Functional connectivity abnormalities and associated cognitive deficits in fetal alcohol Spectrum disorders (FASD)
Consistent with well-documented structural and microstructural abnormalities in prenatal alcohol exposure (PAE), recent studies suggest that functional connectivity (FC) may also be disrupted. We evaluated whole-brain FC in a large multi-site sample, examined its cognitive correlates, and explored its potential to objectively identify neurodevelopmental abnormality in individuals without definitive dysmorphic features. Included were 75 children with PAE and 68 controls from four sites. All participants had documented heavy prenatal alcohol exposure. All underwent a formal evaluation of physical anomalies and dysmorphic facial features. MRI data were collected using modified matched protocols on three platforms (Siemens, GE, and Philips). Resting-state FC was examined using whole-brain graph theory metrics to characterize each individual’s connectivity. Although whole-brain FC metrics did not discriminate prenatally-exposed from unexposed overall, atypical FC (> 1 standard deviation from the grand mean) was significantly more common (2.7 times) in the PAE group vs. controls. In a subset of 55 individuals (PAE and controls) whose dysmorphology examination could not definitively characterize them as either Fetal Alcohol Syndrome (FAS) or non-FAS, atypical FC was seen in 27 % of the PAE group, but 0 % of controls. Across participants, a 1 % difference in local network efficiency was associated with a 36 point difference in global cognitive functioning. Whole-brain FC metrics have potential to identify individuals with objective neurodevelopmental abnormalities from prenatal alcohol exposure. When applied to individuals unable to be classified as FAS or non-FAS from dysmorphology alone, these measures separate prenatally-exposed from non-exposed with high specificity.
KeywordsFetal alcohol (FAS, FASD) Brain Functional MRI (fMRI), resting-state, connectivity Neuropsychology
This work was performed in conjunction with the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD), which is funded by grants from the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Additional information about CIFASD can be found at www.cifasd.org.
Compliance with ethical standards
This study was funded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA). The following support was utilized in this work: NIAAA U01AA017122 (PI: ERS); NIAAA U01AA14834 (PI: SNM); U24AA014811 (EPR); U24AA014815 (PI: KLJ); U24AA014818 (PI: Barnett); support from the Minnesota Supercomputing Institute.
Conflict of interest
None of the authors has a relevant conflict of interest to disclose.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study. All procedures were reviewed and approved by local human subject’s protection programs. This article does not contain any studies with animals performed by any of the authors.
- Benjamini, Y., & Hochberg, Y. (1995). Controlling the false discovery rate: a practical and powerful approach to multiple testing. Journal of the Royal Statistical Society, 57(1), 289–300.Google Scholar
- Bookstein, F. L., Connor, P. D., Covell, K. D., Barr, H. M., Gleason, C. A., Sze, R. W., et al. (2005). Preliminary evidence that prenatal alcohol damage may be visible in averaged ultrasound images of the neonatal human corpus callosum. Alcohol, 36(3), 151–160. doi: 10.1016/j.alcohol.2005.07.007.CrossRefPubMedGoogle Scholar
- Bookstein, F. L., Connor, P. D., Huggins, J. E., Barr, H. M., Pimentel, K. D., & Streissguth, A. P. (2007). Many infants prenatally exposed to high levels of alcohol show one particular anomaly of the corpus callosum. Alcoholism, Clinical and Experimental Research, 31(5), 868–879. doi: 10.1111/j.1530–0277.2007.00367.x.CrossRefPubMedGoogle Scholar
- Cao, W., Li, W., Han, H., O’Leary-Moore, S. K., Sulik, K. K., Allan Johnson, G., et al. (2014). Prenatal alcohol exposure reduces magnetic susceptibility contrast and anisotropy in the white matter of mouse brains. Neuroimage, 102(Pt 2), 748–755. doi: 10.1016/j.neuroimage.2014.08.035.CrossRefPubMedPubMedCentralGoogle Scholar
- Delis, D. C., Kramer, J. H., Kaplan, E., & Ober, B. A. (1994). California Verbal Learning Test Manual, Children’s Version. San Antonio: The Psychological Corporation.Google Scholar
- Delis, D. C., Kaplan, E., & Kramer, J. H. (2001). Delis-Kaplan Executive Function System (D-KEFS). San Antonio, TX: Harcourt Assessment, Inc..Google Scholar
- Donald, K. A., Eastman, E., Howells, F. M., Adnams, C., Riley, E. P., Woods, R. P., et al. (2015a). Neuroimaging effects of prenatal alcohol exposure on the developing human brain: a magnetic resonance imaging review. Acta Neuropsychiatr, 27(5), 251–269. doi: 10.1017/neu.2015.12.CrossRefPubMedGoogle Scholar
- Donald, K. A., Ipser, J. C., Howells, F. M., Roos, A., Fouche, J. P., Riley, E. P., et al. (2016). Interhemispheric functional brain connectivity in neonates with prenatal alcohol exposure: preliminary findings. Alcoholism, Clinical and Experimental Research, 40(1), 113–121. doi: 10.1111/acer.12930.CrossRefPubMedGoogle Scholar
- Elliott, C. D. (2007). Differential Ability Scales - Second Edition (DAS-II): Introductory and technical handbook. San Antonio, TX: PsychCorp.Google Scholar
- Fair, D. A., Cohen, A. L., Power, J. D., Dosenbach, N. U., Church, J. A., Miezin, F. M., et al. (2009). Functional brain networks develop from a "local to distributed" organization. PLoS Computational Biology, 5(5), e1000381. doi: 10.1371/journal.pcbi.1000381.CrossRefPubMedPubMedCentralGoogle Scholar
- Fan, J., Meintjes, E. M., Molteno, C. D., Spottiswoode, B. S., Dodge, N. C., Alhamud, A. A., et al. (2015). White matter integrity of the cerebellar peduncles as a mediator of effects of prenatal alcohol exposure on eyeblink conditioning. Human Brain Mapping, 36(7), 2470–2482. doi: 10.1002/hbm.22785.CrossRefPubMedPubMedCentralGoogle Scholar
- Fryer, S. L., Schweinsburg, B. C., Bjorkquist, O. A., Frank, L. R., Mattson, S. N., Spadoni, A. D., et al. (2009). Characterization of white matter microstructure in fetal alcohol spectrum disorders. Alcoholism, Clinical and Experimental Research, 33(3), 514–521. doi: 10.1111/j.1530-0277.2008.00864.x.CrossRefPubMedGoogle Scholar
- Green, C. R., Mihic, A. M., Nikkel, S. M., Stade, B. C., Rasmussen, C., Munoz, D. P., et al. (2009). Executive function deficits in children with fetal alcohol spectrum disorders (FASD) measured using the Cambridge neuropsychological tests automated battery (CANTAB. Journal of Child Psychology and Psychiatry, 50(6), 688–697. doi: 10.1111/j.1469-7610.2008.01990.x.CrossRefPubMedGoogle Scholar
- Jones, K. L., Robinson, L. K., Bakhireva, L. N., Marintcheva, G., Storojev, V., Strahova, A., et al. (2006). Accuracy of the diagnosis of physical features of fetal alcohol syndrome by pediatricians after specialized training. Pediatrics, 118(6), E1734–E1738. doi: 10.1542/peds.2006-1037.CrossRefPubMedGoogle Scholar
- Jones, K. L., Hoyme, H. E., Robinson, L. K., Del Campo, M., Manning, M. A., Prewitt, L. M., et al. (2010). Fetal alcohol spectrum disorders: extending the range of structural defects. American Journal of Medical Genetics. Part A, 152 A(11), 2731–2735. doi: 10.1002/ajmg.a.33675.CrossRefGoogle Scholar
- Korkman, M., Kirk, U., & Kemp, S. (2007). NEPSY-II (Second ed.). San Antonio, TX: PsychCorp.Google Scholar
- Lebel, C., Rasmussen, C., Wyper, K., Walker, L., Andrew, G., Yager, J., et al. (2008). Brain diffusion abnormalities in children with fetal alcohol spectrum disorder. Alcoholism, Clinical and Experimental Research, 32(10), 1732–1740. doi: 10.1111/j.1530-0277.2008.00750.x.CrossRefPubMedGoogle Scholar
- Ma, X., Coles, C. D., Lynch, M. E., Laconte, S. M., Zurkiya, O., Wang, D., et al. (2005). Evaluation of corpus callosum anisotropy in young adults with fetal alcohol syndrome according to diffusion tensor imaging. Alcoholism, Clinical and Experimental Research, 29(7), 1214–1222.CrossRefPubMedGoogle Scholar
- Malisza, K. L., Buss, J. L., Bolster, R. B., de Gervai, P. D., Woods-Frohlich, L., Summers, R., et al. (2012). Comparison of spatial working memory in children with prenatal alcohol exposure and those diagnosed with ADHD; a functional magnetic resonance imaging study. Journal of Neurodevelopmental Disorders, 4(1). doi: 10.1186/1866-1955-4-12.
- Mattson, S. N., Roesch, S. C., Glass, L., Deweese, B. N., Coles, C. D., Kable, J. A., et al. (2013). Further development of a neurobehavioral profile of fetal alcohol spectrum disorders. Alcoholism, Clinical and Experimental Research, 37(3), 517–528. doi: 10.1111/j.1530-0277.2012.01952.x.CrossRefPubMedGoogle Scholar
- Roussotte, F. F., Rudie, J. D., Smith, L., O’Connor, M. J., Bookheimer, S. Y., Narr, K. L., et al. (2012). Frontostriatal connectivity in children during working memory and the effects of prenatal methamphetamine, alcohol, and Polydrug exposure. Developmental Neuroscience, 34(1), 43–57. doi: 10.1159/000336242.CrossRefPubMedGoogle Scholar
- Shaffer, D., Fisher, P., Lucas, C. P., Dulcan, M. K., & Schwab-Stone, M. E. (2000). NIMH Diagnostic Interview Schedule for Children Version IV (NIMH DISC-IV): description, differences from previous versions, and reliability of some common diagnoses. J Am Acad Child Adolesc Psychiatry, 39(1), 28–38. doi: 10.1097/00004583–200001000-00014.CrossRefPubMedGoogle Scholar
- Sowell, E. R., Johnson, A., Kan, E., Lu, L. H., Van Horn, J. D., Toga, A. W., et al. (2008). Mapping white matter integrity and neurobehavioral correlates in children with fetal alcohol spectrum disorders. The Journal of Neuroscience, 28(6), 1313–1319. doi: 10.1523/JNEUROSCI.5067-07.2008.CrossRefPubMedPubMedCentralGoogle Scholar
- Sowell, E. R., Leow, A. D., Bookheimer, S. Y., Smith, L. M., O’Connor, M. J., Kan, E., et al. (2010). Differentiating prenatal exposure to methamphetamine and alcohol versus alcohol and not methamphetamine using tensor-based brain morphometry and discriminant analysis. The Journal of Neuroscience, 30(11), 3876–3885. doi: 10.1523/JNEUROSCI.4967-09.2010.CrossRefPubMedPubMedCentralGoogle Scholar
- Spottiswoode, B. S., Meintjes, E. M., Anderson, A. W., Molteno, C. D., Stanton, M. E., Dodge, N. C., et al. (2011). Diffusion tensor imaging of the cerebellum and eyeblink conditioning in fetal alcohol spectrum disorder. Alcoholism, Clinical and Experimental Research, 35(12), 2174–2183. doi: 10.1111/j.1530-0277.2011.01566.x.CrossRefPubMedPubMedCentralGoogle Scholar
- Taylor, P. A., Jacobson, S. W., van der Kouwe, A., Molteno, C. D., Chen, G., Wintermark, P., et al. (2015). A DTI-based tractography study of effects on brain structure associated with prenatal alcohol exposure in newborns. Human Brain Mapping, 36(1), 170–186. doi: 10.1002/hbm.22620.CrossRefPubMedGoogle Scholar
- Wozniak, J. R., Muetzel, R. L., Mueller, B. A., McGee, C. L., Freerks, M. A., Ward, E. E., et al. (2009). Microstructural corpus callosum anomalies in children with prenatal alcohol exposure: an extension of previous diffusion tensor imaging findings. Alcoholism, Clinical and Experimental Research, 33(10), 1825–1835. doi: 10.1111/j.1530-0277.2009.01021.x.CrossRefPubMedPubMedCentralGoogle Scholar
- Wozniak, J. R., Mueller, B. A., Muetzel, R. L., Bell, C. J., Hoecker, H. L., Nelson, M. L., et al. (2011). Inter-hemispheric functional connectivity disruption in children with prenatal alcohol exposure. Alcoholism, Clinical and Experimental Research, 35(5), 849–861. doi: 10.1111/j.1530-0277.2010.01415.x.CrossRefPubMedPubMedCentralGoogle Scholar
- Wozniak, J. R., Mueller, B. A., Bell, C. J., Muetzel, R. L., Hoecker, H. L., Boys, C. J., et al. (2013). Global functional connectivity abnormalities in children with fetal alcohol spectrum disorders. Alcoholism, Clinical and Experimental Research, 37(5), 748–756. doi: 10.1111/acer.12024.CrossRefPubMedGoogle Scholar
- Wu, K., Taki, Y., Sato, K., Hashizume, H., Sassa, Y., Takeuchi, H., et al. (2013). Topological organization of functional brain networks in healthy children: differences in relation to age, sex, and intelligence. PloS One, 8(2), e55347. doi: 10.1371/journal.pone.0055347.CrossRefPubMedPubMedCentralGoogle Scholar