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Research Article
Michel Godel
Universite de Geneve Faculte de Medecine
Corresponding Author
ORCiD: https://orcid.org/0000-0002-9789-3540
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: Recent neuroimaging studies have highlighted differences in cerebral maturation in individuals with autism spectrum disorder (ASD) in comparison to typical development. For instance, the contrast of the gray-white matter boundary is decreased in adults with ASD. To determine how gray-white matter boundary integrity relates to early ASD phenotypes, we used a regional structural MRI index of gray-white matter contrast (GWC) on a sample of toddlers with a hereditary high risk for ASD.
Methods: We used a surface-based approach to compute vertex-wise GWC in a longitudinal cohort of toddlers at high-risk for ASD imaged twice between 12 and 24 months (n=20). A full clinical assessment of ASD-related symptoms was performed in conjunction with imaging and again at three years of age for diagnostic outcome. Three outcome groups were defined (ASD, n=9; typical development, n=8; non-typical development, n=3).
Results: ASD diagnostic outcome at age 3 was associated with widespread increases in GWC between age 12 and 24 months. Many cortical regions were affected, including regions implicated in social processing and language acquisition. In parallel, we found that early onset of ASD symptoms (i.e. prior to 18-months) was specifically associated with slower GWC rates of change during the second year of life. These alterations were found in areas mainly belonging to the central executive network.
Limitations: Our study is the first to measure maturational changes in GWC in toddlers who developed autism, but given the limited size of our sample results should be considered exploratory and warrant further replication in independent and larger samples.
Conclusion: These preliminary results suggest that ASD is linked to early alterations of the gray-white matter boundary in widespread brain regions. Early onset of ASD diagnosis constitutes an independent clinical parameter associated with a specific corresponding neurobiological developmental trajectory. Altered neural migration and/or altered myelination processes potentially explain these findings.
Keywords
Autism Spectrum Disorder, Sibling risk, Toddlers, Neurodevelopment, Neuroimaging, FreeSurfer
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
This is a list of supplementary files associated with this preprint. Click to download.
- ReviewS1.jpg
Additional File 1: Figure S1 Graphic representation of individual ADOS CSS at 18 and 24 months of age in our sample (n=20 HR participants). Color code represents individual diagnosis outcome at age 3. HR-TD: high risk for ASD with typical development; HR-non-TD: high risk for ASD with atypical development; HR-TD: high risk for ASD with ASD.
- S1.jpg
Additional File 2: Figure S2 A. Clusters with a significant effect of time on gray-white matter contrast (GWC) in the HR-TD group. Clusters with cluster-wise P-value (CWP) < 0.05 only are displayed. Color code corresponds to P-value of the vertex with the maximal P-value (Pvm) of each cluster. B. On the right are plotted for each hemisphere the individual GWC rates of change (ΔGWC) within each significant cluster (one per hemisphere). We found no significant difference between both clusters (paired T-test, p=0.15).
- reviewS3.jpg
Additional File 3: Figure S3 Results displayed on Fig 3 (Association between GWC at age 12-24 months and symptom severity at 18 months of age) with individual GWC values displayed for each significant cluster in function of ADOS calibrated severity score (CSS) (upper-side graphs), diagnostic outcome group (left down-side graphs) and HR-ASD subgroups (right down-side graphs). A. Results for clusters with significant correlation between GWC and 18-mo ADOS CSS. B. Clusters with significant correlation between GWC and 36-mo ADOS CSS. *p<0.05 **p<0.01 ***p<0.001.
- reviewS4.jpg
Additional File 4: Figure S4 Results displayed on Fig 5 (Association between symptom severity at 18 months of age and GWC rate of change (ΔGWC) between 12 and 24 months of age) with individual ΔGWC displayed for each cluster in function ADOS calibrated severity score (CSS) (upper-side graph), diagnostic outcome group (left down-side graphs) and HR-ASD subgroups (right down-side graphs). *p<0.05 **p<0.01 ***p<0.001.
- ReviewS5.jpg
Additional File 5: Figure S5 Association between cortical thickness at age 12-24 months and diagnostic outcome at 36 months of age (HR-ASD or HR-TD). The single cluster with significantly smaller CT in HR-ASD compared to HR-TD (CWP < 0.05) is displayed. We found no significant cluster in the right hemisphere. Color code corresponds to P-value of the vertex with maximal P-value (Pvm) of the displayed cluster (Table 2). On the right, individual CT values are displayed in function of diagnosis outcome for the displayed cluster. *p<0.05. CWP: cluster-wise P-value.
- reviewS6.jpg
Additional File 6: Figure S6 Results of supplementary analysis comparing LR-TD with HR-ASD (A) and LR-TD with HR-TD (B). Color code corresponds to P-value of the vertex with maximal P-value (Pvm) of the displayed clusters. On the graphs, individual GWC values are displayed in function of diagnosis outcome for the displayed clusters.
- ReviewS7.jpg
Additional File 7: Figure S7 A. Effect of time on GWC within LR toddlers with typical development outcomes at 3 years (LR-TD) represented with vertex-wise ΔGWC values mapped on the common FreeSurfer template. B. Clusters with a significant effect of time on gray-white matter contrast (GWC) in the LR-TD group. Clusters with cluster-wise P-value (CWP) < 0.05 only are displayed. Color code corresponds to P-value of the vertex with the maximal P-value (Pvm) of each cluster.
- Reviewsupptable.docx
Additional File 8: Table S8 Demographic and behavioral information on HR-ASD subgroups (LOA and EOA). P-value of statistical comparison between both subgroups.
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This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Research Article
Michel Godel
Universite de Geneve Faculte de Medecine
Corresponding Author
ORCiD: https://orcid.org/0000-0002-9789-3540
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 3
Posted 18 May, 2021
No community comments so far
No comments provided
No comments provided
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Developmental Neuroscience
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: Recent neuroimaging studies have highlighted differences in cerebral maturation in individuals with autism spectrum disorder (ASD) in comparison to typical development. For instance, the contrast of the gray-white matter boundary is decreased in adults with ASD. To determine how gray-white matter boundary integrity relates to early ASD phenotypes, we used a regional structural MRI index of gray-white matter contrast (GWC) on a sample of toddlers with a hereditary high risk for ASD.
Methods: We used a surface-based approach to compute vertex-wise GWC in a longitudinal cohort of toddlers at high-risk for ASD imaged twice between 12 and 24 months (n=20). A full clinical assessment of ASD-related symptoms was performed in conjunction with imaging and again at three years of age for diagnostic outcome. Three outcome groups were defined (ASD, n=9; typical development, n=8; non-typical development, n=3).
Results: ASD diagnostic outcome at age 3 was associated with widespread increases in GWC between age 12 and 24 months. Many cortical regions were affected, including regions implicated in social processing and language acquisition. In parallel, we found that early onset of ASD symptoms (i.e. prior to 18-months) was specifically associated with slower GWC rates of change during the second year of life. These alterations were found in areas mainly belonging to the central executive network.
Limitations: Our study is the first to measure maturational changes in GWC in toddlers who developed autism, but given the limited size of our sample results should be considered exploratory and warrant further replication in independent and larger samples.
Conclusion: These preliminary results suggest that ASD is linked to early alterations of the gray-white matter boundary in widespread brain regions. Early onset of ASD diagnosis constitutes an independent clinical parameter associated with a specific corresponding neurobiological developmental trajectory. Altered neural migration and/or altered myelination processes potentially explain these findings.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
This is a list of supplementary files associated with this preprint. Click to download.
- ReviewS1.jpg
Additional File 1: Figure S1 Graphic representation of individual ADOS CSS at 18 and 24 months of age in our sample (n=20 HR participants). Color code represents individual diagnosis outcome at age 3. HR-TD: high risk for ASD with typical development; HR-non-TD: high risk for ASD with atypical development; HR-TD: high risk for ASD with ASD.
- S1.jpg
Additional File 2: Figure S2 A. Clusters with a significant effect of time on gray-white matter contrast (GWC) in the HR-TD group. Clusters with cluster-wise P-value (CWP) < 0.05 only are displayed. Color code corresponds to P-value of the vertex with the maximal P-value (Pvm) of each cluster. B. On the right are plotted for each hemisphere the individual GWC rates of change (ΔGWC) within each significant cluster (one per hemisphere). We found no significant difference between both clusters (paired T-test, p=0.15).
- reviewS3.jpg
Additional File 3: Figure S3 Results displayed on Fig 3 (Association between GWC at age 12-24 months and symptom severity at 18 months of age) with individual GWC values displayed for each significant cluster in function of ADOS calibrated severity score (CSS) (upper-side graphs), diagnostic outcome group (left down-side graphs) and HR-ASD subgroups (right down-side graphs). A. Results for clusters with significant correlation between GWC and 18-mo ADOS CSS. B. Clusters with significant correlation between GWC and 36-mo ADOS CSS. *p<0.05 **p<0.01 ***p<0.001.
- reviewS4.jpg
Additional File 4: Figure S4 Results displayed on Fig 5 (Association between symptom severity at 18 months of age and GWC rate of change (ΔGWC) between 12 and 24 months of age) with individual ΔGWC displayed for each cluster in function ADOS calibrated severity score (CSS) (upper-side graph), diagnostic outcome group (left down-side graphs) and HR-ASD subgroups (right down-side graphs). *p<0.05 **p<0.01 ***p<0.001.
- ReviewS5.jpg
Additional File 5: Figure S5 Association between cortical thickness at age 12-24 months and diagnostic outcome at 36 months of age (HR-ASD or HR-TD). The single cluster with significantly smaller CT in HR-ASD compared to HR-TD (CWP < 0.05) is displayed. We found no significant cluster in the right hemisphere. Color code corresponds to P-value of the vertex with maximal P-value (Pvm) of the displayed cluster (Table 2). On the right, individual CT values are displayed in function of diagnosis outcome for the displayed cluster. *p<0.05. CWP: cluster-wise P-value.
- reviewS6.jpg
Additional File 6: Figure S6 Results of supplementary analysis comparing LR-TD with HR-ASD (A) and LR-TD with HR-TD (B). Color code corresponds to P-value of the vertex with maximal P-value (Pvm) of the displayed clusters. On the graphs, individual GWC values are displayed in function of diagnosis outcome for the displayed clusters.
- ReviewS7.jpg
Additional File 7: Figure S7 A. Effect of time on GWC within LR toddlers with typical development outcomes at 3 years (LR-TD) represented with vertex-wise ΔGWC values mapped on the common FreeSurfer template. B. Clusters with a significant effect of time on gray-white matter contrast (GWC) in the LR-TD group. Clusters with cluster-wise P-value (CWP) < 0.05 only are displayed. Color code corresponds to P-value of the vertex with the maximal P-value (Pvm) of each cluster.
- Reviewsupptable.docx
Additional File 8: Table S8 Demographic and behavioral information on HR-ASD subgroups (LOA and EOA). P-value of statistical comparison between both subgroups.
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