Exploring fMRI Biomarkers for Early Autism Prediction in Fragile X Syndrome
DOI:
https://doi.org/10.56294/shp2025234Keywords:
Autism Spectrum Disorder, Fragile X Syndrome, Neurodevelopmental Disorders, Neuroimaging, Functional Magnetic Resonance Imaging , Machine Learning, Brain Connectivity, Early DetectionAbstract
Neurodevelopmental disorders like Autism Spectrum Disorder (ASD) and Fragile X Syndrome (FXS) often share similar behavioral and cognitive traits, which can make diagnosis and treatment more complex. While ASD typically arises from a mix of genetic and environmental influences, FXS is directly linked to mutations in the FMR1 gene. This review highlights recent progress in the use of neuroimaging—especially functional MRI (fMRI)—and machine learning, both of which are playing a growing role in improving diagnostic accuracy and deepening our understanding of how the brain functions in ASD and FXS. By exploring the latest research, we show how these tools help uncover both unique and overlapping patterns in brain activity, laying the groundwork for earlier diagnosis and more personalized interventions. These developments point to the powerful potential of combining brain imaging and AI to transform the way we approach diagnosis and care. Continued collaboration across disciplines is key to refining these techniques and moving closer to precision medicine in the field of neurodevelopmental disorders.
References
[1] McKechanie, A.G., Campbell, S., Eley, S.E., & Stanfield, A.C. (2019). Autism in Fragile X Syndrome; A Functional MRI Study of Facial Emotion Processing. Genes, 10(12), 1052.
[2] Mc Devitt, N., Gallagher, L., & Reilly, R. B. (2015). Autism Spectrum Disorder (ASD) and Fragile X Syndrome (FXS): Two Overlapping Disorders Reviewed through Electroencephalography—What Can be Interpreted from the Available Information? (2), 92-117.
[3] Wilson, L. B., Tregellas, J. R., Hagerman, R. J., Rogers, S. J., & Rojas, D. C. (2009). A voxel-based morphometry comparison of regional gray matter between fragile X syndrome and autism. Psychiatry Research: Neuroimaging, 174(2), 138-145.
[4] Hoeft F, Walter E, Lightbody AA, et al. Neuroanatomical Differences in Toddler Boys With Fragile X Syndrome and Idiopathic Autism. Arch Gen Psychiatry. 2011;68(3):295-305.
[5] Budimirovic DB, Kaufmann WE. What Can We Learn about Autism from Studying Fragile X Syndrome? Dev Neurosci. 2011;33(5):379-394.
[6] Subah, F.Z.; Deb, K.; Dhar, P.K.; Koshiba, T. A Deep Learning Approach to Predict Autism Spectrum Disorder Using Multisite Resting-State fMRI. Appl. Sci. 2021,11
[7] Yaya Liu, Lingyu Xu1, Jun Li2, Jie Yu and Xuan Yu. Attentional Connectivity-based Prediction of Autism Using Heterogeneous rs-fMRI Data from CC200 Atlas. Exp Neurobiol. 2020 Feb;29(1):27-37
[8] Liu M, Li B and Hu D (2021) Autism Spectrum Disorder Studies Using fMRI Data and Machine Learning: A Review. Front. Neurosci. 15:697870. doi: 10.3389/fnins.2021.697870
[9]Sjir J. C. Schielen , Jesper Pilmeyer, Albert P. Aldenkamp and Svitlana Zinger. The diagnosis of ASD with MRI: a systematic review and meta-analysis.Translational Psychiatry (2024) 14:318
[10] Hong Li, Qingqing Zhang, Tao Duan, Jing Li, Lei Shi, Qiang Hua, Dandan Li, Gong‑Jun Ji , Kai Wang &Chunyan Zhu.Sex differences in brain functional specialization and interhemispheric cooperation among children with autism spectrum disorders (2024) 14:22096
[11] Prof. Sathish, Yasir Babiker Hamdan, Karunakaran P. Early Prediction of Autism Spectrum Disorder by Computational Approaches to fMRI Analysis with Early Learning Technique. Journal of Artificial Intelligence and Capsule Networks (2020) Vol.02/ No.04,207-216,doi.org/10.36548/jaicn.2020.4.003
[12]Xin Yang, Ning Zhang, PaulSchrader.A study of brain net works for autism spectrum disorder classification using resting state functional connectivity, Machine Learning with Applications 8 (2022)
[13]Zhao F, Zhang H, Rekik I, An Z and Shen D (2018) Diagnosis of Autism Spectrum Disorders Using Multi-Level High-Order Functional Networks Derived From Resting-State FunctionalMRI. Front. Hum. Neurosci. 12:184. doi: 10.3389/fnhum.2018.00184
[14]Eslami T, Mirjalili V, Fong A, Laird AR and Saeed F (2019) ASD-DiagNet: A Hybrid Learning Approach for Detection of Autism Spectrum Disorder Using fMRI Data. Front. Neuroinform. 13:70. doi: 10.3389/fninf.2019.00070
[15]Almuqhim F and Saeed F (2021) ASD-SAENet: A Sparse Autoencoder, and Deep-Neural Network Model for Detecting Autism Spectrum Disorder (ASD) Using fMRI Data. Front. Comput. Neurosci. 15:654315. doi: 10.3389/fncom.2021.654315
[16] Song Y, Epalle TM and Lu H (2019) Characterizing and Predicting Autism Spectrum Disorder by Performing Resting-State Functional Network Community Pattern Analysis. Front. Hum. Neurosci. 13:203. doi: 10.3389/fnhum.2019.00203
[17] Luo T, Zhang M, Li S, Situ M, Liu P, Wang M, Tao Y, Zhao S, Wang Z, Yang Y and Huang Y (2024) Exome functional risk score and brain connectivity can predict social adaptability outcome of children with autism spectrum disorder in 4 years’ follow up. Front. Psychiatry 15:1384134. doi: 10.3389/fpsyt.2024.1384134
[18] Zhou Y, Yu F, Duong T (2014) Multiparametric MRI Characterization and Prediction in Autism Spectrum Disorder Using Graph Theory and Machine Learning. PLoS ONE 9(6): e90405. doi:10.1371/journal.pone.0090405
[19]N.Chaitra, P.A. Vijaya, Gopikrishna Deshpande.Diagnostic prediction of autism spectrum disorder using complex network measures in a machine learning framework,Biomedical Signal Processing and Control Volume 62, September 2020,doi.org/10.1016/j.bspc.2020.102099
[20] Taban Eslami, Fahad Saeed. Auto-ASD-Network: A Technique Based on Deep Learning and Support Vector Machines for Diagnosing Autism Spectrum Disorder using fMRI Data, MODI - Machine Learning Models for Multi-omics Data Integration ACM-BCB ’19, September 7–10,2019
[21] Joseph Stember, Danielle Stember, Luca Pasquini, JenabiMerhnaz, Andrei Holodny and HrithwikShalu.Deepreinforcementlearningfor fMRI predictionofAutismSpectrumDisorder,arXiv:2206.11224v1 [q-bio.NC] 17 Jun 2022
[22] Duan Y, Zhao W, Luo C, Liu X, Jiang H, Tang Y, Liu C and Yao D (2022) Identifying and Predicting Autism Spectrum Disorder Based on Multi-Site Structural MRI With Machine Learning. Front. Hum. Neurosci. 15:765517. doi: 10.3389/fnhum.2021.765517
[23] Thomas RM, Gallo S, Cerliani L, Zhutovsky P, El-Gazzar A and van Wingen G (2020) Classifying Autism Spectrum Disorder Using the Temporal Statistics of Resting-State Functional MRI Data With 3D Convolutional Neural Networks. Front. Psychiatry 11:440.doi:10.3389/fpsyt.2020.00440
[24]Sherkatghanad Z, Akhondzadeh M, Salari S, Zomorodi-Moghadam M, Abdar M, Acharya UR, Khosrowabadi R and Salari V (2020) Automated Detection of Autism Spectrum Disorder Using a Convolutional Neural Network. Front. Neurosci. 13:1325. doi: 10.3389/fnins.2019.01325
[25] Mary Beth Nebel,DanielE.Lidstone, Liwei Wang,DavidBenkeser,Stewart H. Mostofsky, Benjamin B.Risk.Accounting for motion in resting-state fMRI: What part of the spectrum are we characterizing in autism spectrum disorder? NeuroImage Volume 257, 15 August 2022, 119296
[26]Juntang Zhuang, Nicha C.Dvornek, Xiaoxiao Li, Pamela Ventola and James S.Duncan.Prediction of Severity and Treatment Outcome for ASD from fMRI
[27] Lluis Borràs-Ferrís, Úrsula Pérez-Ramírez and David Moratal. Link-Level Functional Connectivity Neuroalterations in Autism Spectrum Disorder: A Developmental Resting-State fMRI Study. Diagnostics 2019, 9, 32; doi:10.3390/diagnostics9010032
[28] Qiao J, Wang R, Liu H, Xu G and Wang Z(2022) Brain disorder prediction with dynamic multivariate spatio-temporal features: Application to Alzheimer’s disease and autism spectrum disorder. Front. Aging Neurosci. 14:912895. doi: 10.3389/fnagi.2022.912895
[29] Elizabeth Dryburgh, Stephen McKenna and Islem Rekik. Predicting full-scale and verbal intelligence scores from functional Connectomic data in individuals with autism Spectrum disorder Brain Imaging and Behavior (2020) 14:1769–1778
[30 ]Saggar, M., Bruno, J. L., & Hall, S. S. (2023). Brief intensive social gaze training reorganizes functional brain connectivity in boys with fragile X syndrome. Cerebral Cortex, 33(9), 5218–5227.
[31Maltman, N. et al. (2024). Language use predicts symptoms of fragile X-associated tremor/ataxia syndrome in men and women with the FMR1 premutation. Scientific Reports, 14, 20707.
[32]McKechanie, A. G., Campbell, S., Eley, S. E. A., & Stanfield, A. C. (2019). Autism in Fragile X Syndrome; A Functional MRI Study of Facial Emotion-Processing. Genes, 10(12), 1052. 1
[33]Knoth, I.S., Lajnef, T., Rigoulot, S., Lacourse, K., Vannasing, P., Michaud, J.L., Jacquemont, S., Major, P., Jerbi, K., &Lippé, S. (2018). Auditory repetition suppression alterations in relation to cognitive functioning in fragile X syndrome: a combined EEG and machine learning approach. Journal of Neurodevelopmental Disorders, 10, 4.
[34] Hoeft, F., Walter, E., Lightbody, A. A., Hazlett, H. C., Chang, C. C., Piven, J., & Reiss, A. L. (2011). Neuroanatomical differences in toddler boys with fragile X syndrome and idiopathic autism. Archives of general psychiatry, 68(3), 295-305.
[35] Crawford DC, Acuña JM, Sherman SL. FMR1 and the fragile X syndrome: Human genome epidemiology review. Genet Med. 2001;3(5):359-371.
[36] Bruno, J. L., Romano, D., Mazaika, P., Lightbody, A. A., Hazlett, H. C., Piven, J., & Reiss, A. L. (2017). Longitudinal identification of clinically distinct neurophenotypes in young children with fragile X syndrome. Proceedings of the National Academy of Sciences, 114(40), 10767-10772.
[37] Schneider, A., Hagerman, R. J., &Hessl, D. (2009). Cognitive profiles in fragile X syndrome. Developmental Disabilities Research Reviews, 15(4), 338-345. 4
[38] Razak, K. A., Dominick, K. C., & Erickson, C. A. (2020). Developmental studies in Fragile X Syndrome: trends, challenges, and future directions. Journal of Neurodevelopmental Disorders, 12(1), 1-13. 2
[39] Hoeft, F., Lightbody, A. A., Hazlett, H. C., Patnaik, S., Piven, J., & Reiss, A. L. (2008). Morphometric Spatial Patterns Differentiating Boys With Fragile X Syndrome, Typically Developing Boys, and Developmentally Delayed Boys Aged 1 to 3 Years. Archives of General Psychiatry, 65(9), 1087-1097
[40] Careaga M, Rose D, Tassone F, Berman RF, Hagerman R, et al. (2014) Immune Dysregulation as a Cause of Autoinflammation in Fragile X Premutation Carriers: Link between FMRI CGG Repeat Number and Decreased Cytokine Responses. PLoS ONE 9(4): e94475.
[41] Garrett, A. S., Menon, V., MacKenzie, K., & Reiss, A. L. (2004). Here's looking at you, kid: neural systems underlying face and gaze processing in fragile X syndrome. Archives of general psychiatry, 61(3), 281-288.
[42] Watson, C., Hoeft, F., Garrett, A. S., Hall, S. S., & Reiss, A. L. (2008). Aberrant brain activation during gaze processing in boys with fragile X syndrome. Archives of General Psychiatry, 65(11), 1315-1323.
[43]Schmitt LM, Shaffer RC, Hessl D, Erickson C. Executive Function in Fragile X Syndrome: A Systematic Review. Brain Sci. 2019 Jan 16;9(1):15.
[44] Bruno, J. L., Garrett, A. S., Quintin, E. M., Mazaika, P. K., & Reiss, A. L. (2014). Aberrant face and gaze habituation in fragile X syndrome. American Journal of Psychiatry, 171(10), 1099-1106.
[45] Brunberg, J. A., Jacquemont, S., Hagerman, R. J., Berry-Kravis, E. M., Grigsby, J., Leehey, M. A., ... & Hagerman, P. J. (2002). Fragile X premutation carriers: characteristic MR imaging findings of adult male patients with progressive cerebellar and cognitive dysfunction. American Journal of Neuroradiology, 23(10), 1757-1766.
[46] Hansen, F. S., Canfield, T. K., Lamb, M. Y., Gartler, S. M., & Laird, C. D. (1993). Association of Fragile X Syndrome with Delayed Replication of the FMR1 Gene. Cell, 73(7), 1403-1409.
[47] Pedapati, E. V., Schmitt, L. M., Ethridge, L. E., Liu, R., Smith, E., Sweeney, J. A., Shaffer, R. C., Dominick, K. C., Gilbert, D. L., Wu, S. W., Horn, P. S., Binder, D., Lamy, M., Axford, M., Miyakoshi, M., & Erickson, C. A. (2022). Neocortical Localization and Thalamocortical Modulation of Neuronal Hyperexcitability in Fragile X Syndrome. medRxiv.
[48] Schneider, A., Hagerman, R. J., &Hessl, D. (2009). Cognitive profiles in fragile X syndrome. Developmental Disabilities Research Reviews, 15(4), 338-345
[49] Hantash, F. M., Goos, D. M., Crossley, B., Anderson, B., Zhang, K., Sun, W., & Strom, C. M. (2011). FMR1 premutation carrier frequency in patients undergoing routine population-based carrier screening: insights into the prevalence of fragile X syndrome, fragile X-associated tremor/ataxia syndrome, and fragile X-associated primary ovarian insufficiency in the United States. Genetics in Medicine, 13(1), 39-45.
[50] Strom, C. M., Huang, D., Li, Y., Hantash, F. M., Rooke, J., Potts, S. J., & Sun, W. (2007). Development of a novel, accurate, automated, rapid, high-throughput technique suitable for population-based carrier screening for Fragile X syndrome. Genetics in Medicine, 9(4), 199-207.
[51] Kaufmann, W. E., Cohen, S., Sun, H. T., & Ho, G. (2002). Molecular Phenotype of Fragile X Syndrome: FMRP, FXRPs, and Protein Targets. Microscopy Research and Technique, 57(3), 135-144.
[52] Morton, N. E., & Macpherson, J. N. (1992). Population genetics of the fragile-X syndrome: Multiallelic model for the FMR1 locus. Proceedings of the National Academy of Sciences, 89(9), 4215-4217.
[53] Famula, J., Ferrer, E., Hagerman, R. J., Tassone, F., Schneider, A., Rivera, S. M., &Hessl, D. (2022). Neuropsychological changes in FMR1 premutation carriers and onset of fragile X-associated tremor/ataxia syndrome. Journal of Neurodevelopmental Disorders, 14(1), 1-10
[54] Scerif, G., Cornish, K., Wilding, J., Driver, J., & Karmiloff-Smith, A. (2007). Delineation of early attentional control difficulties in fragile X syndrome: Focus on neurocomputational changes. Neuropsychologia, 45(9), 1889-1898.
[55] Kenkel WM, Yee JR, Moore K, Madularu D, Kulkarni P, Gamber K, Nedelman M, Ferris CF. Functional magnetic resonance imaging in awake transgenic fragile X rats: evidence of dysregulation in reward processing in the mesolimbic/habenular neural circuit. Translational Psychiatry. 2016;6:e763.
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