Brain Dysmaturation After Very Preterm Birth: A Progressive And Long-Term Challenge

July 2024

Introduction

This Commentary was stimulated by a recent report published in April in Brain.1 The report addresses cerebral cortical growth in very preterm (VPT) and term born (TB) children followed to adolescence and studied by advanced MRI techniques. A major strength of the study is its standing as the first longitudinal study of the same population of VPT and TB individuals from birth to adolescence. The work is notable for insights into normal cortical development in TB infants, disturbances of this development in VPT infants, and the course of these disturbances through childhood and adolescence. The data raise important questions concerning the cellular and mechanistic bases for the cortical disturbances and, critically, concerning the long-term neurological implications for survivors of VPT birth.

Cerebral Cortical Development from Birth to Adolescence in VPT and TB Infants

This unique study (the Victorian Infant Brain Study) concerned infants born between 2001-2004 and included 201 infants born VPT (<30 weeks gestation or <1250 g birth weight) and 66 TB infants. The VPT infants had “no major neonatal brain injuries.” Advanced MRI methodologies allowed assessments of cerebral cortical volume, area and thickness for 62 cortical regions at term, 7 years, and 13 years.

Cerebral Cortical Development in TB Infants 

In TB infants, from term to 7 years, developmental changes in 62 cortical regions consisted, generally, of large increases in cortical volume, area and thickness (375%, 147%, and 78%, respectively). However, notably, from 7 years to 13 years, generally only minor increases or slight decreases were found. It is beyond the scope of this Commentary to discuss regional differences in detail, but the general theme of pronounced increases to mid childhood and subsequent stabilization or slight decreases to adolescence is apparent.

The anatomical correlates of these cortical developmental changes are not entirely known, but for the increases during later infancy and early childhood, available data indicate importance for pronounced axonal input to cortex, cortical dendritic development, synaptogenesis, and intracortical (and likely immediate subcortical) myelination.2-6 A detailed study of human parietal cerebrum with markers of axonal growth and elongation (GAP-43) and axonal maturity (Anti-SMI31) indicates rapid axonal growth in white matter during the preterm period, and in cerebral cortex in the first two years of life.2 Presumably this axonal input into cortex leads to activity-dependent development of cortical dendritic arbors.3,7,8 The classic studies of Huttenlocher and Rakic show that this axonal-dendritic development is followed in cortex by synaptogenesis, with an excess of synapses apparent in mid-childhood in multiple cortical areas.9-12 Later in childhood and into adolescence, synapse elimination is active, and this pruning may be important in the plateau (and the modest decline) in cortical volume and thickness observed by MRI by Kelly et al.1 However, anatomical studies show that myelination of the cortical neuropil and subcortical association areas also becomes prominent in late infancy and early childhood and continues beyond adolescence.13-16 This process likely contributes to the increase in both cortical volume and thickness observed by MRI into childhood.1

Cerebral Cortical Development in VPT Infants

As previously described,17,18 at term-equivalent age VPT infants already exhibited abnormalities of cerebral cortical development, especially lower cortical volume and area.1 From 0-7 years, the volume differences between VPT and TB infants became more pronounced, especially in higher-order frontal, temporal and parietal regions. Earlier work by the same group, utilizing a voxel-based (rather than surface-based) approach, had shown that the lower brain volume in VPT infants becomes more exaggerated between ages 0-7 years, particularly in temporal regions.19,20 The current approach, which allowed fractionation of cortical volume, provided the new insight that the increasingly lower volume in temporal regions in the childhood years is related principally to increasingly lower cortical thickness. Accompanying the latter was persistently reduced cortical area. By the age 13 measurements, values in VPT infants for volumes, area and thickness had nearly plateaued and were persistently lower than in TB infants. No evidence of catch-up was apparent, and indeed pronounced differences between VPT and TB cortical regions persisted. These findings may have major implications for longer-term follow-up (see later).

The anatomical correlates and cellular mechanisms underlying the apparent impairment in cortical development in survivors of VPT birth remain to be elucidated. However, a superb earlier study by the same group provides excellent clues.21 Assessing the same cohort as in the current cortical study, Kelly et al. utilized advanced diffusion MRI analyses, i.e., fixel-based analysis (FBA), to evaluate the long-term development of white matter microstructure. The principal findings were that at ages 7 and 13 VPT children, when compared to TB children, exhibited axonal reductions in many white matter fiber tracts and slower axonal growth in several areas. Degenerative axonal changes have been documented in VP infants with cerebral white matter injury,2 and in the study of Kelly et al., white matter abnormalities were modestly associated with the axonal deficits.21 Notably, however, impairments of axonal development and function have been shown to occur with even milder white matter abnormalities, not readily visible by early-life MRI.17 Such impairment is likely related to the principal cellular abnormality in cerebral white matter injury, i.e., impaired pre-oligodendrocyte (pre-OL) differentiation with failure of oligodendroglial ensheathment of axons.17 This failure would be expected to lead to impaired axonal function, and thereby impaired activity-dependent cerebral cortical differentiation, as described in the previous section. Similarly, impaired intracortical myelination, a process that occurs over many years in childhood, adolescence and adulthood,13 would be affected.

The possibility that impaired cortical neuronal development, as delineated in the study of Kelly et al.,1 represents a primary neuronal dysmaturation, rather than a dysmaturation secondary to altered axonal and oligodendroglial-myelin development as just outlined, needs consideration. An excellent clinical study, involving 95 VPT infants studied by diffusion-based MRI at two time points (32 and 40 weeks post-conceptional age), provided evidence for delayed microstructural development of cerebral cortex (in association with impaired somatic growth), but cerebral white matter appeared unaffected.22 Similarly consistent with primary neuronal dysmaturation, two careful experimental studies, utilizing a well characterized fetal sheep model, showed disturbances in cortex, in dendritic development and synapse formation, and in subplate neurons, in dendritic arborization and synaptic activity, four weeks after a hypoxic-ischemic insult.23,24 Available data in the population studied by Kelly et al.1 suggest that such insults were not likely in their population. A later investigation in the same animal model showed that even a brief hypoxic episode led four weeks later to disturbances of basal and apical dendritic arborization of hippocampal CA1 neurons and impaired connectivity.25 (Such brief hypoxic events, common in VPT infants, likely would not have been detected or quantitated in the study of Kelly et al.1) Importantly, in the animal model the neurophysiological correlate of memory formation, a hallmark of hippocampal function, was impaired in hippocampus.25 Notably, disturbances of working memory have been documented in survivors of VPT birth.26

Long-Term Implications of Disturbed Cerebral Cortical Development in VPT Infants

The current study raises the question of the impact of the magnitude and evolution of the cortical structural deficits found by age 13 in VPT infants by Kelly et al.1 on later neurological outcomes. Clearly the latter study will be at the vanguard of this quest. Current information raises interesting and concerning questions.

Impact of Cerebral Cortical Disturbance on Childhood Neurological Outcomes

As noted in the study of Kelly et al.,1 alterations in frontal and temporal regions are prominent in the VPT infants at childhood age. Previous work has shown that morphological alterations in these regions in VPT children are associated with lower IQ and deficits in language and executive function.27-29 Notably, the hippocampus, an important component of temporal cortex, has been shown to be smaller, straighter and with less infolding in adolescents and young adults after VPT birth.29-31 The findings were related to memory deficits.

Impact of Cerebral Cortical Disturbance on Adult Neurological Outcomes

The possible relation of the cortical disturbances in survivors of VPT birth, especially involving temporal cortex, to still later neurological outcomes should be considered. Thus, Heinonen et al.32 studied 919 Finnish men and women born between 1934 and 1944 as late preterms (34 to 36-6/7 weeks gestational age) and evaluated at 68.1 years of age. Among those who had attained a basic or upper secondary education, late preterm birth was associated with lower scores on multiple cognitive sub-tests and a 2.70 times higher risk of mild cognitive impairment. Among those with tertiary levels of education, late preterm birth was not associated with such deficits. The authors concluded that late preterm birth should be added as “a novel risk factor to the list of neurocognitive impairment in late adulthood.” They also raise the possibility that “lifetime education may mitigate aging-related neurocognitive impairment among those born late preterm.” Although a number of questions could be raised about the study, the findings are noteworthy.

A later MRI study33 of 260 VPT and 229 TB individuals at age 26 years showed MRI features of increased “brain age” in the VPT individuals. Details are beyond the scope of this Commentary, but the morphological difference is interesting. Additionally noteworthy, in older individuals a relationship between increased brain age and dementia has been observed. One potential importance of this observation in this context is that aggregation of tau protein in neurons, a key feature in Alzheimer’s disease, begins in peripheral dendrites and thereby might reach the cell body more rapidly in underdeveloped dendrites, as described earlier in the studies of VPT infants.33

Consistent with these reports, a study of 70 VPT and 67 TB adults identified aberrant connectivity between thalamus and temporal and prefrontal cortices.34 Impairments in verbal cognitive abilities were also observed in the PT adults.

Another study focused on the claustrum, a structure critical in a variety of cognitive functions, in 70 VPT adults and 87 TB adults and found increased diffusivity in the former individuals. Reduced IQ also was observed in the VPT adults.35

Finally, a large literature has focused on the potential relationship between early life stresses and risk of Alzheimer’s disease (see, for review,36). VPT birth is not discussed separately, but many of the “stresses” considered important are characteristic of the premature period and subsequent infancy-childhood. Of particular note, as noted earlier, the cortical areas particularly characterized by aberrant development in VPT infants, children and adolescents, i.e., temporal cortex, hippocampus, are the areas initially and particularly affected by the neuropathology of Alzheimer’s dementia.

Potentially Additive or Potentiating Factors in Long-Term Neurological Outcome in VPT Infants

Although the previous sections have emphasized the long-term implications of the disturbances in cerebral cortical development in VPT children and adolescents, certain non-neurological factors may enhance the possibility of subsequent impairments in neurological outcome. These factors concern cardiac function and cerebrovascular disease. A recent review has focused on factors associated with preterm birth, such as reduced cardiac reserve, smaller left and right ventricular volumes, decreased vascularity, increased vascular stiffness and higher pressure of both the pulmonary and systemic vasculatures.37 In a nationwide Swedish study that included 73,489 adults who were born <37 weeks gestation,38 among those born before 32 weeks gestation, a nearly two-fold increased risk of cerebrovascular disease was observed compared to TB individuals. In a more recent report, also from Sweden, among individuals at ages 18-43 years, when compared with TB infants, the adjusted hazard ratio for stroke associated with preterm birth (<37 weeks gestation) was 1.26 (95% C.I., 1.12-1.43, P<0.001) and when further stratified, was 1.42 (1.11-1.85, P=0.005) for early preterm (22-33 weeks) and 1.22 (1.06-1.40, P=0.004) for late preterm (34-36 weeks).39

Conclusions

The recent report of Kelly et al.1 establishes broad and important points concerning cerebral cortical development in survivors of VPT birth. First, relative to TB infants, cortical development is abnormal, not only at term (as previously reported many times), but progressively so subsequently, at least into late childhood and adolescence, and perhaps beyond. Second, the cellular mechanisms underlying the apparent progression of dysmaturation, although not fully known, appear to reflect a cascade of developmental disturbances, with abnormalities of white matter axons and immature oligodendrocytes likely important at the onset. Additionally, data from other studies suggest that the cortical dysmaturational events may render the brain of the VPT infant more susceptible to later neurodegenerative disorders. Finally, abnormalities of cerebrovascular development may aggravate or render the VPT brain vulnerable to later degenerative or destructive effects.

How to prevent or ameliorate this cascade of dysmaturation and disability? It is beyond the scope of this Commentary to address this key question. However, the potential for beneficial intervention is great, especially in early childhood years, before pronounced deficits are established. For lack of a better word, I have termed these “neurorestorative interventions.”17 Many can be established readily in the neonatal period, such as minimization of pain and stress, provision of optimal nutrition (breast feeding, optimal quality and source of milk, etc.), attention to experiential factors (relating to auditory, verbal and visual input), parenting, family-based interventions, socioeconomic factors and later, educational opportunities.29

Finally, in view of the life-long course of neurologic and related challenges, interventions need to be continued through adult years. With the increasing recognition of the importance of lifestyle changes and perhaps specific drugs to prevent later neurodegenerative disorders,40,41 caregivers beyond the neonatal and pediatric years should be made aware of the long-term challenges potentially faced by survivors of preterm birth. In my view, it behooves those of us who focus on newborn brain disease to alert pediatricians and later caregivers concerning the potential health hazards that survivors of VPT birth may face.

Joseph J. Volpe, MD

Department of Neurology, Boston Children’s Hospital

Bronson Crothers Professor of Neurology, Emeritus, Harvard Medical School

Boston MA

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