. D. (2010). BASC-2 PRS profiles for students with high-functioning autism spectrum disorders. Journal of Autism and Developmental Disorders, 40(2), 188–199. https://doi.org/10.1007/s10803-009-0849-6
Vuilleumier, P., & Pourtois, G. (2007). Distributed and interactive brain mechanisms during emotion face perception: Evidence from functional neuroimaging. Neuropsychologia, 45(1), 174–194.
Wechsler, D. (2003). Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) administration and scoring manual. The Psychological Corporation.
Weinberger, R., Yi, J., Calkins, M., Guri, Y., McDonald-McGinn, D. M., Emanuel, B. S., & Michaelovsky, E. (2016). Neurocognitive profile in psychotic versus nonpsychotic individuals with 22q11.2 deletion syndrome. European Neuropsychopharmacology, 26(10), 1610–1618.
Wickham, H. (2009). Ggplot2: Elegant graphics for data analysis (2nd ed.). Springer. https://doi.org/10.1007/978-0-387-98141-3
Woodin, M., Wang, P. P., Aleman, D., McDonald-McGinn, D., Zackai, E., & Moss, E. (2001). Neuropsychological profile of children and adolescents with the 22q11. 2 microdeletion. Genetics in Medicine, 3(1), 34–39.
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National Institute of Mental Health, 5R00MH086616-05, Elliott Alexander Beaton, National Institutes of Health, T32 MH100019, Ashley F.P. Sanders
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Sanders, A.F.P., Hobbs, D.A., Knaus, T.A. et al. Structural Connectivity and Emotion Recognition Impairment in Children and Adolescents with Chromosome 22q11.2 Deletion Syndrome. J Autism Dev Disord 53, 4021–4034 (2023). https://doi.org/10.1007/s10803-022-05675-z
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DOI: https://doi.org/10.1007/s10803-022-05675-z