Measurement of frontal lobe volume on magnetic resonance imaging scans

PSYCHIATRY RESEARCH NEUROIMAGING

ELSEVIER

Psychiatry Research: Neuroimaging Section 75 (1997) 23-30

Measurement of frontal lobe volume on magnetic resonance imaging scans Elizabeth H. Aylward*, A n n Augustine, Qiang Li, Patrick E. Barta, G o d f r e y D. P e a r l s o n Division of Psychiatric Neuroimaging,Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, 600 North Wolfe St., Baltimore, MD 21287-7362, USA Received 18 January 1997; revised 9 June 1997; accepted 18 June 1997

Abstract This article describes rules for measurement of the frontal lobe on thin SPGR (spoiled gradient recalled echo in steady state) MRI (magnetic resonance imaging) scans. Measurements were performed using a locally-developed software program that allows 3-dimensional reconstruction of images, 'painting' of landmarks on the surface of the brain, and reconstruction of 2-dimensional images in any plane with landmark 'paint' remaining on the surface of the brain. Excellent inter-rater reliability has been achieved for this method. The approach may be particularly useful for studies involving groups of patients whose brains are known to be dysmorphic and who may not, therefore, be appropriate for measurement methods that involve image warping or dependence on arbitrary landmarks for defining the posterior boundary of the frontal lobe. © 1997 Elsevier Science Ireland Ltd.

Keywords: MRI; Neuroimaging; Methodology

I. Introduction

Many studies have been published recently involving measurement of frontal lobe volume on

* Corresponding author. Tel.: + 1 410 5506945; fax: + 1 410 6143676.

MRI scans. In general, two approaches have been used. The first is a stereotaxic image-warping method, developed by Andreasen et al. (1994, 1996), which involves segmenting brain from non-brain tissue (using edge detection techniques and manual tracing), warping of 3-dimensional images into standardized stereotaxic atlas space (Talairach and Tournoux, 1988), overlaying a 3-

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dimensional grid of 'boxes,' assigning each of these boxes to a neuroanatomical region (e.g. frontal lobe) and calculating the volume of the tissue that lies within the boxes assigned to the region of interest. The major advantages to the stereotaxic image-warping method include its incorporation of all of the sections of the frontal lobe, speed, and reliability. The major disadvantage involves the assumption of proportionality, which may not be completely valid because brains do not simply vary in size, but also vary in shape, and these shape differences are removed in the process of linear transformation. This method may cause subtle but important differences to be overlooked (Andreasen et al., 1996). This may be a particular problem for brains that are known to be dysmorphic. For example, brains of individuals with Down syndrome are known to be foreshortened. 'Normalizing' these brains into Talairach space may obscure differences that are an essential feature of the disorder (e.g. smaller frontal lobes). The second method involves defining the boundaries of the frontal lobe, tracing around the area within the boundary in each slice, summing the areas and multiplying by slice thickness. Tracing the surface boundaries is often aided by semi-automated techniques for segmenting tissue and cerebrospinal fluid (CSF). Most investigators have performed these measurements on coronal images, using some specific landmarks [e.g. canthomeatal line or A C - P C (anterior commissureposterior commissure) line] to ensure standardized head tilt. Landmarks for identifying the posterior boundary of the frontal lobe have included the most anterior point of the corpus callosum (Breier et al., 1993; Buchanan et al., 1993; Seidman et al., 1994; Maher et al., 1995; Vita et al., 1995; Castellanos et al., 1996), the anterior commissure (Harvey et al., 1993; Lehtovirta et al., 1996; Sheline et al., 1996), the aqueduct of Sylvius (Murphy et al., 1996), the optic chiasm (Coffey et al., 1993), and the last locator line on the midsagittal image passing thorough the rostrum (Berryhill et al., 1995). Because these landmarks are external to the frontal lobe, they are relatively crude for identifying its posterior boundary. In

recognizing that use of these landmarks results in omission of the posterior sections of the frontal lobe, investigators using this method sometimes refer to the region as 'prefrontal lobe' or 'anterior frontal lobe'. Some investigators have also included rules for separating frontal from temporal lobe in more posterior coronal slices. Turetsky et al. (1995) describe a method for measuring frontal lobe volume on axial slices, using different landmarks at each of several different levels (e.g. for the most superior slices, the landmark for the posterior border is the most anterior aspect of the caudate nucleus on the slice immediately inferior to one containing the splenium of the corpus callosum). The major disadvantages of 'boundary tracing' methods are that they arbitrarily omit fairly large portions of the frontal lobe and that they may be biased for individuals with certain neuroanatomical abnormalities. For example, an individual with dysgenesis of the corpus callosum will 'get credit' for more frontal lobe tissue because the most anterior slice containing the genu of the corpus callosum may be more posterior than for an individual with a larger corpus callosum.

The purpose of the current study was to develop rules for measurement of the frontal lobe that would conform to neuropathological definitions of this region and would yield high interrater reliability coefficients. The method described here results in frontal lobe volumes that include frontal cortex, insular cortex lateral to the Sylvian fissure, and white matter anterolateral to the corpus callosum. 2. Methods

2.1. Subjects The reliability study was performed on scans from 10 healthy individuals (five men and five women; mean age = 47.3 years, (S.D. = 13.61); age range = 26-68 years). Subjects were recruited from the community and hospital staff. They had no history of psychiatric illness, head injury with loss of consciousness, or substance abuse, as assessed by a structured interview. Procedures were

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fully explained to all subjects and written informed consent was obtained before enrollment in the study. 2.2. M R I acquisition MRI scans were performed on a 1.5-Tesla General Electric Signa MRI scanner (General Electric Medical Systems, Milwaukee, WI), using a protocol identical to that described in previous studies by our group (Aylward et al., 1996, 1997). This includes a 1.5-mm SPGR series, which was used for the frontal lobe measurements reported in this study. For each subject, 124 contiguous coronal images were acquired with a repetition time (TR) of 35 ms, echo time (TE) of 5 ms, flip angle of 45°, and one excitation. Field of view was 24 cm, and the image matrix was 256 × 256. Images were transferred via FTP and archived on CD-ROMs. 2.3. Frontal lobe volume measurements Measurements were made on a Gateway 2000 graphics workstation, using locally-developed custom graphics software ('MEASURE'; Barta et al., in press). This program allows 3-dimensional reconstruction of images that can then be rotated in any direction, 'painting' of landmarks on the surface of the brain, and reconstruction of 2-dimensional images in any plane with landmark 'paint' remaining on the surface of the brain. Scans were stripped of extracerebral tissue and CSF (cerebral spinal fluid), using a semi-automated program, yielding images that have all cerebral tissue outlined. The method for measuring the frontal lobes involves erasing all brain tissue not included in this region, as defined by the rules outlined below. If necessary, scans were rotated so that axial slices were parallel to the line connecting the anterior and posterior commissure (AC-PC line) and the interhemispheric fissure was perpendicular to the bottom of the image in both the axial and coronal planes. Because the slices are so thin and because the voxels are almost cubic, this does not noticeably affect the resolution of the resulting images. After brains were stripped of extracerebral tis-

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sue and CSF, a 3-dimensional reconstruction was performed, according to methods described by Hohne et al. (1990). The central sulcus was identified, according to boundaries described by Ono et al. (1990). This was usually accomplished without much difficulty. In cases where the central sulcus was not clearly demarcated, raters found it useful to examine the most superior reconstructed axial slices. The central sulcus was almost always easy to identify at this level and could be traced from this point toward its inferior end. The pre-central and post-central gyri were 'painted' different colors on eachside of the brain. Because these painted regions are used to identify the central sulcus, it is only important that the posterior border of the pre-central gyrus and the anterior border of the post-central gyrus be marked carefully. Fig. la shows the left hemisphere, with red paint demarcating the pre-central gyrus and yellow paint demarcating the postcentral gyrus. Figs. 2 and 3 show a coronal and axial view of the brain, with the paint remaining on the surface. From the coronal and axial views, it is easy to appreciate that the central sulcus might be difficult to identify without specific demarcation of the pre- and post-central gyri. Scans were then resliced in the axial plane, parallel to the AC-PC line. Reslicing was performed at the same resolution at which the scans were originally obtained, yielding slices that were 0.9375 mm thick. Starting in the most superior slice, the central sulcus was identified, using the painted pre- and post-central gyri as guides. All brain area posterior to the central sulcus was erased (Fig. 4a). When the central sulcus no longer completely separated the frontal from parietal lobes, the rater traced the central sulcus in each hemisphere to its deepest point, and cut straight across to the interhemispheric fissure, erasing all pixels posterior to this line (Figs. 4b,c). In the most superior slice in which the frontal lobes were joined by the corpus callosum, the rater traced the central sulcus in each hemisphere to its most medial point and drew lines connecting these points to the most anterior point of the corpus callosum at the midline (Fig. 4d). All brain tissue posterior to this line was then

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la

lb

Fig. 1. (a) Three-dimensional surface view of left hemisphere with pre- and post-central gyri identified by red and yellow 'paint'. (b) Three-dimensional surface view of same brain with central sulcus indicated by the dotted line. Fig. 2. Representative coronal view with pre- and post-central gyri identified by red and yellow 'paint' on the surface of the brain. Fig. 3. Representative axial view with pre- and post-central gyri identified by red and yellow 'paint' on the surface of the brain.

erased. T h e rater continued in the inferior direction, following this rule in every slice until the Sylvian fissure d e a r l y delineated the insular cortex. In the m o s t superior slice in which the insular cortex was d e a r l y delineated, the rater drew a

horizontal line f r o m the point w h e r e pre-central and post-central paint m e t straight across to the Sylvian fissure, followed the Sylvian fissure up to its most anterior point, and then drew a straight line to the most anterior point of the corpus callosum (Fig. 4e, fight side of brain, left side of

E.H. Aylward et al. ~Psychiatry Research: Neuroimaging Section 75 (1997) 23-30

/"

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image). (As demonstrated by Fig. 4e, the slice in which the insular cortex is clearly delineated is not necessarily the same on left and right sides.) The rater followed this rule until the corpus callosum was no longer visible. In slices inferior to the corpus callosum, the rater traced a line from the deepest (most anterior and medial) point of the Sylvian fissure straight across to the interhemispheric fissure, and included only tissue that was lateral to the Sylvian fissure or anterior to this line (Fig. 4f). The rater followed this rule in every slice, continuing in the inferior direction, until the optic chiasm was clearly visible. In this slice and those inferior to it, the suprasellar cistern was used as a guide for demarcating the frontal lobe (Fig. 4g), with a line drawn from the most lateral tip of the suprasellar cistern on each side to the most medial point of the Sylvian fissure. All brain area posterior to this line was erased. In the most inferior slices (Fig. 4h), the frontal lobe is completely separated from the rest of the brain by CSF, and the rater included only tissue clearly belonging to the frontal lobe (e.g. omitting optic tracts). All brain tissue inferior to the most inferior slice of frontal lobe was then erased. The computer software automatically summed the areas in each slice and multiplied by slice thickness to yield total frontal lobe volume. Two raters used this method to measure frontal lobe volumes on 10 scans. In order to compare the current measurement method with the method most commonly used in previous investigations (Breier et al., 1993; Buchanan et al., 1993; Seidman et al., 1994; Maher et al., 1995; Vita et al., 1995; Castellanos et al., 1996), one rater also measured all brain tissue anterior to the most anterior point of the corpus callosum ('plane cutaway method'). This was done by taking the stripped brain files (which had been aligned according to the A C - P C line), identifying the most anterior coronal slice containing the corpus callosum, and using a 'plane cutaway' tool to erase all pixels in this slice and those posterior to it. 3. Results

Inter-rater reliability coefficients for the 10

frontal lobe measures were calculated with intraclass correlations. An intraclass correlation of 0.99 was obtained, with a lower 95% confidence limit of 0.97. Mean volume for Rater 1 was 366.74 cm 3 (S.D. = 25.32) and for Rater 2 was 366.98 cm 3 (S.D.= 23.79). The greatest volume difference between Rater 1 and Rater 2 was 5.16 cm 3, a difference of 1.2%. For this sample, there was no correlation between volume of frontal lobe and age (r = 0.09). In our sample of 10 healthy adults, mean frontal lobe volume (average of the two raters) was 366.86 c m 3 (S.D.=23.91; range = 334.75-422.36). This mean volume is slightly smaller than that reported by Andreasen et al. (1994) for 90 healthy control subjects using the stereotaxic brain-warping method (mean = 387.18 cm a, S.D. = 50.31). As would be expected, our mean volume is considerably larger than those reported by investigators using a 'plane cutaway' method, with the posterior border of the frontal lobe defined as the most anterior point of the corpus callosum. These means range from 101.77 c m 3 for 15 normal adults (Vita et al., 1995) to 174.70 for 18 schizophrenic patients (Maher et al., 1995). Similar to these other investigators, our mean volume for frontal lobes measured by the 'plane cutaway' method (i.e. including all brain tissue pixels anterior to the most anterior point of the corpus callosum) was 126.6 cm 3 (S.D.--19.56 c m 3 ) . Volumes obtained by this method correlated significantly with volumes obtained by our surface landmark-based method (r = 0.868; P < 0.001). Volumes obtained by our surface landmark-based method are closer to those of investigators using a 'plane cutaway' method with more posterior landmarks (e.g. 370.5 cm 3 from the study by Sheline et al. (1996), who used the anterior commissure as the most posterior border of the frontal lobe). 4. Discussion

The current study presents a methodology for measuring frontal lobe volumes using neuroanatomically precise defmitions of the boundaries. This methodology can serve as the basis for measurements of more specific frontal lobe regions (e.g. superior frontal gyrus), as some of the boun-

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daries will have already been defined. After boundaries of the frontal lobe are measured, raters can, of course, apply segmentation programs for measuring volume of gray and white matter within the frontal lobe. This method for measurement of frontal lobe was developed for use with scans from patients with Huntington's disease, and the investigators were particularly interested in measurements that excluded basal ganglia and deep white matter. It would not be difficult, however, to modify the methodology to include such structures. For example, in slices at the level of the corpus callosum, raters could trace the central sulcus to its deepest point on each side of the brain and draw straight across to the midline, rather than drawing the line to the most anterior point of the corpus callosum. We recognize that our method, like other boundary tracing methods, is somewhat dependent on landmarks external to the frontal lobe. Unlike other boundary tracing methods, however, our method does not use arbitrary landmarks for defining a plane posterior to which all tissue is excluded. For example, the rules for defining frontal lobe boundaries on slices in which corpus callosum is observed involve tracing from the deepest point of the central sulcus to the most anterior point of the corpus callosum on each slice. These rules were devised to exclude corpus callosum and other .subcortical gray and white matter structures, and do not arbitrarily exclude all frontal lobe tissue posterior to the coronal plane defined by a specific landmark, as do other boundary tracing methods. The major disadvantage of the method is that it is fairly time-consuming (requiring approx. 1 h per stripped brain for an experienced rater). However, if pre- and post-central gyri are 'painted' by a rater experienced in neuroanatomical definition, the time-consuming 'cutting' can be done by raters with limited neuroanatomical experience. New raters have been able to learn the rules fairly quickly and to establish excellent inter-rater reliability with little difficulty. Furthermore, measurements obtained by this method may be worth the extra effort, as smaller samples may be necessary to demonstrate significant group differences

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that could be obscured by less rigorous measurement methodology. Although the measurements obtained according to the 'plane cutaway' method correlated significantly with volumes obtained according to our surface landmark-based method, they were much smaller, indicating that large amounts of tissue (greater than 50%) are not accounted for by the 'plane cutaway' method. Correlations between the two methods may be considerably different for brains that are known to be dysmorphic (e.g. Down syndrome).

Acknowledgements Supported by grants from the NINDS (16375), NIH Division of Research Resources/Johns Hopkins Outpatient Clinical Research Center (RR00722), and the Huntington's Disease Society of America.

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