A Prospective Evaluation of Infant Cerebellar-Cerebral Functional Connectivity in Relation to Behavioral Development in Autism Spectrum Disorder

IBIS Network

doi:10.1016/j.bpsgos.2021.12.004

A Prospective Evaluation of Infant Cerebellar-Cerebral Functional Connectivity in Relation to Behavioral Development in Autism Spectrum Disorder

IBIS Network

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Abstract

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder diagnosed based on social impairment, restricted interests, and repetitive behaviors. Contemporary theories posit that cerebellar pathology contributes causally to ASD by disrupting error-based learning (EBL) during infancy. The present study represents the first test of this theory in a prospective infant sample, with potential implications for ASD detection. Methods: Data from the Infant Brain Imaging Study (n = 94, 68 male) were used to examine 6-month cerebellar functional connectivity magnetic resonance imaging in relation to later (12/24-month) ASD-associated behaviors and outcomes. Hypothesis-driven univariate analyses and machine learning–based predictive tests examined cerebellar–frontoparietal network (FPN; subserves error signaling in support of EBL) and cerebellar–default mode network (DMN; broadly implicated in ASD) connections. Cerebellar-FPN functional connectivity was used as a proxy for EBL, and cerebellar-DMN functional connectivity provided a comparative foil. Data-driven functional connectivity magnetic resonance imaging enrichment examined brain-wide behavioral associations, with post hoc tests of cerebellar connections. Results: Cerebellar-FPN and cerebellar-DMN connections did not demonstrate associations with ASD. Functional connectivity magnetic resonance imaging enrichment identified 6-month correlates of later ASD-associated behaviors in networks of a priori interest (FPN, DMN), as well as in cingulo-opercular (also implicated in error signaling) and medial visual networks. Post hoc tests did not suggest a role for cerebellar connections. Conclusions: We failed to identify cerebellar functional connectivity–based contributions to ASD. However, we observed prospective correlates of ASD-associated behaviors in networks that support EBL. Future studies may replicate and extend network-level positive results, and tests of the cerebellum may investigate brain-behavior associations at different developmental stages and/or using different neuroimaging modalities.

Original language	English (US)
Pages (from-to)	149-161
Number of pages	13
Journal	Biological Psychiatry Global Open Science
Volume	3
Issue number	1
DOIs	https://doi.org/10.1016/j.bpsgos.2021.12.004
State	Published - Jan 2023

Bibliographical note

Funding Information:
This research was supported by grants from the Autism Science Foundation (Grant No. 19-001 [to ZWH]) and National Institutes of Health (NIH) (Grant Nos. F31 MH120918 [to ZWH], K99 MH121518 [to SM], R01 HD055741 [to KB], R01 MH093510 [to JRP], R01 MH116961 [to JJW], R01 MH118362 [to JRP and JPi], and MH118362-02S1 [to JRP]). In addition, research was supported by Washington University Institute of Clinical and Translational Sciences Grant No. UL1TR002345 from the National Center for Advancing Translational Sciences of the NIH. Computations were performed using the facilities of the Washington University Center for High Performance Computing, which were partially funded by NIH Grant Nos. 1S10RR022984-01A1 and 1S10OD018091-01. Neuroimaging processing pipelines were supported by Grant Nos. P30 NS048056 and P30 NS098577. The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH. The Infant Brain Imaging Study–Early Prediction project is a National Institute of Mental Health–funded study and consists of a consortium of 10 universities in the United States and Canada. The study includes infants at high familial risk for autism spectrum disorder, based on having an older sibling with the diagnosis. Infants are seen at 6, 12, and 24 months of age for brain magnetic resonance imaging scans and behavioral tests. Members and components of the Infant Brain Imaging Study–Early Prediction project include: Co-PIs: J.R. Pruett, Jr. & J. Piven; Clinical Sites: Children's Hospital of Philadelphia (CHOP): R.T. Schultz, J. Pandey, J. Parish-Morris, B. Tunç, W. Guthrie; University of Minnesota (UMN): J.T. Elison, J.J. Wolff, C.A. Burrows; University of North Carolina (UNC): J. Piven, H.C. Hazlett, M.D. Shen, J.B. Girault, R. Grzadzinski; University of Washington (UW): S.R. Dager, A.M. Estes, T. St. John, D.W.W. Shaw; Washington University School of Medicine in St. Louis (WU): K.N. Botteron, R.C. McKinstry, J.N. Constantino, N. Marrus; Admin Core: WU: Alicia Rocca; UNC: Chad Chappell; Behavior Core: UW: A.M. Estes, T. St. John; University of Alberta: L. Zwaigenbaum; UMN: J.T. Elison, J.J. Wolff; University of Texas at Dallas: M.R. Swanson; MRI Core: UNC: M.A. Styner, M.D. Shen; New York University: G. Gerig; WU: J.R. Pruett, Jr. R.C. McKinstry; UMN: J.T. Elison; UW: S.R. Dager; Data Coordinating Center: Montreal Neurological Institute: A.C. Evans, L.C. MacIntyre, S. Torres-Gomez, S. Das; Statistical Analysis Core: UNC: K. Truong; Environmental Risk Core: John Hopkins University (JHU): H. Volk; Genetics Core: JHU: M.D. Fallin; UNC: M.D. Shen; EEG: University of California, Los Angeles: S.S. Jeste; Ethical, Legal, and Social Implications Core: UW: K.E. MacDuffie. RCM serves on the advisory board of Nous Imaging, Inc. and receives funding for meals and travel from Siemens Healthineers and Philips Healthcare. JNC receives royalties from Western Psychological Services for the commercial distribution of the Social Responsiveness Scale. All other authors report no biomedical financial interests or potential conflicts of interest.

Publisher Copyright:
© 2021 The Authors

Keywords

Autism
Cerebellum
Development
Error-based learning
Functional connectivity
Infancy

PubMed: MeSH publication types

Journal Article

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10.1016/j.bpsgos.2021.12.004

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@article{f2e4bdebc19c4c98b682eab60dbfdf74,

title = "A Prospective Evaluation of Infant Cerebellar-Cerebral Functional Connectivity in Relation to Behavioral Development in Autism Spectrum Disorder",

abstract = "Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder diagnosed based on social impairment, restricted interests, and repetitive behaviors. Contemporary theories posit that cerebellar pathology contributes causally to ASD by disrupting error-based learning (EBL) during infancy. The present study represents the first test of this theory in a prospective infant sample, with potential implications for ASD detection. Methods: Data from the Infant Brain Imaging Study (n = 94, 68 male) were used to examine 6-month cerebellar functional connectivity magnetic resonance imaging in relation to later (12/24-month) ASD-associated behaviors and outcomes. Hypothesis-driven univariate analyses and machine learning–based predictive tests examined cerebellar–frontoparietal network (FPN; subserves error signaling in support of EBL) and cerebellar–default mode network (DMN; broadly implicated in ASD) connections. Cerebellar-FPN functional connectivity was used as a proxy for EBL, and cerebellar-DMN functional connectivity provided a comparative foil. Data-driven functional connectivity magnetic resonance imaging enrichment examined brain-wide behavioral associations, with post hoc tests of cerebellar connections. Results: Cerebellar-FPN and cerebellar-DMN connections did not demonstrate associations with ASD. Functional connectivity magnetic resonance imaging enrichment identified 6-month correlates of later ASD-associated behaviors in networks of a priori interest (FPN, DMN), as well as in cingulo-opercular (also implicated in error signaling) and medial visual networks. Post hoc tests did not suggest a role for cerebellar connections. Conclusions: We failed to identify cerebellar functional connectivity–based contributions to ASD. However, we observed prospective correlates of ASD-associated behaviors in networks that support EBL. Future studies may replicate and extend network-level positive results, and tests of the cerebellum may investigate brain-behavior associations at different developmental stages and/or using different neuroimaging modalities.",

keywords = "Autism, Cerebellum, Development, Error-based learning, Functional connectivity, Infancy",

author = "{IBIS Network} and Hawks, {Zo{\"e} W.} and Alexandre Todorov and Natasha Marrus and Tomoyuki Nishino and Muhamed Talovic and Nebel, {Mary Beth} and Girault, {Jessica B.} and Savannah Davis and Scott Marek and Seitzman, {Benjamin A.} and Eggebrecht, {Adam T.} and Jed Elison and Stephen Dager and Mosconi, {Matthew W.} and Lawrence Tychsen and Snyder, {Abraham Z.} and Kelly Botteron and Annette Estes and Alan Evans and Guido Gerig and Hazlett, {Heather C.} and McKinstry, {Robert C.} and Juhi Pandey and Schultz, {Robert T.} and Martin Styner and Wolff, {Jason J.} and Lonnie Zwaigenbaum and Lori Markson and Petersen, {Steven E.} and Constantino, {John N.} and White, {Desir{\'e}e A.} and Joseph Piven and Pruett, {John R.}",

note = "Funding Information: This research was supported by grants from the Autism Science Foundation (Grant No. 19-001 [to ZWH]) and National Institutes of Health (NIH) (Grant Nos. F31 MH120918 [to ZWH], K99 MH121518 [to SM], R01 HD055741 [to KB], R01 MH093510 [to JRP], R01 MH116961 [to JJW], R01 MH118362 [to JRP and JPi], and MH118362-02S1 [to JRP]). In addition, research was supported by Washington University Institute of Clinical and Translational Sciences Grant No. UL1TR002345 from the National Center for Advancing Translational Sciences of the NIH. Computations were performed using the facilities of the Washington University Center for High Performance Computing, which were partially funded by NIH Grant Nos. 1S10RR022984-01A1 and 1S10OD018091-01. Neuroimaging processing pipelines were supported by Grant Nos. P30 NS048056 and P30 NS098577. The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH. The Infant Brain Imaging Study–Early Prediction project is a National Institute of Mental Health–funded study and consists of a consortium of 10 universities in the United States and Canada. The study includes infants at high familial risk for autism spectrum disorder, based on having an older sibling with the diagnosis. Infants are seen at 6, 12, and 24 months of age for brain magnetic resonance imaging scans and behavioral tests. Members and components of the Infant Brain Imaging Study–Early Prediction project include: Co-PIs: J.R. Pruett, Jr. & J. Piven; Clinical Sites: Children's Hospital of Philadelphia (CHOP): R.T. Schultz, J. Pandey, J. Parish-Morris, B. Tun{\c c}, W. Guthrie; University of Minnesota (UMN): J.T. Elison, J.J. Wolff, C.A. Burrows; University of North Carolina (UNC): J. Piven, H.C. Hazlett, M.D. Shen, J.B. Girault, R. Grzadzinski; University of Washington (UW): S.R. Dager, A.M. Estes, T. St. John, D.W.W. Shaw; Washington University School of Medicine in St. Louis (WU): K.N. Botteron, R.C. McKinstry, J.N. Constantino, N. Marrus; Admin Core: WU: Alicia Rocca; UNC: Chad Chappell; Behavior Core: UW: A.M. Estes, T. St. John; University of Alberta: L. Zwaigenbaum; UMN: J.T. Elison, J.J. Wolff; University of Texas at Dallas: M.R. Swanson; MRI Core: UNC: M.A. Styner, M.D. Shen; New York University: G. Gerig; WU: J.R. Pruett, Jr. R.C. McKinstry; UMN: J.T. Elison; UW: S.R. Dager; Data Coordinating Center: Montreal Neurological Institute: A.C. Evans, L.C. MacIntyre, S. Torres-Gomez, S. Das; Statistical Analysis Core: UNC: K. Truong; Environmental Risk Core: John Hopkins University (JHU): H. Volk; Genetics Core: JHU: M.D. Fallin; UNC: M.D. Shen; EEG: University of California, Los Angeles: S.S. Jeste; Ethical, Legal, and Social Implications Core: UW: K.E. MacDuffie. RCM serves on the advisory board of Nous Imaging, Inc. and receives funding for meals and travel from Siemens Healthineers and Philips Healthcare. JNC receives royalties from Western Psychological Services for the commercial distribution of the Social Responsiveness Scale. All other authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2023",

month = jan,

doi = "10.1016/j.bpsgos.2021.12.004",

language = "English (US)",

volume = "3",

pages = "149--161",

journal = "Biological Psychiatry Global Open Science",

issn = "2667-1743",

publisher = "Elsevier BV",

number = "1",

}

TY - JOUR

T1 - A Prospective Evaluation of Infant Cerebellar-Cerebral Functional Connectivity in Relation to Behavioral Development in Autism Spectrum Disorder

AU - IBIS Network

AU - Hawks, Zoë W.

AU - Todorov, Alexandre

AU - Marrus, Natasha

AU - Nishino, Tomoyuki

AU - Talovic, Muhamed

AU - Nebel, Mary Beth

AU - Girault, Jessica B.

AU - Davis, Savannah

AU - Marek, Scott

AU - Seitzman, Benjamin A.

AU - Eggebrecht, Adam T.

AU - Elison, Jed

AU - Dager, Stephen

AU - Mosconi, Matthew W.

AU - Tychsen, Lawrence

AU - Snyder, Abraham Z.

AU - Botteron, Kelly

AU - Estes, Annette

AU - Evans, Alan

AU - Gerig, Guido

AU - Hazlett, Heather C.

AU - McKinstry, Robert C.

AU - Pandey, Juhi

AU - Schultz, Robert T.

AU - Styner, Martin

AU - Wolff, Jason J.

AU - Zwaigenbaum, Lonnie

AU - Markson, Lori

AU - Petersen, Steven E.

AU - Constantino, John N.

AU - White, Desirée A.

AU - Piven, Joseph

AU - Pruett, John R.

N1 - Funding Information: This research was supported by grants from the Autism Science Foundation (Grant No. 19-001 [to ZWH]) and National Institutes of Health (NIH) (Grant Nos. F31 MH120918 [to ZWH], K99 MH121518 [to SM], R01 HD055741 [to KB], R01 MH093510 [to JRP], R01 MH116961 [to JJW], R01 MH118362 [to JRP and JPi], and MH118362-02S1 [to JRP]). In addition, research was supported by Washington University Institute of Clinical and Translational Sciences Grant No. UL1TR002345 from the National Center for Advancing Translational Sciences of the NIH. Computations were performed using the facilities of the Washington University Center for High Performance Computing, which were partially funded by NIH Grant Nos. 1S10RR022984-01A1 and 1S10OD018091-01. Neuroimaging processing pipelines were supported by Grant Nos. P30 NS048056 and P30 NS098577. The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH. The Infant Brain Imaging Study–Early Prediction project is a National Institute of Mental Health–funded study and consists of a consortium of 10 universities in the United States and Canada. The study includes infants at high familial risk for autism spectrum disorder, based on having an older sibling with the diagnosis. Infants are seen at 6, 12, and 24 months of age for brain magnetic resonance imaging scans and behavioral tests. Members and components of the Infant Brain Imaging Study–Early Prediction project include: Co-PIs: J.R. Pruett, Jr. & J. Piven; Clinical Sites: Children's Hospital of Philadelphia (CHOP): R.T. Schultz, J. Pandey, J. Parish-Morris, B. Tunç, W. Guthrie; University of Minnesota (UMN): J.T. Elison, J.J. Wolff, C.A. Burrows; University of North Carolina (UNC): J. Piven, H.C. Hazlett, M.D. Shen, J.B. Girault, R. Grzadzinski; University of Washington (UW): S.R. Dager, A.M. Estes, T. St. John, D.W.W. Shaw; Washington University School of Medicine in St. Louis (WU): K.N. Botteron, R.C. McKinstry, J.N. Constantino, N. Marrus; Admin Core: WU: Alicia Rocca; UNC: Chad Chappell; Behavior Core: UW: A.M. Estes, T. St. John; University of Alberta: L. Zwaigenbaum; UMN: J.T. Elison, J.J. Wolff; University of Texas at Dallas: M.R. Swanson; MRI Core: UNC: M.A. Styner, M.D. Shen; New York University: G. Gerig; WU: J.R. Pruett, Jr. R.C. McKinstry; UMN: J.T. Elison; UW: S.R. Dager; Data Coordinating Center: Montreal Neurological Institute: A.C. Evans, L.C. MacIntyre, S. Torres-Gomez, S. Das; Statistical Analysis Core: UNC: K. Truong; Environmental Risk Core: John Hopkins University (JHU): H. Volk; Genetics Core: JHU: M.D. Fallin; UNC: M.D. Shen; EEG: University of California, Los Angeles: S.S. Jeste; Ethical, Legal, and Social Implications Core: UW: K.E. MacDuffie. RCM serves on the advisory board of Nous Imaging, Inc. and receives funding for meals and travel from Siemens Healthineers and Philips Healthcare. JNC receives royalties from Western Psychological Services for the commercial distribution of the Social Responsiveness Scale. All other authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: © 2021 The Authors

PY - 2023/1

Y1 - 2023/1

N2 - Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder diagnosed based on social impairment, restricted interests, and repetitive behaviors. Contemporary theories posit that cerebellar pathology contributes causally to ASD by disrupting error-based learning (EBL) during infancy. The present study represents the first test of this theory in a prospective infant sample, with potential implications for ASD detection. Methods: Data from the Infant Brain Imaging Study (n = 94, 68 male) were used to examine 6-month cerebellar functional connectivity magnetic resonance imaging in relation to later (12/24-month) ASD-associated behaviors and outcomes. Hypothesis-driven univariate analyses and machine learning–based predictive tests examined cerebellar–frontoparietal network (FPN; subserves error signaling in support of EBL) and cerebellar–default mode network (DMN; broadly implicated in ASD) connections. Cerebellar-FPN functional connectivity was used as a proxy for EBL, and cerebellar-DMN functional connectivity provided a comparative foil. Data-driven functional connectivity magnetic resonance imaging enrichment examined brain-wide behavioral associations, with post hoc tests of cerebellar connections. Results: Cerebellar-FPN and cerebellar-DMN connections did not demonstrate associations with ASD. Functional connectivity magnetic resonance imaging enrichment identified 6-month correlates of later ASD-associated behaviors in networks of a priori interest (FPN, DMN), as well as in cingulo-opercular (also implicated in error signaling) and medial visual networks. Post hoc tests did not suggest a role for cerebellar connections. Conclusions: We failed to identify cerebellar functional connectivity–based contributions to ASD. However, we observed prospective correlates of ASD-associated behaviors in networks that support EBL. Future studies may replicate and extend network-level positive results, and tests of the cerebellum may investigate brain-behavior associations at different developmental stages and/or using different neuroimaging modalities.

AB - Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder diagnosed based on social impairment, restricted interests, and repetitive behaviors. Contemporary theories posit that cerebellar pathology contributes causally to ASD by disrupting error-based learning (EBL) during infancy. The present study represents the first test of this theory in a prospective infant sample, with potential implications for ASD detection. Methods: Data from the Infant Brain Imaging Study (n = 94, 68 male) were used to examine 6-month cerebellar functional connectivity magnetic resonance imaging in relation to later (12/24-month) ASD-associated behaviors and outcomes. Hypothesis-driven univariate analyses and machine learning–based predictive tests examined cerebellar–frontoparietal network (FPN; subserves error signaling in support of EBL) and cerebellar–default mode network (DMN; broadly implicated in ASD) connections. Cerebellar-FPN functional connectivity was used as a proxy for EBL, and cerebellar-DMN functional connectivity provided a comparative foil. Data-driven functional connectivity magnetic resonance imaging enrichment examined brain-wide behavioral associations, with post hoc tests of cerebellar connections. Results: Cerebellar-FPN and cerebellar-DMN connections did not demonstrate associations with ASD. Functional connectivity magnetic resonance imaging enrichment identified 6-month correlates of later ASD-associated behaviors in networks of a priori interest (FPN, DMN), as well as in cingulo-opercular (also implicated in error signaling) and medial visual networks. Post hoc tests did not suggest a role for cerebellar connections. Conclusions: We failed to identify cerebellar functional connectivity–based contributions to ASD. However, we observed prospective correlates of ASD-associated behaviors in networks that support EBL. Future studies may replicate and extend network-level positive results, and tests of the cerebellum may investigate brain-behavior associations at different developmental stages and/or using different neuroimaging modalities.

KW - Autism

KW - Cerebellum

KW - Development

KW - Error-based learning

KW - Functional connectivity

KW - Infancy

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UR - http://www.scopus.com/inward/citedby.url?scp=85135882366&partnerID=8YFLogxK

U2 - 10.1016/j.bpsgos.2021.12.004

DO - 10.1016/j.bpsgos.2021.12.004

M3 - Article

C2 - 36712571

AN - SCOPUS:85135882366

SN - 2667-1743

VL - 3

SP - 149

EP - 161

JO - Biological Psychiatry Global Open Science

JF - Biological Psychiatry Global Open Science

IS - 1

ER -

A Prospective Evaluation of Infant Cerebellar-Cerebral Functional Connectivity in Relation to Behavioral Development in Autism Spectrum Disorder

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