PEDIATRICS Vol. 107 No. 3 March 2001, pp. 593-594

COMMENTARY:
The Necessity and Difficulty of Conducting Magnetic Resonance Imaging Studies on Infant Brain Development

Decision-making in the care of gravely ill, prematurely born infants must balance the long-term effects of numerous medical complications with those of their treatments. Antenatal and postnatal administration of glucocorticoids clearly enhance fetal lung maturation and survival,^1-3 and yet growing clinical and preclinical data suggest that these therapies may be associated with disturbances in long-term brain development and cognition.^4-6 The article by Murphy and colleagues⁷ in the February 2001 issue of Pediatrics contributed importantly to this growing evidence by showing that postnatal glucocorticoid administration is associated with a reduced volume of cortical gray matter in preterm infants. This article is the latest in a series of studies from this investigational team that has helped to characterize normal and pathologic infant brain development.^8-13 The work from this group has been bold, pioneering, and (given the innumerable technical difficulties associated with scanning infants) nothing short of heroic.

Because of the potential implications of this particular study for clinical decision-making, it is important to note its limitations and the inherent difficulties of interpreting findings from similar magnetic resonance imaging (MRI) studies of infant development. First, the number of infants in this study who received postnatal steroids was small and the results must be considered preliminary. Second, antenatal steroid administration was undocumented and may have also influenced brain development in these preterm infants.⁴ Third, the cumulative exposure to dexamethasone was relatively large, and the findings, if confirmed, may not apply to lower cumulative exposures. Fourth, the effects of the medical conditions for which the steroids were administered are exceedingly difficult to dissociate from the effects on brain development of the steroids themselves.¹⁴

These considerations pertain to clinical aspects of studies of preterm birth. Other considerations pertain more specifically to the inherent limitations of imaging methodologies used in this and other studies of infants. First, studies of regional volumes must account for scaling effects within the brain. Bigger infants will have bigger brains, and infants with bigger brains will have bigger subregions within their brains. When comparing brain volumes between preterm and term infants, therefore, the analyses must account for these scaling effects. Precisely how best to do this is a subject of some controversy, but most studies control the analyses statistically either for total body size (using a measure such as height) or for head size (using a measure such as head circumference or intracranial volume).^15-17 In the study from Murphy and colleagues, scaling effects on regional brain volumes were not considered. It is likely that the preterm infants who received dexamethasone had smaller body sizes and reduced intracranial volumes resulting from their greater prematurity and more severe respiratory illnesses.

A subtler but more intractable problem in infant scanning is the inherent difficulty in determining the histologic correlates of the various tissue classes that are assigned using MRI (eg, "cortical gray," "unmyelinated white," "myelinated white," and "cerebrospinal fluid"). The basic unit of information available on an MRI scan is the degree of grayness in any portion of the image. Our ability to discriminate and measure different brain tissues is provided mainly by the image contrasthow "white" the white matter appears, for instance, compared with the "gray" of the adjacent cortical gray matter.¹⁸ Tissue contrast in infant MRI scans differs dramatically from scans in later childhood primarily because of a much higher water content and a much lower myelin deposition in infant brains.^19-21 Unfortunately, the high water content in infant brains alters MRI-based tissue characteristics (relaxation times) and thereby reduces the contrast in images from pulse sequences typically used in older children,²⁰ such as those used in the Murphy et al study. When using main magnetic field strengths of 1.5 Tesla or more, repetition times and echo times need to be considerably longer in infants to achieve adequate tissue contrast.²⁰

In addition, water content and myelin deposition change considerably in the weeks preceding and in the year after term birth. MRI tissue contrast, therefore, also varies significantly during that time^20,21 and so may regional volumes, especially if the change in water content is not constant across tissue types. As noted by other investigators, pulse sequences may need to be tailored specifically to the age of the infants to maximize contrast and improve our ability to discriminate tissue classes.^20,21 Even then, assigning histologic correlates to tissues of varying grayness in MRI scans is difficult. The MRI contrast between tissues called "cortical gray" and "unmyelinated white matter," for instance, must by definition be based on tissue characteristics other than myelin content, and these characteristics currently are unknown. The histologic basis of MRI-based tissue assignment in infants, therefore, requires further clarification.

Regional brain water content, myelin deposition, and the resulting tissue contrast could differ in preterm compared with term children (or compared with preterm children treated with dexamethasone) and thereby systematically alter the volumes of the various tissue compartments measured on MRI scans. These difficulties are not unique to the study from Murphy and colleagues and do not diminish the importance of their findings. They do, however, underscore how difficult it is to interpret group differences and putative developmental changes in regional brain volumes in infants using MRI.

Bradley S. Peterson, MD^*,
Laura R. Ment, MD^§,
* Child Study Center
Departments of  Diagnostic Imaging, ^§ Neurology, and  Pediatrics
Yale University School of Medicine
New Haven, CT 06520

FOOTNOTES

Received for publication Jan 12, 2001; accepted Jan 12, 2001.

Reprint requests to (B.S.P.) Yale Child Study Center, 230 South Frontage Rd, New Haven, CT 06520. E-mail: bradley.peterson{at}yale.edu

ABBREVIATIONS

MRI, magnetic resonance imaging.

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