Fetal neurotropic infection results in long term disruptions of brain structure and function
Presented During:
Thursday, June 26, 2025: 11:30 AM - 12:45 PM
Brisbane Convention & Exhibition Centre
Room:
M1 & M2 (Mezzanine Level)
Poster No:
303
Submission Type:
Abstract Submission
Authors:
Erika Raven1, Joey Charbonneau2, Claude Lepage3, Jelle Veraart1, Jeff Bennett4, Alan Evans3, Jiangyang Zhang1, Eliza Bliss-Moreau5
Institutions:
1Department of Radiology, NYU Grossman School of Medicine, New York, NY, 2Center for Neural Science, New York University, New York, NY, 3Brain Imaging Center, Montreal Neurological Institute, McGill University, Montreal, Quebec, 4California National Primate Research Center, Davis, CA, 5Department of Psychology, University of California, Davis, Davis, CA
First Author:
Co-Author(s):
Claude Lepage
Brain Imaging Center, Montreal Neurological Institute, McGill University
Montreal, Quebec
Brain Imaging Center, Montreal Neurological Institute, McGill University
Montreal, Quebec
Alan Evans
Brain Imaging Center, Montreal Neurological Institute, McGill University
Montreal, Quebec
Brain Imaging Center, Montreal Neurological Institute, McGill University
Montreal, Quebec
Introduction:
Typical brain development is shaped by genetic programming, environmental influences, and learning. For humans and nonhuman primates, there is a complex, protracted sequence of developmental events, including axon formation, synaptic refinement, and myelination that can extend well into adulthood. Structural maturation is reflected in the emergence of brain and behavioral functions, with touch recognized as the earliest sensory milestone achieved in utero [1].
Neurotropic infections, like Zika virus, can invade the brain with outcomes heavily influenced by developmental timing. First trimester infections have been linked to fetal loss and microcephaly, as seen in Congenital Zika Syndrome. In contrast, infections occurring in the mid-to-late trimesters often result in infants with normal appearing head sizes but an elevated risk of developmental delay [2].
The long-term consequences of disruptions during fetal brain development, particularly in primates, remain poorly understood. This study examines the effects of mid-term neurotropic infection within the context of normative structural and functional development using a macaque monkey model of fetal Zika virus infection (fZIKV).
Neurotropic infections, like Zika virus, can invade the brain with outcomes heavily influenced by developmental timing. First trimester infections have been linked to fetal loss and microcephaly, as seen in Congenital Zika Syndrome. In contrast, infections occurring in the mid-to-late trimesters often result in infants with normal appearing head sizes but an elevated risk of developmental delay [2].
The long-term consequences of disruptions during fetal brain development, particularly in primates, remain poorly understood. This study examines the effects of mid-term neurotropic infection within the context of normative structural and functional development using a macaque monkey model of fetal Zika virus infection (fZIKV).
Methods:
The study included 9 control and 10 fZIKV rhesus macaques infected at the beginning of the second trimester [3].
Structural MRI data were acquired at 6, 12, 18, and 24 months of age (~ age 2-8 years in human), including T1-w 3D MP-RAGE (res: 0.3x0.3x0.6mm3; TE/TR=3.7/2500ms; TI=1100ms, FA= 7), and T2-w (res: 0.4x0.4x0.8mm3; TE/TR=308/3000ms). Volumetric trajectories were evaluated by tissue type [4].
Functional MRI data were acquired at 12 and 24 months of age using a tactile stimulation paradigm [5]. A 10-minute functional scan was acquired (2D EPI; TE/TR = 24/2,300ms; res: 0.7×0.7×1.4mm³). This task activates a network of interoceptive-sensory brain regions, which show distinct responses to speed of tactile stimulation (slow: affective touch, fast: discriminative touch) [6].
Intracranial volume (ICV) and tissue type were regressed using linear mixed-effects models, with age and group (control vs fZIKV) as fixed effects and subject as random effect. Tactile response was analyzed with touch speed (fast vs slow), group (control vs fZIKV), and their interaction as fixed effects. Subject was modeled as a random effect with hemisphere nested within visit. Estimated marginal means (EMM) were calculated for post hoc comparisons.
Structural MRI data were acquired at 6, 12, 18, and 24 months of age (~ age 2-8 years in human), including T1-w 3D MP-RAGE (res: 0.3x0.3x0.6mm3; TE/TR=3.7/2500ms; TI=1100ms, FA= 7), and T2-w (res: 0.4x0.4x0.8mm3; TE/TR=308/3000ms). Volumetric trajectories were evaluated by tissue type [4].
Functional MRI data were acquired at 12 and 24 months of age using a tactile stimulation paradigm [5]. A 10-minute functional scan was acquired (2D EPI; TE/TR = 24/2,300ms; res: 0.7×0.7×1.4mm³). This task activates a network of interoceptive-sensory brain regions, which show distinct responses to speed of tactile stimulation (slow: affective touch, fast: discriminative touch) [6].
Intracranial volume (ICV) and tissue type were regressed using linear mixed-effects models, with age and group (control vs fZIKV) as fixed effects and subject as random effect. Tactile response was analyzed with touch speed (fast vs slow), group (control vs fZIKV), and their interaction as fixed effects. Subject was modeled as a random effect with hemisphere nested within visit. Estimated marginal means (EMM) were calculated for post hoc comparisons.
Results:
All tissue types except for CSF volume showed significant age-related effects. fZIKV subjects had smaller ICVs compared to controls; however, this difference did not survive correction for multiple comparisons (F(1)=4.36, P=0.0525). fZIKV subjects showed significantly increased gray matter volumes compared to controls (F(1)=7.39, P=0.0109). Conversely, white matter volumes were significantly smaller in fZIKV subjects (F(1)=9.84, P=0.0034). No group differences were found for subcortical gray matter or cerebrospinal fluid (CSF) volumes.
Similar to findings in adult monkeys, slow, or "affective" touch resulted in significantly increased activation than fast touch across all interoceptive regions. In the primary somatosensory cortex (SI), there was a significant interaction between touch speed and group (χ2(1) = 7.37, P = 0.007). This effect is further demonstrated by a post hoc comparison of estimated marginal means for control (slow: EMM =4.64 (0.41), fast: EMM = 4.07 (0.41)) versus fZIKV subjects (slow: EMM =4.30 (0.40), fast: EMM = 3.21 (0.40)).
Similar to findings in adult monkeys, slow, or "affective" touch resulted in significantly increased activation than fast touch across all interoceptive regions. In the primary somatosensory cortex (SI), there was a significant interaction between touch speed and group (χ2(1) = 7.37, P = 0.007). This effect is further demonstrated by a post hoc comparison of estimated marginal means for control (slow: EMM =4.64 (0.41), fast: EMM = 4.07 (0.41)) versus fZIKV subjects (slow: EMM =4.30 (0.40), fast: EMM = 3.21 (0.40)).
Conclusions:
Volumetric age-effects aligned with previous developmental literature in macaque and human (scaled for age) [7,8]. We observed an immature phenotype in the fZIKV group, with gray and white matter volumes lagging behind those of controls. For functional tactile development, fZIKV subjects had decreased touch response specifically in SI. In future work, we will investigate regional cortical trajectories in fZIKV to identify areas most vulnerable to disruptions in early development.
Disorders of the Nervous System:
Neurodevelopmental/ Early Life (eg. ADHD, autism) 1
Lifespan Development:
Normal Brain Development: Fetus to Adolescence 2
Modeling and Analysis Methods:
Activation (eg. BOLD task-fMRI)
Segmentation and Parcellation
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Anatomy and Functional Systems
Keywords:
ANIMAL STUDIES
Design and Analysis
Development
DISORDERS
Infections
MRI
Neurological
PEDIATRIC
Pediatric Disorders
STRUCTURAL MRI
1|2Indicates the priority used for review
Abstract Information
By submitting your proposal, you grant permission for the Organization for Human Brain Mapping (OHBM) to distribute your work in any format, including video, audio print and electronic text through OHBM OnDemand, social media channels, the OHBM website, or other electronic publications and media.
The Open Science Special Interest Group (OSSIG) is introducing a reproducibility challenge for OHBM 2025. This new initiative aims to enhance the reproducibility of scientific results and foster collaborations between labs. Teams will consist of a “source” party and a “reproducing” party, and will be evaluated on the success of their replication, the openness of the source work, and additional deliverables. Click here for more information. Propose your OHBM abstract(s) as source work for future OHBM meetings by selecting one of the following options:
Please indicate below if your study was a "resting state" or "task-activation” study.
Healthy subjects only or patients (note that patient studies may also involve healthy subjects):
Was this research conducted in the United States?
Are you Internal Review Board (IRB) certified? Please note: Failure to have IRB, if applicable will lead to automatic rejection of abstract.
Were any human subjects research approved by the relevant Institutional Review Board or ethics panel? NOTE: Any human subjects studies without IRB approval will be automatically rejected.
Were any animal research approved by the relevant IACUC or other animal research panel? NOTE: Any animal studies without IACUC approval will be automatically rejected.
Please indicate which methods were used in your research:
For human MRI, what field strength scanner do you use?
Which processing packages did you use for your study?
Provide references using APA citation style.
[2] Nielsen-Saines, K. et al. (2019). Delayed childhood neurodevelopment and neurosensory alterations in the second year of life in a prospective cohort of ZIKV-exposed children. Nature Medicine, 25(August). https://doi.org/10.1038/s41591-019-0496-1
[3] Coffey, L. L. et al (2018). Intraamniotic Zika virus inoculation of pregnant rhesus macaques produces fetal neurologic disease. Nature Communications, 9(1), 1–12. https://doi.org/10.1038/s41467-018-04777-6
[4] Lepage, C. et al. (2021). CIVET-Macaque: An automated pipeline for MRI-based cortical surface generation and cortical thickness in macaques. NeuroImage, 227, 117622. https://doi.org/10.1016/j.neuroimage.2020.117622
[5] Charbonneau, J. A., Santistevan, A. C., Raven, E. P., Bennett, J. L., Russ, B. E., & Bliss-Moreau, E. (2024). Evolutionarily conserved neural responses to affective touch in monkeys transcend consciousness and change with age. Proceedings of the National Academy of Sciences, 121(18), e2322157121. https://doi.org/10.1073/pnas.2322157121
[6] Charbonneau, J. A., Bennett, J. L., Chau, K., & Bliss-moreau, E. (2022). Reorganization in the macaque interoceptive-allostatic network following anterior cingulate cortex damage. Cerebral Cortex, 1–16.
[7] Alldritt, S et al. (2024). Brain Charts for the Rhesus Macaque Lifespan. https://doi.org/10.1101/2024.08.28.610193
[8] Bethlehem, R. A. et al. (2022). Brain charts for the human lifespan. Nature, 604(7906), 525–533. https://doi.org/10.1038/s41586-022-04554-y