Applications of Magnetic Resonance Imaging to the Study of Development

B.J. CASEY, KATHLEEN M. THOMAS, AND BRUCE McCANDLISS

abstract Recent methodological advances in magnetic resonance imaging (MRI) have revolutionized our ability to study the developing human brain. This chapter examines the use and promise of MRI in addressing key developmental questions, including how the healthy normal brain develops and how such development is related to behavior. This methodology can also help us understand the biological substrates of childhood disorders. Examples of studies that examine the biological progression of developmental disorders following treatment and remediation are provided. Used effectively, this methodology could shed light on an array of developmental questions with respect to both healthy and pathological development.

Magnetic resonance imaging (MRI), with its lack of ionizing radiation and capacity to provide exquisite anatomical detail, has revolutionized the study of human brain development. Other imaging modalities, such as conventional radiography, computerized tomography (CT), positron emission tomography (PET), and single photon emission computerized tomography (SPECT), use ionizing radiation. Although these latter techniques may be used with pediatric patient populations when clinically warranted, the ethics of exposing children to radioactive isotopes for the advancement of science are less clear (Casey and Cohen, 1996; Morton, 1996; Za-metkin, 1996). The advent of functional MRI (fMRI) has further extended the utility of MRI to explore the developing human brain in ways not previously possible.

This chapter addresses applications of structural and functional MRI to the study of development. Emphasis is placed on the utility of MRI in understanding (1) brain maturation and its relation to behavioral development, (2) the effects of learning on brain development, and (3) the effects of behavioral and pharmacological intervention on brain development (figure 10.1). Examples of behavioral paradigms and details of b. j. casey, kathleen m. thomas, and bruce mccandliss Sackler Institute for Developmental Psychobiology, Joan and Sanford I. Weill Medical College of Cornell University, New York, New York.

the neuroimaging methodology will be provided within this context.

Magnetic resonance imaging

MRI has had a dramatic impact in the diagnosis of a variety of diseases and the in vivo study of the developing brain. This technique provides high spatial resolution images of the brain based on the nuclear magnetic resonance (NMR) properties of water protons and other nuclei found in brain tissue (Young, 1988). NMR consists of applying a radio frequency (RF) pulse (with an excitation frequency coinciding with the natural frequency of the system, known as the Larmor frequency) to the tissue. The RF pulse flips the net magnetization perpendicular to the main field. The MR image is generated by differences in the concentration of nuclei and their nuclear magnetic relaxation times (Tx and T2) in the different tissue environments (Bloch, 1946; Hahn, 1950). Tj relaxation refers to the return of precessing nuclei to alignment with the main field after excitation (i.e., longitudinal relaxation, or spin-lattice). This relaxation is related to surrounding tissue composition in that small water molecules relax faster than larger lipid molecules, thereby providing information on gray and white matter differences. T2 relaxation refers to the fall of the transverse magnetization leading to decay in the signal even though nuclei remain excited. This relaxation time is associated with interactions among nuclear spins and local inhomogeneities in the applied field. This interaction causes nuclei to precess, or spin, at different rates and deviate from the uniform motion of the initial excitation (Bottomley et al., 1984,1987). The rate of dephasing (loss of uniform motion) depends on resonance within the environment (i.e., spins of neighboring nuclei). For example, T2 in free water is much longer than that in bound water, and so prolonged T2 observed in lesions results from an increase in free/ bound water ratio. Localized inhomogeneities in the applied field lead to local differences in the Larmor frequencies, causing a decrease in T2, which is then des-

Methods

Figure 10.1 Central themes and methods discussed in this chapter.

Themes

Development (biological maturation)

Skill Acquisition (e.g., cognitive, social)

Remediation (e.g., behavioral, Pharmacol ogical)

Figure 10.1 Central themes and methods discussed in this chapter.

Components

Paradigm Development Image Acquisition Image processing and Analysis ignated T2*. T2*-weighted images are important for understanding the basis of functional MRI, as will be described later.

Brain Development MRI-based anatomical studies have revealed some interesting maturational changes in brain structure. The most informative studies to date are those based on carefully quantified volumetric measures and large sample sizes of 50 or more subjects (e.g., Giedd et al., 1996b,c; Reiss et al., 1996). The most consistent findings across these studies include (1) a lack of any significant change in cerebral volume after 5 years of age (Giedd et al., 1996b,c; Reiss et al., 1996); (2) a significant decrease in cortical gray matter after 12 years (Giedd et al., 1999); and (3) an increase in cerebral white matter throughout childhood and young adulthood (Jernigan et al., 1991; Pfefferbaum et al., 1994; Caviness et al., 1996; Rajapakse et al., 1996; Reiss et al., 1996). Specifically, subcortical gray matter regions (e.g., basal ganglia) decrease in volume during childhood, particularly in males (Giedd et al., 1996b; Rajapakse et al., 1996; Reiss et al., 1996), while cortical gray matter in the frontal and parietal cortices does not appear to decrease until roughly puberty (Giedd et al., 1999). White matter volume appears to increase throughout childhood and well into adulthood (Caviness et al., 1996; Rajapakse et al., 1996). These increases appear to be regional in nature. For example, white matter volume increases in dorsal prefrontal cortex, but not in more ventral prefrontal regions (i.e., orbitofron-tal cortex) (Reiss et al., 1996). Total temporal lobe volume appears relatively stable across the age range of 4-18 years, while hippocampal formation volume increases with age for females and amygdala volume in creases with age for males (Giedd et al., 1996c). This latter finding may be consistent with the distribution of sex hormone receptors for these structures, with the amygdala having a predominance of androgen receptors (Clark et al., 1988; Sholl and Kim, 1989) and the hippocampus having a predominance of estrogen receptors (Morse et al., 1986).

Behavioral Development One way of linking mor-phometric changes in the brain with behavior is to correlate MRI-based anatomical measures with behavioral measures. One of the first examples of such a study was reported by Casey and colleagues (1997a). The study examined the role of the anterior cingulate cortex in the development of attention. Attention was assessed with a forced-choice visual discrimination paradigm in 26 normal children between the ages of 5 and 16 years. Performance during attention tasks characterized as predominantly automatic versus effortful was assessed in parallel with MRI-based morphometric measures of the anterior cingulate cortex.

The behavioral paradigm consisted of presenting three stimuli that varied in shape and/or color in a row on a computer screen. The subject's task was to indicate which of the three stimuli was different from the other two in a forced-choice task. Subjects were not informed as to which feature would be salient in making the discriminations. There were two conditions: one requiring predominantly automatic processing and one requiring controlled processing. In the automatic condition the stimuli differed on a single attribute (e.g., color). Forced-choice detection based on a single feature has been suggested to be relatively automatic (Treisman, 1986). In the controlled processing condition, the

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