Inconsistent Predictive Value Of MRI In Early Infancy After Neonatal HIE: Dysmaturation May Be The Explanation

September 2024

Introduction

Many studies have addressed the potential value of MRI in early infancy (beyond the neonatal period) for prediction of later neurodevelopmental outcome in term infants with neonatal hypoxic-ischemic encephalopathy (HIE) (see for reviews1,2). Although severe lesions (especially those involving such deep nuclear structures as thalamus and basal ganglia) are associated clearly with unfavorable outcomes, such lesions involve the small minority of infants and are generally detectable in the neonatal period.3,4 There is a larger proportion of infants who will later exhibit neurodevelopmental abnormality (particularly, cognitive impairments) but who do not show severe lesions in the neonatal period. Indeed, in a recent study of 451 term infants with HIE, infants with no injury on MRI at a median age of 5 days had similar cognitive, language and motor impairment scores as those infants with observable injury.3 A reasonable question is whether such infants with only mild or moderate or perhaps no observable neonatal injury might exhibit prognostically important structural abnormalities later, e.g., three months of age. Detection of structural abnormalities in early infancy, e.g., three months of age, is desirable for many reasons. The most important of these reasons is identification of those infants who should receive therapies to enhance neurodevelopmental potential (see later). The focus of this Commentary is this large proportion of infants with neonatal HIE who later exhibit neurodevelopmental impairment, but without severe neonatal brain injury.

Brain Abnormalities Identified on Late MRI Studies

Approximately 20 reports over the past 34 years have reported MRI data obtained in the months after neonatal HIE (see Table 1 in Sotelo et al.2). In general (see later for a few exceptions), compared to neonatal MRI data, later conventional MRIs do not consistently show more clearly useful information regarding prediction of later neurodevelopmental impairment. Severe neurological deficits involving motor (“cerebral palsy”) and cognitive functions are predicted by overt injury (usually necrosis) to deep nuclear structures (e.g., thalamus, putamen) or cerebral cortex or both. However, as just noted, these lesions generally are identified readily in the neonatal period and occur in only a small minority of current survivors of neonatal HIE.

The principal late MRI findings in the first postnatal months among the large majority of survivors without overt necrotic lesions have included signal abnormalities in cortex, deep nuclear structures and cerebral white matter, often with modest increases in lateral ventricular size or extracerebral space or both. The anatomic bases generally have been considered to be related to “Wallerian degeneration” and “atrophy.” Thus, in essence, the concept has been that the infant sustained a neonatal hypoxic-ischemic injury with cellular/tissue loss and that subsequent anatomic and neurodevelopmental findings are secondary to this loss. However, these modest later structural MRI findings do not show a robust relation to subsequent neurodevelopmental outcome.1,2 

In this Commentary, I propose that the reasons for this lack of a robust relation of later MRI studies to subsequent neurodevelopmental outcomes are that (1) the anatomic bases are not related simply to cellular/tissue loss, and (2) the previous later MRI approaches have not been adequate to capture the essence of the brain abnormalities.

Proposed Nature of the Brain Abnormalities in Neonatal HIE in Early Infancy

The hypothesis set forth in this Commentary is that the brain abnormalities in early infancy in those infants destined to have neurodevelopmental impairment are principally dysmaturational in nature, involve both gray and white matter structures, are persistent and dynamic, and potentially are modifiable. This dysmaturational concept5,6 is accepted generally for premature infants with neonatal injury, and the manifestations are definable in such infants at term equivalent age by MRI studies of regional brain volumes, cerebral cortical gyrification, fiber tract development and connectivity (among other parameters).6,7 I suggest that the dysmaturational concept is relevant also to the term infant in the months following neonatal hypoxic-ischemic injury. Indeed, vulnerable maturational events are very active in the term newborn brain and continue robustly over the months postnatal, as discussed next.

Principal Developmental Events at Term and in the First Postnatal Months

To place this dysmaturational idea in context, it is important to consider the principal developmental events at term and in the first postnatal months following term birth. These events involve key structures in cerebral white matter, thalamus and cerebral cortex.

Cerebral White Matter

The major developmental events in cerebral white matter at term and during the early post-term period include oligodendroglial maturation with ensheathment of axons (critical for such axonal growth as thalamo-cortical, cortico-callosal and cortico-cortical fibers and for early cerebral myelination).5,6,8 Cerebral myelination begins during this period in the corona radiata (central cerebral white matter), the optic tract and chiasm, the auditory radiation, Heschl’s gyrus, thalamus and thalamic connections, among others.9 

An additional important event in cerebral white matter involves migration of GABAergic neurons to cerebral cortex.10 This migration is especially active prior to term but continues until six postnatal months. Differentiation of these GABAergic neurons in cortex is also very active during this period (see later).

Thalamus

Thalamic development is very active at term and during the first months of life. The principal events involve axonal growth, myelination and connectivity.8,9 This structure serves as a complex way station for axons ascending from brain stem, cerebellum and spinal cord and descending from cerebral cortex. Indeed, thalamic connections to the entirety of cerebral cortical and diencephalic neurons are crucial for a wide variety of complex motor, cognitive and behavioral functions. Thalamic neurons are highly sensitive to hypoxic-ischemic injury in the term infant.11,12 Not surprisingly, a strong relation exists between overt hypoxic-ischemic thalamic/putaminal injury and severely impaired cognitive and motor outcomes.13 However, little is known about the relations of less obvious disturbance to thalamus during early development and a variety of subsequent neurodevelopmental impairments. Although not yet elucidated, in view of the very wide spectrum of thalamic connections, it seems reasonable to speculate that less obvious disturbances of thalamic developmental parameters could contribute importantly to later neurodevelopmental impairments.

Cerebral Cortex

The first several months after term birth is a remarkable period for cortical development. The key events are elaboration of the dendritic arbor and axonal ramifications, culminating in cortical synaptogenesis.14-21 A detailed computerized analysis of Conel’s remarkable corpus of study of human cerebral cortical development in the first months and years of life showed that the first six months of life account for fully one-third of the developmental change in human cerebral cortex from term birth to 72 months of age.18

As noted earlier, GABAergic neuronal development is very active during the first postnatal months. Migration to upper cortical areas comes to a conclusion during this period. Differentiation of these neurons in upper cortical layers increases superficial cortical surface area and is important in provoking formation of gyri.22 During this time frame, GABAergic neurons differentiate from an initial, largely excitatory phenotype to their familiar inhibitory phenotype. These neurons play critical roles in development of cortical circuitry and determination of cortical critical periods.23-25

Interaction of Cell Injury/Loss and Altered Development

Although not yet clearly accomplished for all parameters, it seems highly likely that the remarkable developmental events just described are highly vulnerable to such major perturbations as hypoxic-ischemic insults and especially to the subsequent persistent gliosis, involving both microglia and astrocytes (see later). This dysmaturational consequence to a destructive process would be entirely consistent with the phenomena shown for premature infants.5,6 

A particularly important brain area in this context of rapid developing structures likely to be affected by neonatal HIE is the hippocampus. Several seminal preclinical studies by Gunn and colleagues highlighted the particular vulnerability of hippocampal neurons.26,27 The hippocampus is located deep in the medial temporal lobe, and contains a series of subfields of pyramidal cells that connect to multiple other structures, such as thalamus, hypothalamus, amygdala, and prefrontal cortex, among other structures (for review, see28,29). The hippocampus later mediates key functions involved in memory, learning, emotional regulation and cognitive function. Hippocampal neurons, especially those of the CA1 and CA3 regions, are exquisitely vulnerable to injury by hypoxic-ischemic insults.11,12

The loss of these hippocampal neurons during the acute period, as well as the deleterious effect of subsequent gliosis (see later), would be expected to disrupt the subsequent development of the hippocampus and its connections. The most active developmental processes occurring in hippocampus around the time of birth and in the first months of life are dendritic arborization, synaptogenesis and myelination. It is noteworthy in this context that later MRI studies of infants with HIE have shown evidence of decreased hippocampal volumes, parahippocampal white matter, and mammillary bodies.30 ,31,32 Decreased hippocampal volumes and mammillary body “atrophy” were associated with impaired cognition and memory at school age after neonatal HIE.30 Notably, “atrophy” of the mammillary bodies has been shown as early as three postnatal months.33 Experimental data suggest that the abnormalities of these hippocampal structures and connections may reflect impaired development rather than simply atrophy. Thus, Back and colleagues have shown in a preterm sheep model that hippocampal volume deficits identified four weeks after hypoxia-ischemia are not related to cell loss but rather to impaired development of basal and dendritic arborization.34 These observations have important clinical implications (see later).

Interaction of cell loss, cell injury and impaired cerebral development likely involves other aspects of brain development active at term and in the first months of life, as outlined earlier. Disturbances of axonal growth, myelin elaboration, cortical and thalamic neuronal development and connectivity would be likely possibilities. A few earlier MRI studies in term infants months after HIE have noted impaired cerebral myelination35 and reduced volumes.36 However, more detailed information with state-of-the-art measures is lacking.

Likely Mechanisms Underlying Dysmaturation after Neonatal HIE

The mechanisms underlying potential dysmaturational events in the weeks and months after neonatal HIE likely relate largely to the persistent gliosis and related neuroinflammation characteristic of the so-called “tertiary phase” of perinatal hypoxic-ischemic injury (see37,38). The key role of gliosis, involving both microglia and astrocytes, has been delineated best by Gressens and collaborators.39,40 The mechanisms by which this gliosis leads to dysmaturation of differentiating oligodendroglial and neuronal-axonal structures are diverse. Pro-inflammatory (M1) microglia release reactive oxygen/nitrogen species and cytokines that then act on developing cells. Additionally, these pro-inflammatory microglia can induce formation of neurotoxic reactive astrocytes.41,42 These astrocytes secrete cytokines and other molecular products important in impaired developmental events. Additionally, because microglia and astrocytes not in an active pro-inflammatory state are important in normal development of neurons, axons, and oligodendrocytes, vascularization, synaptic development, pruning and neural circuit formation,43 diversion to the pro-inflammatory phenotypes could contribute importantly to disturbed maturational events subsequent to neonatal HIE.

Identification of Brain Dysmaturation in the First Months After Neonatal HIE

In view of the considerations just discussed, a reasonable goal in the term infant with HIE is to assess brain dysmaturation by approximately three months of age, principally to identify the nature and loci of the abnormalities and to institute interventions to improve outcomes. Three months of age obviously is a somewhat arbitrary time point, but the nature and loci of the dysmaturational events are likely to be apparent by this age and interventions should be instituted as early as possible.

To identify the nature of the likely abnormalities described earlier, state-of-the-art MRI approaches will be necessary. These approaches have been described in detail elsewhere (see, for example, Kelly et al.44). It is beyond the scope of this Commentary to describe these techniques in detail. Suffice it to say here, such methods should include careful measures of volumes of cerebral cortical regions, including hippocampus, cerebral white matter, thalamus and other nuclear structures (basal ganglia, mammillary bodies), as well as measures of axonal growth and early myelination by diffusion based tractographic approaches (see later), and of intracortical and cortico-thalamic connectivity by functional MRI measures.

Detailed microstructural assessments will be critical in detecting early dysmaturational events.44,45 For example, measures of cerebral cortical surface area, thickness and gyrification will provide insights into the cortical dysmaturational disturbances referred to earlier. In cerebral white matter, major white matter tracts can be interrogated by such advanced diffusion MRI analyses as fixel-based analysis44 to provide insight into axonal growth and elaboration. Similarly, so-called NODDI imaging (Neurite Orientation Dispersion and Density Imaging) could provide major insight into axonal development in white matter tracts. Insight into disturbances of pre-oligodendroglial (pre-OL) ensheathment of axons and myelination in cerebral white matter, as well as dendritic and axonal development in cerebral cortex and such deep nuclear structures as thalamus and putamen, can be deduced by these approaches.

Clearly, all or most of these approaches are not available to the vast proportion of neonatal facilities. Moreover, the capacity to study a control population is limited and difficult. However, some research programs could pursue such a major investigative effort (with appropriate external funding). The aim then would be that some of the findings generated from such research could help direct use of specific MRI measures more generally available among neonatal facilities to target specific structures or regions of especial prognostic value. For example, could measures related to hippocampal structure and connections or to specific white matter maturational features be especially valuable for estimates of prognosis or for direction of areas of intervention?

Is There Value to Detect Dysmaturation by MRI at Three Months of Age?

Although understanding the neurobiology of dysmaturation by MRI at three months of age after HIE would be of major academic interest, could the information also lead to improved outcomes? I suggest that potentially it could lead to improved outcomes, for several reasons. First, neuro- restorative interventions could be instituted with force and direction. Interventions have been discussed in detail elsewhere6,7 and will not be repeated here. In broad terms, the interventions include experiential factors (visual, auditory, pain, stress, early intervention programs, parenting-educational-social factors) and nutritional factors (breast-feeding; quality, source and components of milk, etc.).

Of potentially great importance, but not yet studied in human infants, are manipulations of microglia or astrocytes from a damaging pro-inflammatory to a neuroprotective/pro-repair, pro-development, anti-inflammatory phenotype.37 This approach could minimize dysmaturational effects while restoring the important roles of these glial cells in promoting such normal developmental events as pre-OL development, axonal growth, synaptogenesis and synaptic pruning. In several experimental models, including hypoxic-ischemic injury, such agents as metformin, resveratrol, and pioglitazone have shown benefit for long-term outcomes via promotion of the M2 (anti-inflammatory) microglial phenotype.46-49

A number of other agents show promise in this context. IGF-1 and EPO may have benefit for neuronal and pre-OL development.37 Hyaluronidase inhibitors may be beneficial for pre-OL development.50 A variety of stem cells has been shown beneficial for recovery from experimental stroke and related ischemic brain injuries in neonatal animals.51,52 Intranasal delivery has been effective.53 Exosomes derived from stem cells, also delivered intranasally, are similarly beneficial.54 These issues are discussed in detail elsewhere (see, for examples,37,40,55).

Conclusions

In this relatively brief Commentary, I have suggested (1) an explanation for the relatively disappointing predictive value of MRI in early infancy for prediction of long-term neurological outcome, (2) brain dysmaturation rather than simply tissue loss or atrophy is the principal mechanism for impaired outcomes, (3) highly advanced MRI techniques are capable of, and necessary for, identifying many of the dysmaturational deficits in the first months of life, and (4) early identification of such deficits could lead to both targeted and novel interventions to counteract or prevent such dysmaturation. The principal difficulty is that the needed highly advanced MRI techniques for in vivo detection are not available widely. In my view, carefully designed research that likely will require multiple institutions with the necessary MRI capabilities is needed. Supportive funding obviously is a major issue, and it is beyond the scope of this presentation to suggest the mechanisms. However, I hope that federal and nonfederal sources will accept this challenge.

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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