Knowledge to improve long-term consequences of extremely preterm births and improve quality of life for our "smallest survivors”
Despite significant advances in perinatal care, children born extremely/very prematurely (EP/VP) still face a high risk of long-lasting motor, cognitive and mental impairments. Aim of the RJ Sabbatical is to analyses how neurobiological processes is reflected in sensorimotor and cognitive functions and to identify abnormalities related with early risk factors and health. Thus, gathered by using data from a recent follow-up study in which we investigated the effects of EP birth in children who reached the age of 12-y, and in comparison with children born at normal birth. All children included in this study followed since the newborn period, and tested on two previous occasions with extensive test battery, thus, to get information of the children's mental and physical health conditions over time. At the 12-year follow-up, advanced measurements of mobility (kinematics), and structural and functional brain imaging was included. My expectation is that such integrated, advanced examination methods and analyses enable improved interpretations of the relationship between brain structure/function and behavioral abnormalities/abilities. Such knowledge is of the utmost importance for improving diagnosis and creating a prerequisite for personalized treatments for this increasing group of children in focus. Research outputs produced during the planned RJ Sabbatical expected to generate new and important knowledge for the benefit of our "smallest survivors", their families and society.
Final report
Brain white matter injury (WMI) in neonates born preterm is well documented and found to be a major risk factor for long-term neurodevelopmental disabilities and disorders. Particularly in those born at extremely low age of gestation (22 - 27 weeks). Though, the knowledge how very-/extremely preterm births generating long lasting (chronic) disturbances of white matter myelination and structural organization and connectivity that may associate with impaired and/or adverse cognitive and sensory-motor functions in preterm born children is still limited. Thus, there is a need for more detailed understanding of how a very (VP)/extremely preterm (EP) birth affects long-term neurodevelopment and behaviors. The main aim of the present project was to further investigate the potential long-lasting consequences of varied degree of VP/EP birth may have on the evolving brain white matter macro- and microstructure; volumetrics, organization, connectivity and myelination, and its role on acquired motor and cognitive functions in children when at 8- and 12-year of age. The focus has been to increase our understandings how the brain regions and networks affected by VP/EP birth associate to long-lasting cognitive and motor impairments and/or diversities in comparison to children born at term. Furthermore, to bring further knowledge and provide support for evaluation of different interventional strategies.
Method: In the present project we applied multi-parametric brain imaging approach, by use of 3-Tesla MRI measurement including Diffusion Tensor Imaging (DTI) and Synthetic MRI (SyMRI). The DTI to provide sensitive analysis of white matter microstructure variations and diversities (i.e., architecture and density), generated from fractional anisotropy (FA), mean diffusivity (MD), axial- (AD), and radial diffusivity (RD) measurements. The SyMRI used to measure myelin content and intracranial volumes (ICV), brain parenchyma volume (BPV), white matter volume (WM), grey matter volume (GM), and cerebrospinal fluid (CSF). SyMRI is based on multi-parametric measurements using spin-echoes; using simultaneous T1, T2, and proton density quantification to model the myelin volume fraction and the absolute tissue properties of the brain that enable calculation of myelin correlated volumes. Additionally, to investigate possible effects of gestational age (GA), as well as different pre- and perinatal risk-factors (based on medical record) in relationship with functional performance and abilities at the children’s testing age, high-resolution 3D-movement registrations, assessments of functional laterality, and cognitive performances (by Wechsler Intelligence Scale for Children, 4th edition (WISC-IV), including composite scores of Verbal Comprehension, Perceptual Reasoning, Working Memory, Processing Speed, and Full-scale IQ (FSIQ) was carried out and analyzed. For the cohort including extremely-preterm-born children and term born age-matched peers when at 12-years of age, the WISC-V and the Visio-Motor-Integration test (Beery-VMI) was additionally applied.
The main results showed that both global as well as more specific brain white matter properties associated significantly with the degree of prematurity at birth. On group level, the overall total intracranial volume and cortical volume (ICV and BPV), and the Cerebellum volume in EP-born children was significantly smaller and with less GM, WM (even when corrected for total brain volume), and with increased CSF (indication inflated ventricles), in comparison to FT-born. Gestational age (GA) at birth correlated positively with brain volumes, myelin, and IQ; for EP, myelin correlated positively with GA, IQ, and visuomotor integration. At 12-y the EP born exhibited significantly increased mean total MD, RD, and AD than FT, but no significant group-difference for mean total FA. Although Myelin correlated positively with FA and negatively with MD, RD and AD within the EP-group. Moreover, in specific brain regions such as the Corpus Callosum (CC-genu, CC-body, and CC-splenium; the key tracks to long-distance inter-hemispheric connectivity), Internal Capsule, Posterior Limb was found less myelinated (lower FA-values and higher RD) in children born EP. The EP born was also found to have poorer sensory-motor and cognitive functions, which can be traced to white matter diffuse lesions with lower FA in high order systems.The involvement of diffusional aberrations in higher order motor-sensory pathways in the EP born children suggest that altered brain microstructure play a role in the neurodevelopmental outcomes for both cognition and sensory-motor functions. In line with these findings, the cognitive functions of the EP born when at 12-years of age was poorer when compared to earlier observations with EP and VPT combined groups at 8-years of age. Full scale IQ, as well as the WISC-V composite scores was also lower for the EP compared to earlier analysis of combined groups, and the difference compared to the age matched term born children was greater. Findings of affected Visio-Motor-Integration scores also support the idea of EP born having an altered ability to process and integrate sensory-motor information. These results confirm the high-risk for long-term widespread WM alterations and diffuse white -matter injury (WMI) in the very- and extremely preterm born children.
Overall, the results are consistent with the hypothesis that an extremely/very preterm birth affect brain maturation and white matter myelination, leading to long-term changes that affect EP born children way beyond infancy. Our findings signifying that even in the absence of overt brain lesions, (i.e., intraventricular hemorrhage as neonates and/or cerebral pares) an extreme-/very preterm birth are associated with long-lasting, widespread diffuse brain white matter abnormality. This was confirmed by decreased myelin, diversity affecting axon morphology and density, and increasing representation of aberrant microstructural inter-hemispheric connectivity and lateralization, particularly in EP born children. Additionally, the findings of brain white matter abnormality and less myelin content also associated with neurodevelopmental adversity indicated by poorer cognitive and motor functions in the very- and extremely-preterm-born children; i.e., lower FIQ scores (even on the sub-scores level); poorer sensory-motor integration; and sub-optimal 3D movement kinematics found of the upper-limb movement organization and performance (e.g., indicate longer onset latency indicating slower movement initiation and planning, and more segmented movements, and less synchronized bimanual movement performances). Taken together, this suggest that a very- and extremely early birth (22-27-32 weeks GA; the timeline of the late second and third trimester – one of the most sensitive and vulnerable period of early brain development (*Liu XS et al., 2013)) most likely is one of the main causes for long-lasting adversities of brain white matter myelination, and thus, the explanation of the motor and cognitive functional adversities observed in children born EPT/VPT in comparison to full term born. These findings also stress the importance of investigating more refine, sensory-motor integrated functions i.e., action planning and performance difficulties/diversity in children born preterm with high-risk for diffuse white matter injuries (WMI). Thus, by combining detailed 3D measurements with advanced multi-modal brain imaging techniques for more refine analysis of sensory-motor organizations and diversities. The findings may have clinical implications by survey presence and degree of WMI in preterm born children. In addition, the multimodal method may be useful for evaluating the effects of different interventions intended to increase brain myelination and neuronal connectivity and thus, to improve of cognitive and sensorimotor functions/abilities at different developmental stages.
*Liu XB, Shen Y, Plane JM and Deng W. Vulnerability of premyelinating oligodendrocytes to white-matter damage in neonatal brain injury. Neurosci Bull 29: 229-238, 2013.
What the project has resulted in in addition to the publications:
The possibility to facilitate multidisciplinary international and national collaboration between scientists, clinicians and others with the focus on increasing our knowledge on preterm born children’s brain care – behaviors – and specific needs.
The results generated within this project also highlight the need for further research to better understand the dynamics (moderating and mediating variable) among individual effects of risk- and environmental factors that may influence neuropsychiatric and mental health in extremely-preterm-born children. Further studies may also link brain volumetric, myeline and WM morphometric findings with brain function acquired from functional MRI (fMRI) data and from behavioral and/or mental health assessments. Children born extremely/very preterm have also been found with an increased risk developing mental health problems and disorders (e.g., *Domellöf et al., 2020) and with an increased risk for autism spectrum disorder (ASD) and attention-deficit / hyperactivity disorder (ADHD). A recent meta-analysis (**Agrawal S. et al., 2018), reporting a preterm ASD prevalence of 7% (SI 4%–9%), which is more than three times higher than in the general population, and a likelihood that this tends to increase with GA decrease. The question of interest to further investigate is how brain structure and function on MRI measures differ in children born EP with autism spectrum disorder (ASD) in comparison to age matched EP without ASD, and children born at term with ASD. By investigate brain myelin changes at both global and microstructural level and to compare the congruency of the novel SyMRI–based myelin estimation with established DTI-derived parameters and functional MRI (fMRI). Furthermore, to investigate the relationship between significant myelin content alterations, core symptom severity level associated with ASD (i.e., difficulties with social interactions and communication, restricted interests and repetitive behaviors), and cognitive and sensory-motor functions. The use of multimodal neuroimaging to examination of various aspects of the brain is expected to enable identifying neuropathological mechanism related to ASD behavior symptoms and level of severities.
* Domellöf, E., Johansson, A-M., Farooqi, A., Domellöf, M., & Rönnqvist. L. Risk for behavioral problems independent of cognitive functioning in children born at low gestational ages. Frontiers in Pediatrics, section Children and Health, 2020; 8, 1-11.
**Agrawal S, et al., Prevalence of autism spectrum disorder in preterm infants: a meta-analysis. Pediatrics. 2018; 142(3).
How the results have been disseminated and how the collaboration has taken place:
To stimulate interdisciplinary and international networking within the framework of the project, two visits were made (during 2022) at the Integrative Neuroscience and Cognition Center (INCC), Université Paris Cité, and at CEA, NeuroSpin UNIACT, Gif-sur-Yvette, Paris. This is to further exchange knowledge with Dr. Jessica Dubois and co-workers, whose research concerns early organization and maturation of the brain white matter, and method development/analyses of subcortical structures and the brain's surface-based morphometry in preterm and term bon infants. Thus, to further refine and develop new analysis methods/models for studies of how the child's brain develops in association with behavioral acquisition, and how these processes can be disrupted by several circumstances and early risk factors. During the same visits I go to see Professor Jacqueline Fagard and collaborators working at Université Paris Cité, French Institute of Health and Medical Research, and Université Descartes, with a focus on studies/collaboration regarding method applications and developmental aspects of laterality abnormalities related to language and motor development in premature infants and in children with congenital developmental disorders.
Moreover, within the framework of the project I participated in 5-Modul Brain Webinars arranged by the Union of European Neonatal & Perinatal Societies (UENPS), with the focus on discussion and information about early brain development and deviations. UENPS mission is to advance brain care through international multidisciplinary collaboration, education, and innovation. The UENPS 5-Modul Brain Webinars topics: UENPS 5-Modul Brain Webinars topics: Module 1, February 14th, 15th, 16th, 2022 - GERMINAL MATRIX AND SURROUNDINGS, Titles: “Intravenrticular heamorrhage (IHV) thought different gestational ages”; “Why the hemorrhage?”; “How does the brain of premature babies respond to IHV”. Module 2 - CEREBELLUM, April 11th, 12th, 13th, 2022, Titles: “The neonatal cerebellum from a neuroscience perspective”; “Imaging of the posterior fossa in the newborn”; “Advanced MR imaging of the preterm cerebellum and long-term outcome “. Module 3, June 13th, 14th, 15th, 2022 - WHITE MATTER DEVELOPMENT IN PRETERM BABIES THE IMPORTANCE OF CONNECTIVITY, Titles: “Why is WM so vulnerable”; “WMI, imaging and early outcome”; “Adult outcomes after extremely preterm birth - influence of neonatal brain injury”. Module 4, September 12th, 13th, 14th, 2022- TECHNOLOGIES IN NEONATAL NEUROLOGY, Titles: “MRI and HIE mimics”; “Role of advanced MR techniques in assessing brain development”; “EEG in the NICU in the 21st century”. Module 5, November 21st, 22nd, 2022 - NEONATAL STROKE and Hypoxic-Ischemic Encephalopathy (HIE) IN THE TERM NEWBORN, Titles: “Perinatal arterial ischemic stroke”; “Long term outcome in HIE”.
The results generated within the project have been presented at:
The Fetal and Neonatal Neurology meeting - From basic science to clinical application, The Union of European Neonatal & Perinatal Societies, M.A.C. scientific event (online), May 2021. The 34th annual meeting of the European Academy of Childhood Disability (EACD) Barcelona, Spain, May 2022. The NeuroSpin center, Paris-Saclay, France, during the visit in Paris, October 2022.
Own website: https://www.umu.se/personal/louise-ronnqvist/
Method: In the present project we applied multi-parametric brain imaging approach, by use of 3-Tesla MRI measurement including Diffusion Tensor Imaging (DTI) and Synthetic MRI (SyMRI). The DTI to provide sensitive analysis of white matter microstructure variations and diversities (i.e., architecture and density), generated from fractional anisotropy (FA), mean diffusivity (MD), axial- (AD), and radial diffusivity (RD) measurements. The SyMRI used to measure myelin content and intracranial volumes (ICV), brain parenchyma volume (BPV), white matter volume (WM), grey matter volume (GM), and cerebrospinal fluid (CSF). SyMRI is based on multi-parametric measurements using spin-echoes; using simultaneous T1, T2, and proton density quantification to model the myelin volume fraction and the absolute tissue properties of the brain that enable calculation of myelin correlated volumes. Additionally, to investigate possible effects of gestational age (GA), as well as different pre- and perinatal risk-factors (based on medical record) in relationship with functional performance and abilities at the children’s testing age, high-resolution 3D-movement registrations, assessments of functional laterality, and cognitive performances (by Wechsler Intelligence Scale for Children, 4th edition (WISC-IV), including composite scores of Verbal Comprehension, Perceptual Reasoning, Working Memory, Processing Speed, and Full-scale IQ (FSIQ) was carried out and analyzed. For the cohort including extremely-preterm-born children and term born age-matched peers when at 12-years of age, the WISC-V and the Visio-Motor-Integration test (Beery-VMI) was additionally applied.
The main results showed that both global as well as more specific brain white matter properties associated significantly with the degree of prematurity at birth. On group level, the overall total intracranial volume and cortical volume (ICV and BPV), and the Cerebellum volume in EP-born children was significantly smaller and with less GM, WM (even when corrected for total brain volume), and with increased CSF (indication inflated ventricles), in comparison to FT-born. Gestational age (GA) at birth correlated positively with brain volumes, myelin, and IQ; for EP, myelin correlated positively with GA, IQ, and visuomotor integration. At 12-y the EP born exhibited significantly increased mean total MD, RD, and AD than FT, but no significant group-difference for mean total FA. Although Myelin correlated positively with FA and negatively with MD, RD and AD within the EP-group. Moreover, in specific brain regions such as the Corpus Callosum (CC-genu, CC-body, and CC-splenium; the key tracks to long-distance inter-hemispheric connectivity), Internal Capsule, Posterior Limb was found less myelinated (lower FA-values and higher RD) in children born EP. The EP born was also found to have poorer sensory-motor and cognitive functions, which can be traced to white matter diffuse lesions with lower FA in high order systems.The involvement of diffusional aberrations in higher order motor-sensory pathways in the EP born children suggest that altered brain microstructure play a role in the neurodevelopmental outcomes for both cognition and sensory-motor functions. In line with these findings, the cognitive functions of the EP born when at 12-years of age was poorer when compared to earlier observations with EP and VPT combined groups at 8-years of age. Full scale IQ, as well as the WISC-V composite scores was also lower for the EP compared to earlier analysis of combined groups, and the difference compared to the age matched term born children was greater. Findings of affected Visio-Motor-Integration scores also support the idea of EP born having an altered ability to process and integrate sensory-motor information. These results confirm the high-risk for long-term widespread WM alterations and diffuse white -matter injury (WMI) in the very- and extremely preterm born children.
Overall, the results are consistent with the hypothesis that an extremely/very preterm birth affect brain maturation and white matter myelination, leading to long-term changes that affect EP born children way beyond infancy. Our findings signifying that even in the absence of overt brain lesions, (i.e., intraventricular hemorrhage as neonates and/or cerebral pares) an extreme-/very preterm birth are associated with long-lasting, widespread diffuse brain white matter abnormality. This was confirmed by decreased myelin, diversity affecting axon morphology and density, and increasing representation of aberrant microstructural inter-hemispheric connectivity and lateralization, particularly in EP born children. Additionally, the findings of brain white matter abnormality and less myelin content also associated with neurodevelopmental adversity indicated by poorer cognitive and motor functions in the very- and extremely-preterm-born children; i.e., lower FIQ scores (even on the sub-scores level); poorer sensory-motor integration; and sub-optimal 3D movement kinematics found of the upper-limb movement organization and performance (e.g., indicate longer onset latency indicating slower movement initiation and planning, and more segmented movements, and less synchronized bimanual movement performances). Taken together, this suggest that a very- and extremely early birth (22-27-32 weeks GA; the timeline of the late second and third trimester – one of the most sensitive and vulnerable period of early brain development (*Liu XS et al., 2013)) most likely is one of the main causes for long-lasting adversities of brain white matter myelination, and thus, the explanation of the motor and cognitive functional adversities observed in children born EPT/VPT in comparison to full term born. These findings also stress the importance of investigating more refine, sensory-motor integrated functions i.e., action planning and performance difficulties/diversity in children born preterm with high-risk for diffuse white matter injuries (WMI). Thus, by combining detailed 3D measurements with advanced multi-modal brain imaging techniques for more refine analysis of sensory-motor organizations and diversities. The findings may have clinical implications by survey presence and degree of WMI in preterm born children. In addition, the multimodal method may be useful for evaluating the effects of different interventions intended to increase brain myelination and neuronal connectivity and thus, to improve of cognitive and sensorimotor functions/abilities at different developmental stages.
*Liu XB, Shen Y, Plane JM and Deng W. Vulnerability of premyelinating oligodendrocytes to white-matter damage in neonatal brain injury. Neurosci Bull 29: 229-238, 2013.
What the project has resulted in in addition to the publications:
The possibility to facilitate multidisciplinary international and national collaboration between scientists, clinicians and others with the focus on increasing our knowledge on preterm born children’s brain care – behaviors – and specific needs.
The results generated within this project also highlight the need for further research to better understand the dynamics (moderating and mediating variable) among individual effects of risk- and environmental factors that may influence neuropsychiatric and mental health in extremely-preterm-born children. Further studies may also link brain volumetric, myeline and WM morphometric findings with brain function acquired from functional MRI (fMRI) data and from behavioral and/or mental health assessments. Children born extremely/very preterm have also been found with an increased risk developing mental health problems and disorders (e.g., *Domellöf et al., 2020) and with an increased risk for autism spectrum disorder (ASD) and attention-deficit / hyperactivity disorder (ADHD). A recent meta-analysis (**Agrawal S. et al., 2018), reporting a preterm ASD prevalence of 7% (SI 4%–9%), which is more than three times higher than in the general population, and a likelihood that this tends to increase with GA decrease. The question of interest to further investigate is how brain structure and function on MRI measures differ in children born EP with autism spectrum disorder (ASD) in comparison to age matched EP without ASD, and children born at term with ASD. By investigate brain myelin changes at both global and microstructural level and to compare the congruency of the novel SyMRI–based myelin estimation with established DTI-derived parameters and functional MRI (fMRI). Furthermore, to investigate the relationship between significant myelin content alterations, core symptom severity level associated with ASD (i.e., difficulties with social interactions and communication, restricted interests and repetitive behaviors), and cognitive and sensory-motor functions. The use of multimodal neuroimaging to examination of various aspects of the brain is expected to enable identifying neuropathological mechanism related to ASD behavior symptoms and level of severities.
* Domellöf, E., Johansson, A-M., Farooqi, A., Domellöf, M., & Rönnqvist. L. Risk for behavioral problems independent of cognitive functioning in children born at low gestational ages. Frontiers in Pediatrics, section Children and Health, 2020; 8, 1-11.
**Agrawal S, et al., Prevalence of autism spectrum disorder in preterm infants: a meta-analysis. Pediatrics. 2018; 142(3).
How the results have been disseminated and how the collaboration has taken place:
To stimulate interdisciplinary and international networking within the framework of the project, two visits were made (during 2022) at the Integrative Neuroscience and Cognition Center (INCC), Université Paris Cité, and at CEA, NeuroSpin UNIACT, Gif-sur-Yvette, Paris. This is to further exchange knowledge with Dr. Jessica Dubois and co-workers, whose research concerns early organization and maturation of the brain white matter, and method development/analyses of subcortical structures and the brain's surface-based morphometry in preterm and term bon infants. Thus, to further refine and develop new analysis methods/models for studies of how the child's brain develops in association with behavioral acquisition, and how these processes can be disrupted by several circumstances and early risk factors. During the same visits I go to see Professor Jacqueline Fagard and collaborators working at Université Paris Cité, French Institute of Health and Medical Research, and Université Descartes, with a focus on studies/collaboration regarding method applications and developmental aspects of laterality abnormalities related to language and motor development in premature infants and in children with congenital developmental disorders.
Moreover, within the framework of the project I participated in 5-Modul Brain Webinars arranged by the Union of European Neonatal & Perinatal Societies (UENPS), with the focus on discussion and information about early brain development and deviations. UENPS mission is to advance brain care through international multidisciplinary collaboration, education, and innovation. The UENPS 5-Modul Brain Webinars topics: UENPS 5-Modul Brain Webinars topics: Module 1, February 14th, 15th, 16th, 2022 - GERMINAL MATRIX AND SURROUNDINGS, Titles: “Intravenrticular heamorrhage (IHV) thought different gestational ages”; “Why the hemorrhage?”; “How does the brain of premature babies respond to IHV”. Module 2 - CEREBELLUM, April 11th, 12th, 13th, 2022, Titles: “The neonatal cerebellum from a neuroscience perspective”; “Imaging of the posterior fossa in the newborn”; “Advanced MR imaging of the preterm cerebellum and long-term outcome “. Module 3, June 13th, 14th, 15th, 2022 - WHITE MATTER DEVELOPMENT IN PRETERM BABIES THE IMPORTANCE OF CONNECTIVITY, Titles: “Why is WM so vulnerable”; “WMI, imaging and early outcome”; “Adult outcomes after extremely preterm birth - influence of neonatal brain injury”. Module 4, September 12th, 13th, 14th, 2022- TECHNOLOGIES IN NEONATAL NEUROLOGY, Titles: “MRI and HIE mimics”; “Role of advanced MR techniques in assessing brain development”; “EEG in the NICU in the 21st century”. Module 5, November 21st, 22nd, 2022 - NEONATAL STROKE and Hypoxic-Ischemic Encephalopathy (HIE) IN THE TERM NEWBORN, Titles: “Perinatal arterial ischemic stroke”; “Long term outcome in HIE”.
The results generated within the project have been presented at:
The Fetal and Neonatal Neurology meeting - From basic science to clinical application, The Union of European Neonatal & Perinatal Societies, M.A.C. scientific event (online), May 2021. The 34th annual meeting of the European Academy of Childhood Disability (EACD) Barcelona, Spain, May 2022. The NeuroSpin center, Paris-Saclay, France, during the visit in Paris, October 2022.
Own website: https://www.umu.se/personal/louise-ronnqvist/