Cerebral cortex: a topographic segmentation method using magnetic resonance imaging

Psychiatry Research: Neuroimaging Section 100 Ž2000. 97᎐126

Cerebral cortex: a topographic segmentation method using magnetic resonance imaging Benedicto Crespo-Facorro, Jae-Jin Kim, Nancy C. AndreasenU , Ruth Spinks, Daniel S. O’Leary, H. Jeremy Bockholt, Gregory Harris, Vincent A. Magnotta Mental Health-Clinical Research Center, Department of Psychiatry, College of Medicine, Uni¨ ersity of Iowa Hospitals & Clinics, 2911 JPP, 200 Hawkins Dri¨ e, Iowa City, IA 52242-1057, USA Received 4 May 2000; received in revised form 21 September 2000; accepted 21 September 2000

Abstract Remarkable developments in magnetic resonance imaging ŽMRI. technology provide a broad range of potential applications to explore in vivo morphological characteristics of the human cerebral cortex. MR-based parcellation methods of the cerebral cortex may clarify the structural anomalies in specific brain subregions that reflect underlying neuropathological processes in brain illnesses. The present study describes detailed guidelines for the parcellation of the cerebral cortex into 41 subregions. Our method conserves the topographic uniqueness of individual brains and is based on our ability to visualize the three orthogonal planes, the triangulated gray matter isosurface and the three-dimensional Ž3D. rendered brain simultaneously. Based upon topographic landmarks of individual sulci, every subregion was manually segmented on a set of serial coronal or transaxial slices consecutively. The reliability study indicated that the cerebral cortex could be parcelled reliably; intraclass correlation coefficients for each subregion ranged from 0.60 to 0.99. The validity of the method is supported by the fact that gyral subdivisions are similar to regions delineated in functional imaging studies conducted in our center. Ultimately, this method will permit us to detect subtle morphometric impairments or to find abnormal patterns of functional activation in circumscribed cortical subregions. The description of a thorough map of regional structural and functional cortical abnormalities will provide further insight into the role that different subregions play in the pathophysiology of brain illnesses. 䊚 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Cerebral cortex; Magnetic resonance imaging; Segmentation; Brain; Gray matter

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Corresponding author. Tel. q1-319-356-1533; fax: q1-319-353-8300. E-mail address: [email protected] ŽN.C. Andreasen.. 0925-4927r00r$ - see front matter 䊚 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 9 2 5 - 4 9 2 7 Ž 0 0 . 0 0 0 7 2 - X

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1. Introduction The human cerebral cortex is a remarkable product of brain evolution that has long been a focus of attention with regard to the understanding of the pathophysiology of major mental illnesses. The cerebral cortex is functionally organized into specific subregions that are differentially involved in particular behavioral and cognitive functions ŽMountcastle, 1978; Pandya and Yeterian, 1985.. Ideally, functional brain mapping should be based on cortical cytoarchitectonic subdivisions ŽRoland and Zilles, 1998.. However, it is difficult to define a cortical map based on microstructural domains, because of the interindividual variability of both topography and patterns of distribution of microstructural variables with respect to anatomic landmarks ŽZilles, 1990; Rademacher et al., 1993.. An alternative method is to define individual brain regions by using topographic landmarks of individual gyri and sulci, heuristically assuming that morphological differences might reflect differences at the microanatomic level ŽRakic, 1988; Jouandet et al., 1989.. The coincidence of macroanatomic subregions and microstructural areas is the critical assumption for imaging studies of structure ᎐function relationships ŽSanides, 1964; Roland and Zilles, 1998.. Thus, MR-based parcellation methods use a set of topographic landmarks to provide an explicit anatomical guide for the definition of functionally relevant regions ŽRademacher et al., 1992.. The central hypothesis postulated in this approach is that the neocortical functional map is individually unique and that this uniqueness is directly reflected in gyral shapes and sizes. Recent developments in magnetic resonance imaging ŽMRI. technology have provided a broad range of potential applications to explore in vivo morphological characteristics of the human cerebral cortex. Measurements of gray matter volume, cortical surface size, cortical depth and patterns of gyrification can provide valuable information about cerebral cortex characteristics in normal volunteers and in patients with mental or neurological illnesses. MRI-based morphological analysis allows neuroscientists and clinicians to investigate structural correlates of brain disorders, to

recognize the presence of degenerative lesions, and to characterize rates of progression of certain diseases ŽCaviness et al., 1999.. In addition, parcellation methods will provide reliable regions of interest ŽROIs. applicable to quantitative flow measurement in co-registered MRrPET and functional MR images. Spatial resolution is currently one of the most challenging aspects of functional neuroimaging techniques. Most functional neuroimaging studies have relied on the linear proportional scaling system of Talairach and Tournoux Ž1988. for intersubject comparison. However, this approach effaces interindividual and interhemispheric variability of functional organization by normalizing to a standard brain by linear transformation ŽSteinmetz and Seitz, 1991; Kennedy et al., 1998.. Rademacher et al. Ž1992. and Caviness et al. Ž1996. have previously described a topographic parcellation method for the cerebral cortex. Their method parcels the entire neocortex of human brain into 48 parcellation units using a set of 16 conventional coronal planes and the trajectories of 31 sulci as the unit boundaries. In the ‘real-life’ situation of tracing MR for topographic parcellation, however, huge variability of sulcal patterns is observed, making it difficult to identify reliable landmarks using a simple definition. Indeed, most prior methods have not attempted to examine the slice-to-slice contiguity of an ROI, which obviously is fairly time-consuming. Thus, these studies have ignored the anatomical reality that sulcal trajectories vary greatly and it is often difficult to identify the landmarks in the serial orthogonal planes. Given that morphological brain abnormalities in mental illnesses, if they exist, are subtle, we have sought to develop a more detailed topographic method, in which each plane is consecutively analyzed with reference to adjacent serial slices. Detailed descriptions of frontal and temporal lobe parcellation methods have previously been reported ŽCrespo-Facorro et al., 1999; Kim et al., 2000a,b.. Our method preserves the topographic uniqueness of the individual cerebral cortex and relies on the strengths of two-dimensional and three-dimensional visualization by identifying cerebral landmarks and conducting measure-

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Fig. 1. A view of the three two-dimensional planes Žtransaxial, coronal and sagittal. and the three-dimensional rendered brain. The red line on the two-dimensional planes represents the intersection between the triangulated surface and each two-dimensional plane. Fig. 2. Schematic diagrams of the lateral, medial, and ventral surface of brain showing the relation between the sulcal topography Žleft., and the different cortical subregions and reference planes defined in our segmentation method Žright.. See Table 1 for key to abbreviations. Fig. 3. Coronal slice that shows the black line that represents the intersection between the triangulated surface and each two-dimensional plane. Sulci utilized as anatomical landmarks Žright hemisphere. and cortical surface of several frontal subregions Žleft hemisphere. have been highlighted in different colors. The surface area and gray matter volume of the frontal subregions are defined by clipping this contour according to the anatomical landmarks, as described by dotted lines. See Table 1 for key to abbreviations. Fig. 4. Three views Žlateral, medial and ventral. of the three-dimensional rendered brain on which the different FRONTAL subregions have been displayed in distinctive colors. The names of the different regions have been labeled on each view accordingly. See Table 1 for key to abbreviations.

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ments with information from the three orthogonal planes Žtransaxial, coronal and sagittal. and the three-dimensional rendered brain Žsee Fig. 1.. Using this approach, we describe a comprehensive and reliable procedure using MRI for subdividing the neocortex of each hemisphere into 41 subregions Žsee Fig. 2..

2. Methods 2.1. Subjects A reliability study of parcelling the neocortex was performed on a set of 10 MR scans for each subregion. The MR scans were randomly selected from the MR data set of the Mental Health Clinical Research Center at the University of Iowa Hospitals and Clinics and included both healthy volunteers recruited from the community and individuals suffering from several different psychiatric illnesses Ži.e. schizophrenia, schizophreniform disorder, autism and schizoaffective disorder.. A mixture of subjects Ži.e. healthy volunteers and patients. was used because the method was developed for application to such populations. Informed consent was obtained from all subjects in accordance with the Human Subjects Institutional Review Board of the University of Iowa. 2.2. MRI acquisition All multi-modal MRI scans were obtained at the University of Iowa Hospitals & Clinics using a 1.5 Tesla General Electric SIGNA System ŽGE Medical Systems, Milwaukee, WI.. The MR methodology is described in detail elsewhere ŽHarris et al., 1999. and is summarized briefly below. Three-dimensional T1-weighted images, using a spoiled grass ŽSPGR. sequence, were acquired in the coronal plane with the following parameters: echo time ŽTE. s 5 ms, repetition time ŽTR. s 24 ms, numbers of excitations ŽNEX. s 2, rotation angle s 45⬚, field of view ŽFOV. s 26 = 24 = 18.8 cm, slice thickness s 1.5 mm and a matrix of 256 = 192 = 124. Two-dimensional PD Žproton density. and T2 sequences were acquired

as follows: 3.0- or 4.0-mm-thick coronal slices, TRs 3000 ms, TEs 36 ms Žfor PD. and 96 ms Žfor T2., NEXs 1, FOVs 26 = 26 cm, matrix s 256 = 192. The in-plane resolution is 1.016= 1.016 mm for the three modalities. 2.3. Image processing MR data were processed on Silicon Graphics workstations using our locally developed software, BRAINS ŽAndreasen et al., 1992.. The T1-weighted images were spatially normalized and resampled to 1.0 mm3 voxels so that the anterior᎐posterior axis of the brain was realigned parallel to the ACPC line and the interhemispheric fissure aligned on the other two axes. The T2- and PDweighted images were aligned to the spatially normalized T1-weighted image utilizing an automated image registration program ŽWoods et al., 1992.. The data sets were then segmented using a Bayesian classifier based on discriminant analysis in order to reduce the variability in signal intensity across individual image sets and to correct for partial voluming ŽHarris et al., 1999.. Segmentation was done using T1-, T2- and PD-weighted images. Our discriminant analysis segmentation method permitted us to identify the range of values that characterized gray matter ŽGM., white matter ŽWM., and cerebrospinal fluid ŽCSF. in our multispectral data Ž10᎐70 for CSF, 70᎐190 for GM, and 190᎐250 for WM.. Each voxel was assigned an intensity value that was based on the weights assigned by the discriminant function and that reflected the relative combinations of GM, WM, and CSF in a given voxel that allowed us to correct for partial volume ŽHarris et al., 1999.. 2.4. Generation of the triangulated surface The tissue-classified image was then used to generate a triangle-based isosurface, reflecting the parametric center, 130, of the GM as the outer boundary of the brain ŽMagnotta et al., 1999.. An initial polygonalization of the cortical surface was done using the method described by Wyvill et al. Ž1986.. Since the initial surface contained 300 000᎐500 000 triangles per hemisphere, the surface was retiled to reduce the image down to a

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more manageable size of approximately 100 000 triangles per hemisphere following a retiling algorithm ŽTurk, 1992.. Decimation yielded a very similar surface with fewer triangles. This triangulated surface was used as the guide for finding sulcal landmarks during tracing, and formed the basis for our calculation of surface area and GM volume of each traced subregion. Also, this surface was used to yield a three-dimensional highquality image that permitted visualization of the patterns of the sulci and gyri.

minimize dependence of volume on the ROI raters, and to maximize its dependence on the automatic tissue classification ŽMagnotta et al., 1999.. The surface area of any specific frontal subregion was measured by summing areas of all triangles within the tracings that were made to define that specific subregion.

2.5. Manual segmentation procedure

Our method relies on the identification of particular sulci and their patterns on MR images. Due to the substantial variability of cerebral sulci, simple definitions make it difficult to identify reliable and valid landmarks. Particularly, interruptions and branches complicate the identification of comparable locations in different brains. Specific directions and arbitrary conventions therefore have to be implemented to reach an agreement regarding how to identify sulci and to define gyri on MR images. Only those hallmark sulci relevant to our method are described below.

For all cortical subregions, manual segmentation was performed on serial coronal or transaxial slices and consisted of three steps. The initial step was to identify the reference anatomical landmarks that served as boundaries for each subregion. The second step was to choose the ROIs that would be traced. Following the anatomical landmarks that had been established to define the different ROIs, the third step was to trace by hand each ROI on the appropriate coronal and transaxial slices. Tracing was performed by drawing a closed ROI that clipped the triangulated surface within the appropriate location Žsee Fig. 3.. 2.6. Gray matter ¨ olume and surface area measurements The manually segmented ROIs were used to surround contiguous areas of the triangulated isosurface. The corresponding gray matter volume of the cortical plate was found by using our thickness measure for the selected surface region, picking a ‘surface GM radius’ as the mean thickness q2.0 S.D., traversing the surface contour marking voxels that intersected the surface ‘in’ the area or ‘out’ of the area; and inflating the ‘in’ and ‘out’ volumes one voxel at a time until a voxel of the opposite value was encountered or the surface GM radius had been exceeded. ŽThe actual ‘inflation’ algorithm involved repeated averaging of known adjacent contagion scores to fill in ‘unknowns’ and finally dividing the contagion scale in the middle.. This method was chosen to

3. Tracing guidelines 3.1. Identification of the sulcal landmarks

3.1.1. Frontal lobe 3.1.1.1. Cingulate sulcus (CiS) and superior cingulate sulcus (SCiS). The CiS is a single continuous sulcus Žin 60% of cases. that runs parallel to the callosal sulcus ŽCaS. on the medial wall of the brain ŽOno et al., 1990.. Its posterior end Žmarginal ramus. usually extends to the lateral surface and is commonly posterior to the superior end of the central sulcus ŽCS. ŽOno et al., 1990.. When the CiS is segmented, an orthogonal line is dropped from the posterior end of the anterior segment to complete the course of the sulcus. If this arbitrary vertical line does not intersect the posterior segment, the shortest imaginary line between both CiS segments will connect them. In approximately 35% of the cases, the CiS shows a double parallel distribution ŽOno et al., 1990; Vogt et al., 1995.. The SCiS has a characteristic continuous course that lies parallel to the anterior part of the CiS and usually runs from a ventrocaudal point below the genu of the corpus callosum ŽCC. to the dorsocaudal point above the genu of the CC ŽVogt et al., 1995..

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3.1.1.2. Paracentral sulcus (PaCS). The PaCS represents the anterior border of the paracentral lobe on the medial wall of the hemisphere. It often corresponds to the medial extension of the pre-central sulcus ŽPCS., although a great variability exists in the pattern of the PaCS ŽOno et al., 1990.. Due to this great variability, we arbitrarily defined the PaCS as the nearest sulcus posterior to an orthogonal line that passes through the anterior commissure and is perpendicular to the AC᎐PC line. When the PaCS is a short sulcus, a vertical line is drawn from its end either to the CiS or to the margin of the hemisphere, depending on where it arises. The PaCS has been described as a suitable anatomical landmark to define the posterior border of the SMA on the medial wall ŽZilles et al., 1996.. 3.1.1.3. Superior rostral sulcus (SRS). The SRS is usually defined as a long sulcus inferior to the CiS on the anterior portion of the medial wall of the hemisphere ŽEberstaller, 1890; Ono et al., 1990.. The SRS is connected to the anterior part of the CiS or to the SCiS in approximately 25% of the cases ŽOno et al., 1990.. If the SRS is not easily identifiable, we define it as the nearest sulcus above the AC᎐PC axis on the anterior portion of the medial surface. The SRS is considered the medial border of the orbitofrontal cortex ŽOFC. anterior to the end of the olfactory sulcus ŽOS., and is also the inferior border of the superior frontal gyrus ŽSFG. on the anterior medial surface of the brain. 3.1.1.4. Lateral orbital sulcus (LOS). The LOS is defined as the most ventral sulcus on the lateral surface of the frontal lobe and represents the lateral boundary of the OFC. The LOS is easily identified on the intermediate aspect of the OFC. At the anterior aspect of the frontal lobe, the LOS disappears and the frontomarginal sulcus ŽFMS. is the lateral border of the OFC. At the posterior aspect of the OFC when the LOS disappears, the lateral border changes to the orbitoinsular sulcus ŽOIS.. The relationship of the posterior end of the LOS and the anterior horizontal ramus of the Sylvian fissure ŽSF. is hugely variable ŽOno et al., 1990.. The three-dimensional rendered brain is helpful in identifying the dif-

ferent patterns of the sulci at the posterior lateral portion of the frontal lobe. 3.1.1.5. Olfactory sulcus (OS). The olfactory sulcus ŽOS. is a constant single sulcus on the ventral surface of the frontal cortex. It represents a reliable and easily identifiable anatomical boundary between the straight gyrus ŽSG. medially and the orbitofrontal cortex ŽOFC. laterally ŽOno et al., 1990; Rademacher et al., 1992.. 3.1.1.6. Central (CS) and pre-central sulcus (PCS). The CS is a continuous sulcus that usually extends onto the medial surface and rarely reaches the lateral fissure ŽEberstaller, 1890; Ono et al., 1990.. An orthogonal line from its inferior extremity to the lateral fissure is drawn to complete the course of the CS on the three-dimensional reconstructed brain. The CS is the posterior border of the pre-central gyrus ŽPCG. and the anterior border of the post-central gyrus ŽPoCG.. The PCS is frequently segmented into the superior and the inferior portions of PCS ŽEbeling et al., 1989.. When the two segments of the PCS are seen on a single transaxial slice, the most prominent segment is followed as the anterior boundary of the PCG. The PCS represents the anterior border of the pre-central gyrus and posterior border of the lateral frontal subregions. Both sulci, the CS and the PCS, are easily identified on the lateral surface of the three-dimensional rendered brain. 3.1.1.7. Superior frontal sulcus (SFS). In most cases, the SFS is a continuous or twice-segmented furrow that runs parallel to the superior margin of the hemisphere ŽOno et al., 1990.. Its posterior end is commonly connected to the superior segment of the PCS. When the SFS is not connected to the PCS, a straight line is drawn from its posterior end to the PCS to complete its course. The length of the SFS varies and it does not always reach the FMS at the anterio-ventral portion of the superior frontal gyrus ŽSFG.. The SFS constitutes the lateral border of the superior frontal gyrus and the boundary between the SFG and the middle frontal gyrus ŽMFG.. 3.1.1.8. Inferior frontal sulcus (IFS). The IFS is a short continuous furrow that runs anterior and perpendicular to the inferior segment of the PCS. When the posterior end of the IFS is not con-

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nected to the inferior segment of the PCS Ž30% of the cases, Eberstaller, 1890., an imaginary horizontal line is drawn from its posterior tip to complete its pattern. The IFS is easily identified on the three-dimensional rendered brain and in the sagittal view. The IFS represents the superior border of the inferior frontal gyrus ŽIFG.. 3.1.2. Insular cortex 3.1.2.1. Circular sulcus of the insula (CSI) and orbitoinsular sulcus (OIS). The superior ŽSCSI. and the inferior circular sulcus of the insula ŽICSI. clearly demarcate the insula from the surrounding cortical areas at the posterior aspect. The fusion of the SCSI and the ICIS within the fundus of the Sylvian fissure constitutes the caudal end of the insula. Since the ICIS does not extend rostral to the limen insula, there is no well-defined boundary between the anterior aspect of the insula and the OFC. The OIS is considered the topographic boundary between the anterior insula and the adjacent OFC at this portion ŽMesulam and Mufson, 1985; Ture ¨ et al., 1999.. The OIS often has a diagonal course running from the anterior end of the SCSI to the ventral aspect of the insular cortex. Anatomical landmarks are easily visualized on the coronal view. 3.1.3. Temporal lobe 3.1.3.1. Heschl’s sulcus (HS) and sulcus intermedius (SI). Several convolutions and grooves exist on the supratemporal plane, which is hidden on the depth of the Sylvian fissure ŽSF.. HS is defined as the most anterior deep sulcus that begins medially and commences from the immediate retroinsular region ŽSteinmetz et al., 1989.. HS forms a border between Heschl’s gyrus ŽHG. medially and the planum temporale ŽPT. laterally in the coronal view. Sometimes, there are two convolutions that are incompletely divided by the sulcus not originating from the retroinsular region, called the SI, which share a unique medial stem originating from the retroinsular region. The SI, if it exists, is considered to be an additional border between HG and the PT. 3.1.3.2. First trans¨ erse sulcus (FTS). This sulcus arises from the circular sulcus of insula ŽCSI. near the retroinsular region and runs diagonally

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parallel to HS. It forms a medial border of HG on the bluff of the supratemporal plane opposing the insula. The medial and anterior area to the FTS is defined as the planum polare ŽPP.. 3.1.3.3. Superior temporal sulcus (STS). The trunk of the STS runs horizontally parallel to the posterior horizontal ramus of the SF and defines the inferior border of the superior temporal gyrus ŽSTG. and the superior border of the middle temporal gyrus ŽMTG.. The STS is continuously long and prominent but often segmented; the occurrence of two segments is the most frequent pattern ŽOno et al., 1990.. If two sulci that can be considered as the STS are simultaneously visible on a given coronal slice, the more prominent sulcus is chosen as the border. The anterior portion of the sulcus typically ends close to the temporal pole ŽTP., whereas its posterior part is extremely varied and often gives rise to two branches. The upper branch is often connected to the angular sulcus ŽAS. that is axial to the angular gyrus ŽAG. in the parietal lobe while the lower branch occasionally extends to the anterior occipital sulcus ŽAOS. that arches posteriorly to the angular gyrus ŽOno et al., 1990.. When the lower branch of the STS does not reach the AOS, the AOS can be alternatively defined as a superior border of the caudal portion of the MTG. 3.1.3.4. Inferior temporal sulcus (ITS). The overall course of the ITS is parallel to the STS. In comparison with the STS, however, the ITS is relatively shallow and always interrupted into several segments; the proportion comprising four or more segments is above 60% ŽOno et al., 1990.. The direction, depth and length of each segment are extremely variable. The ITS is not confined to the lateral cerebral surface, but also frequently extends onto the ventral surface. The posterior end of the ITS is also quite variable; it frequently terminates near the pre-occipital incisura or connects with the lateral occipital sulcus. The ITS forms the border between the MTG and the inferior temporal gyrus ŽITG.. Since the ITS always consists of several segments, two or more sulci appear simultaneously on the coronal slices of the transitional zone. We have chosen the lowest sulcus on the lateral surface as a border. Thus, whether or not the lowest lateral sulcus

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runs on the ventral surface, it is not considered to be the border. 3.1.3.5. Occipitotemporal sulcus (OTS). The OTS follows an approximately parasagittal course, just medial to the inferolateral margin of the hemisphere in the caudal part and just lateral to the collateral sulcus in the rostral part. The OTS becomes a border between the ITG and the occipitotemporal gyrus ŽOTG.. The OTS is frequently interrupted, particularly in the posterior part near the pre-occipital incisura; the proportion that is a single continuous sulcus is 48% for the right side and 24% for the left side ŽOno et al., 1990.. When two sulci are visible on coronal slices of the transition area, the more prominent one Žor the lateral one if equal. is chosen as the border. Occasionally, the OTS is duplicated through part of its course, in which case the lateral sulcus is defined as the border. 3.1.3.6. Collateral sulcus (CLS) and rhinal sulcus (RS). The CLS is a constant deep fissure that courses along the ventro-medial side of the temporal and occipital lobe. It separates the OTG from the parahippocampal gyrus ŽPHG. anteriorly and the lingual gyrus posteriorly ŽNaidich et al., 1987.. The CLS is frequently bifurcated in the caudal area ŽOno et al., 1990., where the lateral branch is defined as the medial border of the OTG while the medial border represents the intralingual sulcus. The RS separates the uncus and the head of the PHG from the TP. Its direction is variable, and sometimes it is connected to the CLS ŽOno et al., 1990.. It is considered to be an anterolateral border of the PHG when the CLS does not exist in the rostral area near the TP. 3.1.4. Parietal lobe 3.1.4.1. Post-central sulcus (PoCS). The PoCS is, in most cases, a continuous or twice-segmented Žsuperior and inferior segments. narrow furrow that runs parallel to the CS ŽOno et al., 1990.. When the two segments are not connected or do not overlap, an imaginary line is drawn to complete the pattern of the PoCS. If both segments overlap, the lateral one is considered the anatomical landmark. In approximately 40% of cases, the inferior end of the PoCS does not reach the

SF, so an orthogonal line is drawn to complete it. The superior end normally has a Y-shape without extension to the medial surface of the hemisphere. The posterior branch is taken as the anatomical border, and an orthogonal line is drawn connecting the superior end and the medial surface of the brain. The PoCS may have a double parallel pattern in a few brains Žleft: 16%, right: 8%; Ono et al., 1990.. In those cases, the posterior sulcus is considered the inferior postcentral sulcus. The PoCS is optimally visualized in the transaxial plane and on the three-dimensional rendered brain. It forms the posterior border of the post-central gyrus and the anterior border of the lateral parietal subregions. 3.1.4.2. Intraparietal sulcus (IPS). The IPS is either continuous or consists of two segments Žanterior and posterior segments.. The IPS is a prominent sulcus that runs through the lateral surface of the parietal lobe and subdivides it into superior ŽSPG. and inferior parietal gyri, encompassing the supramarginal ŽSMG. and the angular gyri ŽAG. ŽOno et al., 1990; Duvernoy, 1991.. The anterior end of the IPS is often connected to the PoCS, and the posterior end normally extends into the occipital lobe. Coronal and transaxial planes provide an optimal visualization of the IPS. 3.1.4.3. Primary intermediate sulcus of Jensen (PISJ). This sulcus is defined as the most anterior descending side branch of the intraparietal sulcus ŽIPS. ŽDuvernoy, 1991.. However, its pattern is variable. In some brains the PISJ follows a posterior᎐anterior course and in many others it has an anterior᎐posterior course. The PISJ normally runs posterior to the caudal tip of the SF and anterior to the ascending posterior segment Žangular sulcus. of the superior temporal sulcus. It separates the SMG Žrostrally. from the AG Žcaudally. and is best visualized on the transaxial view. Since it commonly is a short sulcus, a coronal plane including the most anterior-inferior tip of the IPSJ completes the boundary between the SMG and AG on the lateral surface. 3.1.4.4. Subparietal sulcus (SPS). The SPS is not a continuation of the CiS. The anterior end of the SPS is connected to the marginal ramus of the CiS in 32% of the cases ŽOno et al., 1990.. To

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complete its course, a horizontal line from its anterior end to the plane A or to the marginal ramus is drawn. The SPS is often a segmented sulcus. In those cases the shortest possible line between segments connects them. The pattern of the SPS is quite variable, and often several upwardly directed side branches arise from it ŽOno et al., 1990.. If the posterior end presents an H-pattern, the branch of the H that follows a course parallel to the corpus callosum is chosen as the reference sulcus. In spite of its variable anatomical aspect, the SPS forms the border between the pre-cuneus ŽPCuG. Žabove. and the posterior cingulate gyrus ŽPCiG. Žbelow. on the medial surface of the brain. The SPS is easily identified on the sagittal plane. 3.1.5. Occipital lobe 3.1.5.1. Parieto-occipital sulcus (POS). The POS cuts deeply into the medial surface of the hemisphere. It separates the parietal Žpre-cuneus gyrus. from the occipital Žcuneus gyrus. lobes. Its superior end extends to the lateral surface and its inferior end is truly connected with the calcarine sulcus ŽCalS. in approximately 55% of the cases ŽOno et al., 1990.. The superior end of the POS is highly variable in shape and number of side branches. On the midsaggital plane, the superior POS branch that cuts over the lateral surface is chosen as the reference sulcus. The POS is easily seen on the midsagittal plane. 3.1.5.2. Calcarine sulcus (CalS). This sulcus is a clearly definite fissure on the medial surface of the hemisphere. Three segments may be defined: an anterior segment or anterior calcarine sulcus ŽACalS., the calcarine sulcus proper, and a posterior segment or the retrocalcarine sulcus. The intersection point between POS and CalS constitutes the limit between the anterior and proper segments. The retrocalcarine sulcus starts when the proper calcarine sulcus branches off. The ACalS forms the medial border of the parahippocampal gyrus at its posterior portion and separates the PciG from the lingual gyrus ŽLG.. The proper calcarine and the retrocalcarine sulci represent the border between the cuneus ŽCuG. and the LG.

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3.1.5.3. Lateral occipital sulcus (LOcS). The LOcS runs across the occipital lobe and separates the superior ŽSOcG. and the inferior occipital gyri ŽIOcG.. It is present in almost all brains ŽOno et al., 1990., and it is easily identifiable in sagittal planes. In approximately 38% of cases the LOcS is a double parallel sulcus ŽOno et al., 1990.. If this is the case, the superior one is considered the reference sulcus. 3.2. Definition of reference planes The initial step of our parcellation method was to identify a number of reference planes consisting of coronal slices containing given anatomical landmarks. The reference planes serve as the anterior or posterior boundaries for particular cortical subregions, as well as anatomical landmarks to separate the lobes. 3.2.1. Plane A Plane A is a coronal plane passing through the point where the central sulcus intersects with the midsagittal plane. It represents the posterior border of both the caudal ACiG, and the precentral gyrus on the medial wall. Plane A also represents the border between the frontal and parietal lobes on the medial surface of the hemisphere. 3.2.2. Plane B Plane B is a coronal plane passing through the most anterior tip of the inner surface of the genu of the corpus callosum ŽCC.. It constitutes the posterior border of the rostral ACiG Žabove the CC., and separates the ACiG and MFC from the subcallosal area. Plane B also defines the anterior border of the SMA. 3.2.3. Plane C Plane C is a coronal plane including the anterior end of the SF or temporofrontal junction. It forms the posterior border of the TP and the anterior border of the temporal gyri. 3.2.4. Plane D1 Plane D1 is a coronal plane including the most anterior point of HS or the SI if it exists. It

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becomes a border between HG and the PP, and between the PT and the PP, as well as dividing the STG into the rostral and caudal portions. 3.2.5. Plane D2 Plane D2 is a coronal plane including the anterior tip of the pons. It subdivides the MTG and the ITG into the rostral and intermediate portions, and the PHG into the rostral and caudal portions. 3.2.6. Plane D3 Plane D3 is a coronal plane including the posterior tip of the corpus callosum. It becomes a landmark for subdividing the MTG and ITG into the intermediate and caudal portions, and subdividing the OTG into the rostral and caudal portions. 3.2.7. Plane E1 Plane E1 is a coronal plane containing the posterior end of the posterior horizontal limb of the SF. Since the SF varies considerably in its posterior end, several steps are needed to identify it. First, the overall course of the SF needs to be followed through the serial slices of the sagittal view. The SF variably branches into rami, such as the posterior ascending ramus ŽPAR. and the posterior descending ramus ŽPDR.. The second step is to examine the continuity of the deepest point of the SF through the serial coronal slices. According to its continuity, plane E1 is selected in two different manners. When the SF gradually curves upward into the PAR in the sagittal view, plane E1 is defined as the most posterior coronal slice containing the component of the Sylvian fossa regardless of the ends of the PAR and PDR. It frequently forms an isolated area of gray matter ŽGM. that is surrounded with white matter ŽWM. and separated from the PAR in the lateral surface. When there is no PAR, plane E1 is defined as the most posterior coronal slice containing the component of the SF, in which the deepest point of the Sylvian fossa continues to a small sulcus on the lateral brain surface. 3.2.8. Plane E2 Plane E2 is a coronal plane containing the

anterior tip of the parieto-occipital sulcus ŽPOS. on the midsagittal plane, from which it frequently continues to the anterior calcarine sulcus. It represents the boundary between the temporal lobe and the occipital lobe, defining the posterior borders of the MTG, ITG, and OTG. 3.2.9. Plane E3 Plane E3 is a coronal plane containing the posterior tip of the hippocampus. It becomes the posterior border of the PHG. 3.3. Segmentation procedure guidelines for each subregion 3.3.1. Frontal lobe 3.3.1.1. Supplementary motor area (SMA). On the coronal view, tracing begins at the level of the plane B Žanterior border. and, moving caudally in the serial coronal slices, ends when the PaCS is reached Žposterior border.. The most superior point on the medial surface of the hemisphere and the most medial point of the dorsal bank of the CiS represent the two anatomical landmarks needed to trace the SMA on each coronal slice. Nonetheless, on the posterior aspect of the SMA, the PaCS constitutes, depending on its course, either the superior or the inferior boundary of the SMA on each coronal slice. 3.3.1.2. Anterior cingulate gyrus (ACiG). The ACiG is traced on the serial coronal slices. Tracing begins at plane A. Moving rostrally, tracing continues until the most anterior coronal slice in which the CiS is clearly visualized. The deepest point of the CaS and the most medial point of the dorsal bank of the CiS constitute the inner and the outer boundaries of the ACiG in each coronal slice, respectively. The ACiG has been subdivided into r-ACiG and c-ACiG portions. Plane B is used as the arbitrary border between the two portions. Between plane B and the anterior tip of the CC, the r-ACiG is presented as a double structure that extends above and below the CC in each coronal slice. 3.3.1.3. Superior cingulate gyrus (SCiG). The SCiG is traced on serial coronal slices. Tracing starts at the coronal plane containing the posterior extreme of the SCiS. The portion of the

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medial surface of the brain between the most medial point of the dorsal bank of the CiS and the most medial point of the dorsal bank of the SCiG is defined as the SCiG in each coronal slice. Moving rostrally, tracing continues until the most anterior coronal slice in which the SCiS is clearly identified. Anterior to plane B, the SCiG is defined as a double structure that extends above and below the dorsal bank of the CiG in each coronal plane. Above the genu of the CC, when the SCiS extends posterior to plane B, tracing ends at the most caudal coronal slice on which the SCiS is seen. However, when the SCiS has a short course and does not extend posteriorly to plane B, a horizontal line is drawn from its dorsal posterior tip to plane B. 3.3.1.4. Medial frontal cortex (MFC). The MFC is traced on coronal slices. Tracing starts at plane B and continues rostrally until the anterior end of the OS is reached. The most medial point of the ventral bank of the CiS and the medial border of the SG constitute the superior and the inferior boundaries on each coronal slice, respectively. In some cases the OS extends anteriorly to the most anterior coronal slice in which the CiS is seen. In those cases, the SRS is considered the superior boundary on the coronal slices when the SRS is connected to the CiS. However, if the SRS is not connected to the CiS, the superior boundary is defined by the shortest virtual line connecting the most posterior dorsal point of the SRS to the anterior aspect of the CiS. The MFC is usually the last medial wall subregion to be traced, making reference landmarks easily identifiable. 3.3.1.5. Subcallosal area (SCA). On the series of coronal slices, tracing begins on the posterior slice to plane B. The medial border of the SG is the inferior border. The inferior border of the CC represents the superior border of the SCA on coronal slices. Moving caudally, these anatomical landmarks disappear and the SCA, is then defined by the natural limits of the brain on the medial wall. 3.3.1.6. Straight gyrus (SG) or gyrus rectus. We chose transaxial slices to trace the SG. Tracing begins on the most inferior slice that contains the SG. In each transaxial slice, the SG is defined as the portion of the frontal lobe medial to the

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length of the OS. In the series of transaxial slices when the OS is interrupted by another frontal region, an orthogonal line is traced from the anterior end of the OS to the medial surface of the hemisphere. Moving upwards, tracing ends on the most superior slice in which the OS is visualized. Following these guidelines, the boundary of the SG on the medial wall is defined by an imaginary line parallel to the line running through the depth of the OS. This represents a reliable medial boundary of the SG. The large variability in length and pattern of the SRS and inferior rostral sulcus on the medial wall ŽOno et al., 1990. makes them unreliable anatomical landmarks to define the medial border of the SG. 3.3.1.7. Orbitofrontal cortex (OFC). The OFC is traced in the coronal plane. Before tracing begins, the LOS is identified on the intermediate aspect of the frontal lobe where it is clearly identified as the most ventral sulcus on the lateral surface of the frontal lobe. On serial coronal slices, the deepest point of the LOS constitutes the lateral boundary of the OFC. Moving rostrally from this intermediate segment, the lateral boundary changes to the FMS when the LOS disappears. At the posterior aspect, the OIS defines the lateral boundary of the OFC when the LOS disappears. Tracing ends at the most posterior coronal slice containing some aspect of the posterior medial orbitofrontal gyrus that corresponds to the most posterior edge of the OFC ŽDuvernoy, 1991.. In those cases that the LOS and either the FMS on the anterior portion or the orbito insular sulcus ŽOIS. on the posterior portion of the OFC are seen on the same slice, the deepest point of the LOS is always used as the lateral boundary. If the LOS disappears before the OIS appears on the series of coronal slices, a point on the lateral surface at the same level to the posterior extreme of the LOS is used as the lateral boundary. The deepest point of the OS constitutes the medial boundary of the OFC on the posterior and intermediate portions of the OFC. On the anterior portion, when the OS disappears, the deepest point of the SRS represents the medial boundary of the OFC. 3.3.1.8. Pre-central gyrus (PCG). The PCG is traced on the transaxial plane. First, the CS and

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the PCS are identified and traced on the three-dimensional rendered brain. Tracing begins at the superior aspect of the hemisphere, using the deepest point of the CS and the PCS as the posterior and the anterior boundaries, respectively. When the two segments of the PCS are seen on a single transaxial slice, the most prominent one is taken as the anterior boundary of the PCG. Tracing continues downward on serial transaxial slices and ends at the inferior transaxial slice that contains some aspects of the PCG. On the inferior transaxial slices when the PCS is not visualized on the lateral surface, the SF represents the natural posterior border of the PCG. Above the CiS, the PCG is defined in both the medial and the lateral surfaces of the hemisphere. On the medial surface, plane A is considered to be the posterior border, and the deepest point of the PaCS constitutes the anterior boundary. Below the CiS the PCG is exclusively defined on the lateral surface. The inner surface of the frontal operculum between the PCS and the CS is considered to be part of the PCG. 3.3.1.9. Superior frontal gyrus (SFG). Tracing begins at plane B on the coronal slices. The deepest point of the SFS constitutes the lateral boundary, and the medial point of the dorsal bank of the cingulated sulcus ŽCiS. or the Žsuperior cingulated gyrus ŽSciG., if it exists, is the medial border. In those slices on which the two segments of the SFS can be seen, the lateral one is considered the lateral border. However, the SFS does not extend onto the most anterior portion of the frontal lobe. Therefore, when the SFS is not visualized at the anterior portion, the intermediate frontal sulcus ŽIntFS. is taken as the lateral boundary of the SFG. The IntFS frequently crosses over the SFG at the anterior aspect of the frontal lobe ŽOno et al., 1990.. At the anterior portion, when the CiS disappears, the SRS constitutes the inferior boundary of the SFG on the medial wall. When the SRS is not connected to the CiS, the inferior boundary of the SFG on the anterior aspect of the medial wall is defined by the shortest virtual line connecting the most posterior dorsal point of the SRS to the anterior aspect of the CiS. The inferior border of the SFG on the medial wall consti-

tutes at the same time the superior border of the MFC. Posterior to plane B, the SFG is traced on transaxial slices. Tracing begins at the most superior slice that contains the SFG and continues downwards until the SFS disappears. On each transaxial slice, the deepest point of the SFS is considered the posterior border and plane B is the anterior border. 3.3.1.10. Inferior frontal gyrus (IFG). On serial coronal slices, tracing begins on plane B and ends on the coronal slice containing the most anterior point of the IFS. The deepest point of the IFS constitutes the superior boundary on each coronal slice. The inferior boundary of the IFG is the deepest point of the FMS or the LOS in the anterior part, and the deepest point of the SCIS at the level of the frontal operculum. The IFG is traced on the transaxial plane posterior to plane B. Tracing on the transaxial view begins at the most superior slice containing IFG and ends at the most inferior slice in which the IFG can be identified. To select these two slices, we use the two-dimensional sagittal plane. On transaxial slices, the deepest point of the PCS and the deepest point of the IFS are the posterior and the anterior borders, respectively. Moving downwards, the IFS disappears on the series of transaxial slices and then the IFG is defined by and the intersection point between the plane B and the triangle surface contour Žanterior border. and the deepest point of the PCS Žposterior lateral border.. The inner surface of the frontal operculum anterior to the PCS is considered to be part of the IFG. The IFS and the inferior portion of the PCS are easily identified primarily on the three-dimensional rendered brain and in the two-dimensional sagittal plane. 3.3.1.11. Middle frontal gyrus (MFG). On serial coronal slices, tracing begins on plane B. On each coronal slice, the deepest point of the SFS and the IFS constitute the superior and inferior boundaries of the MFG, respectively. The IFS does not reach the anterior portion of the frontal lobe. Anterior to the end of the IFS, the inferior boundary changes to the LOS or the FMS. The MFG is usually defined after tracing the SFG and

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the IFG. Previously identified anatomical landmarks, therefore, help define the MFG. Posterior to plane B the MFG is traced on the transaxial view. On transaxial slices, plane B constitutes the anterior border, and the deepest point of the PCS and the deepest point of the SFS constitute the posterior and the anterior borders, respectively. Moving downwards, the SFS disappears and the intersection point between plane B and the triangle surface contour Žanterior border. and the deepest point of the PCS Žposterior lateral border. constitute the anatomical boundaries for the SFG. When both superior and inferior segments of the PCS are simultaneously seen on a given transaxial slice, the prominent one is taken as the posterior boundary. 3.3.2. Insular cortex The insula is easily defined and traced on serial coronal slices. On the coronal view, tracing starts from the caudal end and moves forward using the deepest point of the SCSI and the ICSI as superior and inferior boundaries, respectively. When the ICSI disappears at the anterior aspect of the insular cortex, the OIS is chosen as the inferior border. If neither the ICSI nor the OIS can be seen in a given coronal slice, the most ventral lateral point of the insula is chosen as the inferior boundary. Examining the transaxial and sagittal views is helpful to determine insular anatomical borders. In the coronal plane, the OIS often begins, at its most posterior aspect, as a shallow furrow on the ventral surface of the hemisphere and runs diagonally to join the anterior end of the SCSI. Anatomical landmarks are easily visualized on the coronal view. 3.3.3. Temporal lobe 3.3.3.1. Temporal pole (TP). Tracing for the TP starts on plane C where there is no frontotemporal junction. Since the lateral, medial, anterior, superior, and inferior boundaries of the TP are defined by the natural limits of the temporal lobe anterior to the frontotemporal junction, tracings are simply done by including all triangulated surface lines reflecting the temporal cortex. Moving

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rostrally, tracing is continued until the triangular surface disappears. 3.3.3.2. Heschl’s gyrus (HG). The first step for tracing HG is to identify HS, a prominent deep transverse sulcus originating from the retroinsular area and extending to the lateral surface. Searching the transaxial and sagittal views is helpful to determine the overall pattern of the gyri and sulci on the supratemporal plane and to differentiate HS among many sulci. Tracing begins on the most caudal coronal slice containing HS, in which it commences as a notch near the medial end of the supratemporal plane. Medial and lateral borders for tracing are the deepest point of the SF and the deepest point of HS, respectively, before the insula appears. The medial border is changed to the CSI after the insula appears. After the FTS appears, the medial border is changed again to the FTS, from which the area between the CSI and the FTS is considered to be the planum polare ŽPP.. The medial border is defined by the SF Žposterior portion of the HG., the CSI Žintermediate portion., and the FTS Žanterior portion.. The lateral border is constantly HS. In those rare cases when the SI appears on the medial side of HS, the lateral border of HG is changed to the SI. Tracing stops when HS Žor the SI, if it exists. is no longer visible or reaches the lateral rim of the supratemporal plane. 3.3.3.3. Planum temporale (PT). While tracing is done on coronal slices, sagittal and transaxial slices need to be examined to obtain an overall view of the course of HS and the pattern of the PT. Tracing begins on plane E1, which indicates the posterior boundary of the PT and STG. Until HS appears, the superior surface of the temporal lobe is traced as the PT; following the deepest point of the SF medially and the lateral rim of the supratemporal plane laterally, a Sylvian fossa presenting with a PAR creates an isolated island of GM or a small notch with an abrupt angle in the depth of the PAR in some coronal slices anterior to plane E1, in which the lateral border of the PT is the lateral extreme of the Sylvian fossa. After HS appears, the medial border is replaced from the deepest point of the SF to HS. If the SI appears on the medial side of HS, the medial

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border of the PT is changed again to the SI. Tracing ends at the coronal slice where HS Žor the SI, if it exists. disappears on the superior surface or reaches the lateral rim. The anterior border depends on the definition of HG, while the posterior one relies on the variability of the SF. 3.3.3.4. Planum polare (PP). Tracing begins at the level of the posterior end of the FTS, in which the FTS is separated from the circular sulcus of the insula ŽCSI.. Tracing is continued following the FTS laterally and the CSI medially. On the level of the anterior tip of HS or the SI, the lateral border of the PP is changed from the FTS to the lateral rim of the supratemporal plane. The FTS, at the posterior aspect, and the lateral rim of the supratemporal plane, anterior to the end of the HG, is considered the lateral border. Tracing ends on plane C. 3.3.3.5. Superior temporal gyrus (STG). Tracing begins on plane E1, the same as the starting point of the PT tracing. In almost all coronal slices, tracing is easily done along the lateral rim of the supratemporal plane dorsally and the deepest point of the STS ventrally. Exceptionally in the caudal area near plane E1, the lateral rim of the supratemporal plane is not found in the type of SF having the PAR because the SF has no extension to the lateral brain surface. In this case, the superior border is the point of the lateral brain cortex at the same level with the most lateral point of the PT. The STG is further subdivided into rostral and caudal portions ŽrSTG and cSTG. in the current method. The portions before arriving at plane D1 are included in the cSTG, and those from plane D1 through plane C are traced as the rSTG. 3.3.3.6. Middle temporal gyrus (MTG). Before tracing, the longitudinal course of the STS and AOS needs to be checked in the serial sagittal slices because the posterior end of the STS is highly variable. In this step, the existence of the lower branch of the STS and the AOS has to be decided. The MTG is further subdivided into rostral, intermediate and caudal portions ŽrMTG, iMTG and cMTG.. After assigning an ROI name as cMTG, tracing starts on plane E2, which represents the posterior boundary separating it from

the occipital lobe. The dorsal border is the AOS until it disappears, and then changes to the STS Žor its lower branch.. The ITS is constantly the ventral border. In cases where the ITS does not reach plane E2, the ventral border is an imaginary point at the same level as the posterior end of the ITS. Moving rostrally, the ROI names are changed to iMTG and rMTG, in turn, when passing plane D3 and plane D2, respectively. Tracing ends at plane C. 3.3.3.7. Inferior temporal gyrus (ITG). Tracing starts on plane E2, continues rostrally following the ITS as a dorsolateral border and the OTS as a ventromedial border, and ends on plane C. As with the MTG, the ITG is further subdivided into rostral, intermediate and caudal portions ŽrITG, iITG and cITG.. The ROI name at the starting point is cITG. Moving rostrally, it is changed to iITG and rITG, in turn, when passing plane D3 and plane D2, respectively. As described in the procedure for the MTG tracing, the same imaginary point is used as the dorsolateral border if the ITS finishes caudally before arriving at plane E2. In the area rostral to the anterior end of the OTS Žit does not usually extend to plane C., the ventromedial border is the CLS or the RS if the CLS also disappears in this level. 3.3.3.8. Occipitotemporal gyrus (OTG). Tracing begins on plane E2 and continues rostrally following the CLS as a medial border and the OTS as a lateral border. Tracing finishes rostrally on the most anterior coronal slice that contains the OTS; at this level, the OTS commonly is embedded within or just lateral to the CLS. Sometimes, the CLS disappears behind the anterior end of the OTS, from which the RS becomes the medial border of the OTG. It is further subdivided into rostral and caudal portions ŽrOTG and cOTG.. The ROI name is cOTG at first, and changes to rOTG from plane D3. 3.3.3.9. Parahippocampal gyrus (PHG). Tracing begins on plane E3. The lateral border is always the CLS, whereas the medial border is variable. The medial boundary is not clear because it is transformed medially into the subicular part of the hippocampal formation without any gross landmark ŽNaidich et al., 1987.. The medial border near the posterior end is often the anterior cal-

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carine sulcus ŽACS.. The sagittal view is helpful to determine whether the ACS extends rostral to the posterior end of hippocampus. The area between the hippocampus and the ACS is considered to be the isthmus. If there is no overlapping portion between the ACS and the hippocampus, the hippocampal sulcus is the medial border of the PHG from the posterior end. Moving rostrally to the ACS, the medial border is changed to the superomedial rim, creating a border between the PHG ventrally and the subiculum dorsally. Near the TP, the medial border is the most medial point of the gyral surface line; consequently, the uncal cortex Ždorsal surface . is excluded in the PHG tracing. Although the CLS keeps its characteristic shape along most of the PHG, it does not usually reach plane C. In the area rostral to the anterior end of the CLS, the lateral border is changed to the RS. The PHG is also subdivided into rostral and caudal portions ŽrPHG and cPHG. in the current method. The ROI name is cPHG at first, and is changed to rPHG when passing plane D2. Tracing ends on plane C. 3.3.4. Parietal lobe 3.3.4.1. Pre-cuneus gyrus (PCuG). Tracing is done on coronal slices and begins at the coronal plane in which the POS intersects with the interhemispheric fissure. Moving rostrally, the deepest point of the POS and the superior rim of the medial surface of the hemisphere are considered the inferior and superior boundaries on each coronal slice, respectively. The inferior border first changes to the deepest point of the ACS when the POS disappears and to the most medial point of the dorsal bank of the SPS when the SPS appears in the series of coronal slices. The superior margin of the hemisphere is constantly the superior border until the marginal ramus of the CiS is reached. Then the deepest point of the marginal ramus of the CiS represents the superior border of the PCuG. Tracing ends either at plane A when the SPS does not intersect the marginal ramus of the CiS, or at the intersection point between the marginal ramus of the CiS and the SPS. 3.3.4.2. Posterior cingulate gyrus (PCiG). Tracing is conducted on coronal slices. Due to the vari-

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able pattern of the SPS ŽOno et al., 1990., the first step is to define the pattern of the SPS on sagittal planes Žsee above.. Tracing starts at plane A. The inferior border changes throughout the series of coronal slices. From plane A to plane E3 Žposterior end of hippocampus., the deepest point of the CaS represents the inferior border and changes to the deepest point of the ACalS posterior to plane E3. If plane E3 is posterior to plane D3, the hippocampal sulcus constitutes the inferior border of the PCiG posterior to plane D3. At the posterior portion, when the anterior portion of the POS appears, the medial point of its dorsal bank defines the inferior border. The medial point of the dorsal bank of the SPS is constantly the superior border on each coronal slice. At the anterior portion, when the SPS is connected to the marginal ramus of the CiS, the deepest point of the marginal ramus constitutes the superior border. Tracing ends at the coronal plane in which the posterior end of the SPS is visualized. 3.3.4.3. Post-central gyrus (PoCG). The PoCG is traced on a series of transaxial slices. Tracing begins at the most superior slice in which some portion of the POG is visualized. On the transaxial slices above the marginal ramus of the CiS, the PoCG consists of a medial and a lateral portion. The deepest point of the marginal ramus and the point in which plane A intersects the midsagittal plane constitute the posterior and the anterior anatomical landmarks to define the medial aspect of the PoCG. On the lateral surface, the deepest points of the CS and the PoCS are the anterior and posterior boundaries, respectively. Moving downward, tracing ends at the most inferior transaxial slice on which part of the parietal operculum can be identified. Inferior to the slice in which the PoCS intersects with the SF, the SF represents the natural posterior border on transaxial slices. The inner surface of the parietal operculum between the PoCS and the CS is considered to be part of the PoCG. 3.3.4.4. Superior parietal gyrus (SPG). The SPG is traced on coronal and transaxial slices. Before tracing, the parieto-occipital boundary on the lateral surface of the brain is defined. There is no clear anatomical landmark between the occipital and the parietal lobes on the convex outer surface

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of the brain ŽCritchley, 1953.. On each coronal slice, the lateral parieto-occipital boundary is defined by the lateral surface points located at the same level as the deepest points of the POS. Thus, an imaginary oblique line starting at the superior marginal end of the POS and following those lateral telegraphed points defines the parieto-occipital line on the lateral surface. Tracing starts at the coronal slice anterior to the junction point between the parieto-occipital line and the superior rim of the medial surface of the hemisphere. On each coronal slice, the superior rim of the hemisphere and the parieto-occipital boundary constitute the superior and the inferior borders. The inferior border changes to the IPS when it appears on the series of coronal slices. When the two segments of the IPS are seen on a given coronal slice, the most lateral segment is taken as the inferior border. Tracing is conducted on coronal slices until the coronal plane containing the posterior portion of the CS is reached. Rostrally to this slice, the SPG is traced on transaxial slices. Tracing begins at the superior slice that contains the SPG and continues downward until the IPS disappears on transaxial planes. On each transaxial slice, the deepest point PoCS is the anterior border, the IPS represents the inferior boundary, and the most coronal plane in which the SPS was traced defines the posterior border of the SPS. 3.3.4.5. Supramarginal gyrus (SMG). The SMG is traced on coronal slices. Determining the overall pattern of the PISJ is crucial for tracing both the SMG and the AG. Searching transaxial and sagittal views facilitates this task. When the PISJ follows a posterior᎐anterior course on the lateral surface, tracing begins on the coronal slice in which the PISJ stems from the IPS. The deepest point of the IPS and the deepest point of the PISJ are the superior and the inferior borders of the SMG on each coronal slice. Moving rostrally, the inferior border changes to the lower branch of the STS when the IPSJ disappears. In those cases that the PISJ follows an anterior᎐posterior course on the lateral surface, tracing begins on the coronal slice containing the posterior᎐inferior extreme of the IPSJ. The deepest point of the PISJ and the deepest point of the lower branch of the

STS are the superior and the inferior borders of the SMG on each coronal slice. Moving rostrally, the superior border changes to the deepest point of the IPS when the IPSJ disappears on the coronal slice. Moving rostrally, the inferior border changes from the lower branch of the STS to the SF when plane E1 is reached. The superior border is the deepest point of the IPS. When two segments of the IPS are seen on the same coronal slice, the most lateral one is selected as the superior border. At the most anterior aspect, the PoCS Žcommonly the inferior segment. represents the superior border on the coronal slices. The SMG is subdivided into rostral and caudal portions Žr-SMG and c-SMG. in the current method. The ROI name is c-SMG at first and then changed to r-SMG when passing plane E1. When the PISJ is located anterior to plane E1, the SMG only consists of the caudal portion Žc-SMG.. 3.3.4.6. Angular gyrus (AG). The AG is traced on coronal slices. The anterior slice containing the AG is defined according to the pattern of the PISJ being complementary to the c-SMG on the lateral surface of the inferior parietal gyrus Žsee above.. On each coronal slice, the superior border is constantly the IPS. Moving caudally, the inferior border on coronal slices changes from the lower branch of the STS to the AOS Žsee the description of the dorsal border of the MTG above.. An overall picture of the temporoparieto-occipital junction on the lateral surface of the brain is required to determine the inferior border of the AG at the posterior portion. If the parieto-occipital line on the lateral surface intersects plane E2, which defines the posterior border of the MTG, ITG, and OTG, the parieto-occipital line constitutes the inferior border. Occasionally the parieto-occipital boundary does not intersect the plane E2. In this case, the LOcS constitutes the inferior border of the AG until the parietooccipital line is visualized in the coronal planes. Tracing ends at the coronal slice in which the IPS cuts over the parieto-occipital line. 3.3.5. Occipital lobe 3.3.5.1. Cuneus gyrus (CuG). The CuG is traced on coronal slices. Tracing begins at the coronal

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slice in which the POS cuts over the medial surface of the hemisphere. Rostrally, the deepest point of the POS is the superior border of the cuneus. Moving caudally from the starting slice, the superior boundary changes to the rim of the medial wall when the POS disappears. The deepest point of the CalS is constantly the inferior border of the coronal slice. Tracing continues rostrally until the most anterior coronal slice in which the CuG is visualized, which is defined by the fusion point between the POS and CalS. The posterior end of the CuG is defined by the natural limits of the occipital pole. The POS at the anterior portion and the superior rim of the hemisphere posterior to the end of the POS on the medial wall are considered the superior border. The proper and the retrocalcarine fissure constitute the inferior border of the CuG. 3.3.5.2. Lingual gyrus (LG). The LG is traced on coronal slices. Tracing starts on plane E3 and ends at the most posterior coronal slice in which the occipital lobe is visualized. The medial border is defined constantly by the CalS. The lateral border is the CLS. However, the pattern of the CLS at the posterior aspect is not always simple ŽOno et al., 1990.. When the CLS is bifurcated, or segmented, the most lateral branch is chosen as the lateral reference sulcus. At the posterior aspect of the ventral surface of the occipital lobe, the intralingual sulcus usually runs medial to the CLS. In some brains, it is not easy to clearly distinguish between the CLS and the intralingual sulcus on the ventral surface. If this is the case, the most lateral sulcus is considered the CLS and therefore considered the anatomical landmark. If the CLS does not reach the posterior end of the occipital lobe, on each coronal slice the point at the same level as the endpoint of the CLS is considered the lateral border. 3.3.5.3. Fusiform gyrus (FG). The FG is traced on coronal slices. Tracing starts at plane E2. The medial border is defined constantly by the CLS. The lateral border is the OTS on the anterior slices. When the OTS disappears on the coronal slice, the lateral border changes to the most lateral point of the ventral surface. There is not a clear anatomical landmark to define the posterior end of the FG. Therefore, we arbitrarily es-

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tablished the posterior boundary as the coronal slice in which the angle between the lateral and the ventral surfaces of the occipital lobe disappears. 3.3.5.4. Superior lateral occipital gyrus (SLOcG). The SLOcG is traced on coronal slices. Tracing starts at the slice in which the parieto-occipital boundary and the LOcS intersect. The superior border is defined by the parieto-occipital boundary at the anterior portion and changes to the most superior point on the medial surface of the hemisphere when the parieto-occipital boundary cuts over the superior rim of the medial wall. The deepest point of the LOcS is the inferior boundary. When the LOcS disappears at the posterior portion of the occipital lobe, the point at the same level as the posterior endpoint of the LOcS defines the inferior border. The posterior coronal slice containing part of the SOG is defined by the natural limits of the occipital pole on the lateral surface. 3.3.5.5. Inferior lateral occipital gyrus (ILOcG). The ILOcG is traced on coronal slices. Tracing starts at plane E2. On each coronal slice, the lateral border is constantly the deepest point of the LOcS. The inferior-medial border is the OTS on the ventral surface of the brain, and changes to the most lateral point of the ventral surface when the OTS disappears. Posterior to the end of the FG, the deepest point of the CLS is considered the inferior-medial border of the IOG.

4. Reliability On each two-dimensional slice, the cortical surface is visualized as a continuous contour that represents the intersection between the two-dimensional plane and the three-dimensional triangulated surface Žsee Fig. 1.. With this surface contour being used as a guide, the different cortical subregions are defined on each two-dimensional slice by the segments of this surface contour that are encompassed within the macroscopic anatomical boundaries described above to define each subregion. Two raters ŽBCF and JK. used this method to trace all cortical subregions. It takes 12᎐14 hours for the cerebral cortex to be

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completely parcelled by a tracer who has neuroanatomical knowledge and is familiar with neuroimaging technology. Before the reliability study began, the two raters worked on several brains to establish all the conventions and anatomical landmarks that had been used for methodological development in order to reduce the legitimate differences in anatomical judgments by raters. The set of brains on which the raters ‘practiced’

was entirely different from the set of brains on which the reliability study was done. A set of 10 brains was used to trace each subregion Žfor list of abbreviations, see Table 1.. The mean cortical gray matter volume Žcm3 . measurements of each subregion are shown in Table 2. Inter-rater reliability for all subregions was calculated with intra-class R coefficients ŽICC. for the cortical gray matter volume measurements

Table 1 Abbreviations Sulcal landmarks

Cortical subregions

ACalS AG AOS CaS CalS CC CiS CLS CS CSI FMS FTS HS ICSI IFS IntFS IPS ITS LOS LOcS OIS OS OTS PaCS PAR PCS PDR PISJ POS PoCS RS SCiS SCSI SF SFS SI SPS SRS STS

ACiG c-ACiGrr-ACiG AG CuG FG FP HG IFG ILOcG InsC ITG r-ITGri-ITGrc-ITG LG MFC MFG MTG r-MTGri-MTGrc-MTG OFC OTG r-OTGrc-OTG PCG PCiG PCuG PoCG PHG r-PHGrc-PHG PT PP SCA SCiG SFG SG SLOcG SMA SMG r-SMGrc-SMG SPG STG r-STGrc-STG TP

Anterior calcarine sulcus Angular gyrus Anterior occipital sulcus Callosal sulcus Calcarine sulcus Corpus callosum Cingulate sulcus Collateral sulcus Central sulcus Circular sulcus of the insula Frontomarginal sulcus First transverse sulcus Heschl’s sulcus Inferior circular sulcus of the insula Inferior frontal sulcus Intermediate frontal sulcus Intraparietal sulcus Inferior temporal sulcus Lateral orbital sulcus Lateral occipital sulcus Orbitoinsular sulcus Olfactory sulcus Occipitotemporal sulcus Paracentral sulcus Post. ascending ramus of Sylvian fissure Pre-central sulcus Post. descending ramus of Sylvian fissure Primary intermediate sulcus of Jensen Parieto-occipital sulcus Post-central sulcus Rhinal sulcus Superior cingulate sulcus Superior circular sulcus of the insula Sylvian fissure Superior frontal sulcus Sulcus intermedius Subparietal sulcus Superior rostral sulcus Superior temporal sulcus

Anterior cingulate gyrus Rostralrcaudal portion of the ACiG Angularis gyrus Cuneus gyrus Fusiform gyrus Frontal pole Heschl’s gyrus Inferior frontal gyrus Inferior lateral occipital gyrus Insular cortex Inferior temporal gyrus Rostralrinterm.rcaudal portion of ITG Lingual gyrus Medial frontal cortex Middle frontal gyrus Middle temporal gyrus Rostralrinterm.rcaudal portion of MTG Orbitofrontal cortex Occipitotemporal gyrus Rostralrcaudal portion of the OTG Pre-central gyrus Posterior cingulate gyrus Pre-cuneus gyrus Post-central gyrus Parahippocampal gyrus Rostralrcaudal portion of the PHG Planum temporale Planum polare Subcallosal area Superior cingulate gyrus Superior frontal gyrus Straight gyrus Superior lateral occipital gyrus Supplementary motor area Supramarginal gyrus Rostralrcaudal portion of the SMG Superior parietal gyrus Superior temporal gyrus Rostralrcaudal portion of the STG Temporal pole

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shown in Table 2. A double cingulate sulcus pattern was found in only three out of the 10 brains

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that we used for the reliability study of the ACiG. Consequently, we do not report any reliability

Table 2 Mean and standard deviation ŽS.D.. of gray matter volumes Žcm3 . of cortical subregions traced in a sample of 10 brains by two raters, the coefficient of variance ŽCV., and their inter-rater reliabilities estimated by intraclass correlation coefficient ŽICC. Cortical subregions

SMA r-AciG c-AciG MFC SCA SG OFC PCG SFG IFG MFG TP HG PT PP r-STG c-STG r-MTG i-MTG c-MTG r-ITG i-ITG c-ITG

R L R L R L R L R L R L R L R L R L R L R L R L R L R L R L R L R L R L R L R L R L R L R L

Tracer 1

Tracer 2

ICC

Mean ŽS.D..

CV Ž%.

Mean ŽS.D..

CV Ž%.

1.96 Ž0.50. 2.78 Ž0.84. 5.67 Ž1.89. 6.29 Ž1.80. 5.02 Ž0.64. 4.92 Ž1.02. 1.51 Ž0.58. 1.07 Ž0.74. 0.33 Ž0.13. 0.43 Ž0.16. 2.46 Ž0.64. 2.11 Ž0.54. 14.23 Ž1.75. 14.32 Ž2.09. 12.14 Ž2.05. 12.08 Ž1.79. 18.68 Ž3.27. 18.98 Ž3.76. 7.81 Ž1.80. 8.76 Ž1.82. 6.09 Ž3.92. 6.46 Ž3.73. 6.36 Ž1.22. 7.51 Ž1.05. 1.06 Ž0.24. 1.14 Ž0.25. 1.50 Ž0.39. 1.61 Ž0.42. 1.37 Ž0.37. 1.34 Ž0.34. 0.91 Ž0.49. 1.13 Ž0.58. 3.54 Ž0.78. 3.57 Ž1.36. 2.83 Ž0.61. 2.37 Ž0.59. 4.92 Ž1.53. 4.41 Ž0.77. 2.37 Ž1.06. 2.48 Ž1.12. 2.62 Ž0.66. 2.78 Ž0.73. 3.04 Ž0.68. 3.40 Ž0.77. 2.28 Ž0.82. 2.30 Ž0.49.

25 30 33 28 12 20 38 69 39 34 26 25 12 14 16 14 17 19 23 20 24 22 19 13 22 21 26 26 27 25 53 51 22 38 21 24 31 17 44 45 25 26 22 22 35 21

2.00 Ž0.53. 2.77 Ž0.80. 6.15 Ž2.12. 6.54 Ž1.85. 5.24 Ž0.62. 5.01 Ž1.06. 1.46 Ž0.50. 1.16 Ž0.76. 0.36 Ž0.12. 0.43 Ž0.12. 2.38 Ž0.61. 2.06 Ž0.50. 14.35 Ž2.26. 14.82 Ž2.25. 12.60 Ž1.60. 12.30 Ž2.05. 18.65 Ž3.23. 18.57 Ž3.94. 8.48 Ž2.07. 8.70 Ž1.78. 16.34 Ž3.96. 16.77 Ž3.55. 6.37 Ž1.24. 7.53 Ž0.95. 1.06 Ž0.23. 1.15 Ž0.27. 1.41 Ž0.45. 1.57 Ž0.43. 1.40 Ž0.37. 1.37 Ž0.40. 1.00 Ž0.53. 1.09 Ž0.48. 3.34 Ž0.80. 3.36 Ž1.20. 2.75 Ž0.60. 2.43 Ž0.78. 5.13 Ž1.17. 4.53 Ž0.79. 2.31 Ž0.89. 2.34 Ž1.01. 2.51 Ž0.69. 2.83 Ž0.68. 3.11 Ž0.64. 3.58 Ž0.59. 2.37 Ž0.92. 2.40 Ž0.62.

26 28 34 28 11 21 34 65 33 27 25 24 15 15 12 16 17 21 24 20 24 21 19 12 21 23 31 27 26 29 53 44 23 35 21 32 22 17 38 43 27 24 20 16 38 25

0.93 0.98 0.94 0.88 0.86 0.94 0.93 0.96 0.89 0.91 0.99 0.98 0.92 0.96 0.92 0.90 0.98 0.97 0.87 0.91 0.96 0.97 0.99 0.99 0.94 0.94 0.98 0.93 0.98 0.96 0.96 0.83 0.97 0.93 0.80 0.74 0.91 0.88 0.91 0.83 0.80 0.88 0.97 0.81 0.90 0.82

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116 Table 2 Ž Continued. Cortical subregions

r-OTG c-OTG r-PHG c-PHG InsC PoCG PcuG PciG SPG r-SMG c-SMG AG CuG LG FG SLOcG ILOcG 1

R L R L R L R L R L R L R L R L R L R L R L R L R L R L R L R L R L

Tracer 1

Tracer 2

ICC

Mean ŽS.D..

CV Ž%.

Mean ŽS.D..

CV Ž%.

4.43 Ž1.14. 3.87 Ž1.43. 3.56 Ž1.33. 3.33 Ž0.80. 1.19 Ž0.46. 1.14 Ž0.47. 2.97 Ž0.61. 3.48 Ž1.06. 8.02 Ž0.86. 8.10 Ž0.73. 10.11 Ž1.28. 11.28 Ž1.51. 10.03 Ž2.22. 9.74 Ž2.29. 3.67 Ž0.90. 3.91 Ž0.99. 7.67 Ž1.98. 8.04 Ž2.09. 5.77 Ž1.51. 6.88 Ž1.36. 4.21 Ž2.61. 4.74 Ž2.67. 7.11 Ž3.85. 6.45 Ž3.28. 6.50 Ž0.77. 5.75 Ž0.98. 11.14 Ž1.83. 10.22 Ž1.11. 4.27 Ž1.13. 4.41 Ž0.76. 7.60 Ž1.85. 8.13 Ž1.06. 6.01 Ž1.42. 6.14 Ž2.10.

25 36 37 24 38 41 20 30 10 9 12 13 22 23 24 25 25 25 26 19 61 56 54 50 12 17 6 1 26 17 24 13 23 34

4.34 Ž1.13. 3.71 Ž1.40. 3.59 Ž1.24. 3.41 Ž0.60. 1.32 Ž0.42. 1.22 Ž0.61. 2.94 Ž0.62. 3.47 Ž1.08. 8.10 Ž0.88. 8.22 Ž0.75. 10.04 Ž1.46. 10.84 Ž1.63. 9.63 Ž2.21. 9.45 Ž2.22. 3.87 Ž0.84. 4.08 Ž0.59. 7.76 Ž1.62. 7.88 Ž1.86. 6.15 Ž1.60. 7.29 Ž1.81. 4.19 Ž2.62. 5.78 Ž2.77. 6.99 Ž3.86. 5.74 Ž3.21. 6.73 Ž0.97. 5.62 Ž0.79. 10.91 Ž1.73. 10.20 Ž1.06. 4.75 Ž1.13. 5.04 Ž1.05. 7.62 Ž1.65. 8.90 Ž1.22. 5.76 Ž1.50. 5.28 Ž1.94.

26 37 34 17 31 50 21 31 10 9 14 15 22 23 21 14 20 23 26 24 62 47 55 55 14 14 15 10 23 20 21 13 26 36

0.98 0.97 0.98 0.62 0.88 0.86 0.93 0.98 0.98 0.97 0.93 0.79 0.87 0.95 0.84 0.70 0.89 0.92 0.96 0.81 0.95 0.84 0.99 0.81 0.76 0.93 0.96 0.94 0.83 0.60 0.96 0.65 0.91 0.82

See Table 1 for abbreviations.

score for the SCiG in this report. Instead, the SCiG was considered to be part of the ACiG in those few cases of a double cingulate sulcus. The reliability study of the insular cortex was conducted on a set of 20 brains.

5. Validity Determining the validity of a method is always difficult for in vivo imaging studies. The population variability of both structure and function of a

specific anatomic subregion is a major source of concern. Brodmann’s maps are sometimes thought of as a standard reference for functional specialization, but they are, in fact, based on structural post-mortem studies and must confront the same problem of variability. Although there is a consensus about the cytoarchitectonic and fiberarchitectonic character of some cortical regions Že.g. primary visual: Brodmann’s area 17., even many of these are highly variable in size and in the relation to gyral patterns among normal brains ŽZilles, 1990; Rademacher et al., 1993.. Since

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individual variability is a topic of great interest in human in vivo imaging studies, we felt it was important to choose a method for parcellating cortical areas that would permit preservation of information about individual variations in size and function. Our selection of subregions was based on a carefully chosen compromise that would achieve good reliability, preserve information about individual variation so that this could subsequently be measured, and identify regions that are likely to be functionally relevant to the study of normal brain activity and disease processes. The regions chosen for parcellation were based on a review of multiple PET studies of healthy volunteers and people suffering from schizophrenia who have been studied in our center over the past 8 years. In the process of analyzing PET scans from approximately 300 individuals, which are always registered on MR scans, we have observed that activations frequently follow recognizable gyri ŽAndreasen et al., 1995a,b,c, 1996; Arndt et al., 1996; O’Leary et al., 1996, 1997; Miller et al., 1997; Johnson et al., 1999; Crespo-Facorro et al., 2000; Kim et al., 2000a,b; Wiser et al., 2000.. Sometimes adjacent regions are activated andror dissociate from one another Že.g. motor vs. sensory cortex. in ways that are expected based on known functions and the lesion literature, and sometimes we have identified dissociations not previously described, but that are reproducible with repeated PET studies of different groups of subjects performing different, but related, tasks. Thus, our selection of gyri for parcellation was driven, in part, by a recognized need to be able to use the gyri themselves in functional imaging studies, as a complement to the standard function-of-interest methods that are currently widely used ŽWorsley et al., 1992.. One PET study has been chosen to illustrate this rationale. This particular study illustrates both aspects of our approach to validation: separation of gyri that have known functional significance based on lesion literature Žlingual gyrus and cuneus., as well as gyri not previously described as dissociated in lesion studies, but which consistently dissociate in our PET studies Žstraight gyrus and orbital frontal cortex..

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The two images shown in Fig. 7 are from a PET study that examined novel vs. well-learned memory for faces ŽWiser et al., 2000.. This study measured regional cerebral blood flow using PET with O 15 H 2 O in 34 healthy normal volunteers who were recruited from the community by newspaper advertising. Subjects were screened using a structured interview to rule out psychiatric, neurological, or serious medical illnesses. Twenty-one were female and 13 male; their mean age was 26.3 ŽS.D. 7.8.. Two conditions were used to make direct comparisons between practiced memory vs. novel memory: recognition memory for well-learned faces and recognition memory for recently learned faces. The tasks were matched in all respects except the degree of familiarity with the previously learned material. Subjects were trained for the condition referred to as ‘practiced memory’ by having them come in 1 week before the PET study and allowing them to train until they were perfectly familiar with a set of 18 faces. During a second ‘refresher course’, on the day before the study, they were allowed to review the faces again. Their performance was evaluated using a ‘yes’r‘no’ recognition test with the learned faces intermixed with distractor faces. Performance on both occasions was faultless, as it also was during PET data acquisition. For the condition referred to as ‘novel memory’, subjects were exposed to a new set of 18 faces 1 min before the PET study. They were subsequently asked to identify as ‘seen before’ or ‘never seen’ during the PET data acquisition by saying ‘yes’ or ‘no’, respectively. Statistical analysis of the images was performed using an adaptation of the method of Worsley et al. ŽWorsley et al., 1992; Arndt et al., 1996.. The figure shows the results of subtracting novel memory Žblue. from practiced memory Žred.. Several findings from this study support the validity of our parcellation strategies. For example, differences are clearly seen in ventral frontal regions, which have not been separated in previous frontal lobe parcellation methods Že.g. Caviness et al., 1996.. The straight gyrus ŽSG. is quite distinct from the orbital frontal cortex ŽOFC., with the former being more active in practiced memory and the latter in novel memory, as seen

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clearly in the transaxial plane in Fig. 7B. Further, medial frontal cortex ŽMFC. is differentiated and seen as a discrete gyral area more active in practiced memory, as seen in the sagittal view in Fig. 7B. In this same near-midline sagittal view, three discrete regions are also identified that are identical to gyri identified through our parcellation methods: a lower area of activation during practiced memory that is equivalent to medial frontal cortex ŽMFC., as well as two distinct areas with higher flow in novel memory that are equivalent to rostral anterior cingulate gyrus ŽrACiG. and superior frontal gyrus ŽSFG.. This same plane also shows the discrete separation of two gyri with increased flow during practiced memory that are also separated by our parcellation methods, the lingual gyrus ŽLG. and cuneus gyrus ŽCG.. We have previously discussed the interpretation of these differential activations for novel vs. practiced memory for new vs. familiar faces in the context of the lesion literature and our current understanding of the neural basis for facial recognition ŽAndreasen et al., 1995b; Wiser et al., 2000.. For example, practiced memory produced peaks in a widely distributed network that is presumed to be involved in memory storage, based on the lesion literature concerning prosopagnosia. Areas activated during practiced memory include the straight gyrus ŽSG., the medial frontal cortex ŽMFC., the middle temporal gyrus ŽrMTG and iMTG., and the cuneus and lingual gyri ŽCG, LG.. Those areas form the equivalent of a lexicon, but for faces instead of words. Indeed, storage for modality-specific information Žhere visual and more specifically facial. appears to be in the proximity of the sensory areas processing those stimuli. From the perspective of examining the validity of our parcellation decisions, this PET study Žas well as others that cannot be described in detail due to space constraints . demonstrates that the individual gyri we have selected to differentiate have some biological validity. They correspond to areas activated discretely in functional imaging studies, and they also are consistent with areas considered to be differentiated through lesion studies. Although selected in part because they are based on visible sulcal boundaries, they were

also chosen after we had analyzed PET data from a broad range of tasks involving memory, language, attention, and emotion. Observation of discrete activations in these tasks helped us to select gyral regions for parcellation that were based on empirical observation of neural response to cognitive stimuli. Therefore, these parcellation methods are not simply arbitrary divisions devoid of functional significance, and they are likely to be useful as ROIs in future functional imaging studies employing both fMR and PET.

6. Discussion MRI-based brain morphological research is an established methodology with a broad range of potential applications in basic human brain science ŽCaviness et al., 1999.. The description of accurate cortical maps based upon the pattern of gyri and sulci of the individual brain has been enhanced by the improvement of MRI resolution. The current study, based upon the strengths of three two-dimensional orthogonal planes Žtransaxial, coronal and sagittal. and three-dimensional visualization of cerebral landmarks, describes a new MRI-based parcellation method for subdividing the entire cerebral cortex into 41 functionally relevant regions Žsee Figs. 4᎐6.. This method has proven to be highly reliable and reproducible in measuring the gray matter volume and surface area of specific subregions of the cerebral cortex. Our method will permit quantitative assessments of cortical parameters in circumscribed anatomical cortical regions and, additionally, will provide functionally relevant ROIs in coregistered MRrPET studies so that quantitative cerebral blood flow measurements can be obtained in those regions. Our results have shown the current parcellation method to be highly reliable and reproducible in measuring the surface area and GM volume of specific cortical subregions. As shown in Table 2, most of the subregions have demonstrated high ICCs. The ICCs for the reliability of gray matter volume ranged from a low of r s 0.60 Žleft FG. to a high of r s 0.99 Žseveral subregions..

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Fig. 5. Three views Žlateral, superior, and ventral. of the three-dimensional rendered brain on which the different TEMPORAL subregions have been displayed in distinctive colors. The names of the different regions have been labeled on each view accordingly. See Table 1 for key to abbreviations. Fig. 6. Three views Žlateral, medial and ventral. of the three-dimensional rendered brain on which the different PARIETAL and OCCIPITAL subregions have been displayed in distinctive colors. The names of the different regions have been labeled on each view accordingly. See Table 1 for key to abbreviations. Fig. 7. Two sets of images from a PET study, which indicate the validity of this approach to parcellation, in that activations follow gyral anatomy as defined by our parcellation methods. The images show a subtraction analysis of a group of 33 healthy volunteers who are performing a facial recognition task. Memory for new faces Žblue. has been subtracted from well-practiced memory for familiar faces Žred.. In each pair of images, the ‘peak map’ Žleft side of image. shows the small areas where all contiguous voxels exceed the pre-defined threshold for statistical significance Ž3.61.. The ‘t-map’ Žright side of image. shows the value of t for all voxels in the image and provides a general overview of the landscape of regional differences in blood flow during the two tasks. Green cross-hairs show the location of the slices. Images use radiological convention Ži.e. standing at the foot of the bed.. Two different planes have been chosen to illustrate the location of the relevant activity for each specific task. A shows an inferior and lateral location, while B shows a location that is nearly midsagittal and higher. During the novel memory condition significant activations are seen in the OFC, the rACiG and the SFG. During the practiced memory condition significant activations are seen in SG, MFC, rMTG and iMTG, LG and CG.

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For 73 out of 80 cortical subregions Ž91%., the reliability scores of gray matter volumes were r s 0.80 or greater. In spite of complexities of topographic variation in the slice-to-slice approach adopted in the current method, strong inter-rater agreement is achieved by our detailed tracing guidelines and useful tools such as the visualization of the triangulated cortical surface. Considerable individual variation of sulcal patterns and occasional lack of obvious gyral boundaries are not only inherent problems for cortical parcellation methods, but also are valid in that they reflect variation in neural connectivity ŽVan Essen, 1997.. As in previous topography-based parcellation methods, our method is also based on the assumption that macroscopic variability of interindividual and interhemispheric gyral and sulcal patterns reflects functional and cytoarchitectonic differences ŽFig. 7.. This inference is supported by our extensive PET data base. The relationship between microstructurally defined cortical areas and topographical frontal subregions is not considered in this article. The correspondence between functional domains, cortical areas delimited by microstructural borders, and topographic defined anatomic regions is still unknown ŽRoland and Zilles, 1998.. In the absence of an in vivo cytoarchitectonic map of the human brain, the topography-based parcellation method remains a useful approach for the analysis of structural and functional imaging data. The present parcellation system is considered to be a topography-only based mapping method of the cerebral cortex, according to the model proposed by Rademacher et al. Ž1992. and Caviness et al. Ž1996.. Our method is based upon a set of previous topographic landmarks and the strengths of existing methods, but we have also made several modifications and innovations. 6.1. Distincti¨ e features of the current guidelines 6.1.1. Frontal lobe 6.1.1.1. Definition of the supplementary motor area (SMA). Two anatomically and functionally distinct areas, the F6 or pre-SMA Žrostral part. and the F3 or proper-SMA Žcaudal part., form the SMA ŽMatelli et al., 1991.. The pre-SMA is

involved in internal representation of time and internal selection of movement, and is activated during ‘complex’ tasks requiring selection of response ŽHalsband et al., 1993; Picard and Strick, 1996.. Previous studies have described the anterior boundary of the SMA on the medial wall by a line orthogonal to the AC-PC axis and passing through the anterior commissure ŽCaviness et al., 1996; Zilles et al., 1996.. This anatomical landmark, although it includes the proper-SMA, does not seem to be an accurate boundary to include all the pre-SMA. Because our method was designed to encompass the rostral part of the SMA, we have chosen plane B to define the anterior boundary of the SMA on the medial wall. 6.1.1.2. Subdi¨ ision of the anterior cingulate (ACiG). The ACiG is a structurally and functionally heterogeneous brain region. Animal studies, cognitive and functional neuroimaging studies have shown some differences in the connectivity and functions of the rostral-ACiG vs. the caudalACiG ŽDum and Strick, 1991; Shima et al., 1991; Paus et al., 1993; Devinsky et al., 1995.. The macroscopic border between these two distinct ACiG subregions is unclear. We have chosen plane B as a reproducible and reliable anatomical limit between both regions. However, the SCiG was not treated as a structure independent of the ACiG in the reliability study. Because the SCiG is found in approximately only one third of brains, we recommend that the operational definition of the ACiG should include the SCiG in future investigations where the SCiG is present. 6.1.1.3. Subdi¨ ision of the ¨ entral frontal cortex. The ventral frontal cortex is subdivided into two subregions, the OFC and the SG. Animal studies ŽMueller-Preuss et al., 1980. and functional neu¨ roimaging studies ŽAndreasen et al., 1995a; Crespo-Facorro, unpublished results . have shown the SG is specifically engaged in cognitive and behavioral functions. Treating the OFC and the SG as two distinct cortical subregions may benefit the understanding of morphological and functional characteristics of the ventral regions of the frontal lobe. As an addition to our previous article on frontal lobe parcellation ŽCrespo-Facorro et al., 1999., we have included a more detailed definition of the lateral border between the OFC

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and the insular cortex based on previous studies ŽMesulam and Mufson, 1985.. 6.1.1.4. Frontal pole (FP) definition. We sought to parcellate the anterior aspect of the frontal lobe that has been defined more generally as the FP in previous parcellation methods ŽCaviness et al., 1996; Wible et al., 1997.. Commonly, several functionally differentiated frontal subregions Ži.e. SFG, MFG, OFC and ACiG. are included in the FP. Previous volumetric studies considering the FP as a frontal subregion have described that it represents the largest subregion within the frontal lobe Ži.e. the volume of the FP in humans is nearly double the SFG volume; Kennedy et al., 1998.. We felt a new approach to parcel this subregion was necessary to investigate possible structural abnormalities in specific areas of the FP and to enhance the validity of the rest of the functional frontal subregions defined. The anterior aspect of the frontal cortex is considered either part of the SFG or the MFG on the lateral surface, or either part of the OFC or the SFG on the medial surface of the hemisphere. 6.1.1.5. Definition of the subcallosal area (SCA). The region of the medial wall posterior to plane B was not included as a subregion in our previous parcellation method of the frontal cortex. The SCA is considered as part of the paralimbic system and is engaged in emotional and cognitive functions ŽMesulam and Mufson, 1982; Royet et al., 1999.. In our method the posterior coronal slice in plane B is the anterior border of the SCA. This anterior anatomical border is more posterior than those defined in previous methods. Thus, the volume of the SCA following our definition is smaller than described in previous methods. 6.1.2. Insular cortex 6.1.2.1. Anterior᎐inferior border of the insula. The insular cortex has been defined as the fifth lobe of the brain. It has an elliptical shape and is located at the base of the SF covered by the fronto-orbital, frontoparietal and temporal opercula ŽMesulam and Mufson, 1985.. The insular cortex is a limbic integration region that is engaged in emotional and cognitive functions ŽAugustine, 1996.. It is clearly delimited at its posterior portion by the SCSI Žsuperior border. and the ICSI Žinferior

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border.. Yet, at the anterior aspect, since the ICSI does not extend rostrally to the limen of the insula, there is not a clear inferior topographic boundary between the insula and the OFC ŽMesulam and Mufson, 1985.. We have considered the OIS and the most ventral-lateral point of the insula as the inferior border at the anterior portion of the insula. These anatomical landmarks provide a reliable and valid method to define the insular cortex. 6.1.3. Temporal lobe subregions 6.1.3.1. Posterior boundary of the temporal lobe. The temporal lobe posterior limit is indistinct and is conventionally represented by an arbitrary imaginary line drawn from the posterior end of the SF to another imaginary line connecting the posterior tip of the POS and the pre-occipital notch ŽMartin, 1996.. This definition is not appropriate for precise parcellation, because it is difficult to identify the pre-occipital notch, which is seen only in the three-dimensional view. As an alternative, we have chosen the step-shaped posterior boundary that consists of plane E1, the caudal part of the STS or part of the AOS, and plane E2. We have found that plane E2, marked by the anterior tip of the POS on the midsagittal plane, tends to be located just behind the preoccipital notch in the three-dimensional view. 6.1.3.2. Variability of the posterior end of the Syl¨ ian fissure. The SF frequently bifurcates posteriorly into the PAR and PDR. The posterior border of the PT and STG, termed plane E1 here, corresponds to an endpoint of the posterior horizontal limb of the SF. There have been several different classification systems used to clarify the position of this plane ŽSteinmetz et al., 1990; Witelson and Kigar, 1992; Ide et al., 1996.. We have addressed this variability by defining plane E1 in two different manners. First, in cases of gradual upward angulation of the SF into the PAR, plane E1 corresponds to the posterior end of the SF. On the coronal view, this real end is usually located posterior to the bifurcation point. The inverted type, with a forward-directed ascending ramus ŽIde et al., 1996., has not been considered in our method because it is usually shallow and not a continuation of the Sylvian

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fossa. Second, in cases of a straight SF without the PAR, plane E1 corresponds to the simple end of the Sylvian fossa that terminates as a small sulcus on the lateral brain surface. 6.1.3.3. Definition of the supratemporal structures. There are remarkable differences in the anatomical definitions of HG and the PT across authors that stem from the variability of the supratemporal convolution. According to the description by Steinmetz et al. Ž1989., HS is defined by the most anterior deep sulcus that commences from the retroinsular region, and if two transverse sulci originate separately from the retroinsular region, only the anterior one is considered to be HS. Since HS does not always reach the lateral rim of the supratemporal surface, a coronal plane containing the anterior tip of HS has been defined as an anterior border of the PT. According to this definition, the anterior portion of the convolution, which can be considered to be part of HG, would be excluded in the tracing of HG. Consistently, evoked response studies have shown that the primary auditory area was restricted to the posteriomedial region of HG ŽLiegeois-Chauvel et al., 1991.. Defining the border between HG and the PT can pose problems when the SI, which usually does not originate from the retroinsular region, incompletely splits the convolution into an anterior and posterior portion. The identification of HS requires a retroinsular commencement, and the SI is ignored unless it is a single prominent transverse sulcus; the portion between the SI and HS is considered to be part of HG ŽSteinmetz et al., 1989.. In the current study, however, the portion lateral to the SI has been considered to be part of the PT, and the anterior border of HG and the PT has been changed to the coronal plane containing the anterior tip of the SI. This definition is different from that of Steinmetz et al. Ž1989., but compatible with that of Penhune et al. Ž1996. and Rojas et al. Ž1997.. In contrast to previous procedures, we have only used the coronal slices for tracing all subregions. The sagittal and transaxial views have been only used to outline the course of HS and the SI. 6.1.3.4. Subdi¨ ision of the temporal gyri. We found it problematic to apply the same landmarks

to subdivide the visual association cortices such as the MTG, ITG and OTG, as was done in the previous method of Rademacher et al. Ž1992.. The anatomical landmarks chosen for their method are quite variable in position. Therefore, using those landmarks results in a great variability of the subregional volumes among the compartments of the temporal gyri. Such variability is meaningful for the superior temporal structures in terms of asymmetry. However, given that the three temporal gyri are completely different structures in function, they do not appear to be affected by such landmarks with superior location and marked positional variation. We have used a set of different landmarks for their subdivision: the anterior tip of the pons Žplane D2. and the posterior tip of the corpus callosum Žplane D3.. These landmarks are relatively constant in position and give balanced volumes to each of their compartments. 6.1.3.5. Definition of the parahippocampal gyrus (PHG). We have used the gyral ridge, expressed by the superiomedial rim, instead of the hippocampal fissure for the following two reasons. First, as mentioned before, the limbic structures above the rostral PHG such as the uncus and the amygdala, have to be excluded because the triangulated surface, used as a major tool of measurement in the current method, is not appropriate for such a GM complex. Second, the subiculum, which constitutes the largest portion of the lower bank of the hippocampal sulcus above the caudal PHG, needs to be excluded in the PHG tracing. The subiculum has traditionally been classified as a component of the hippocampal formation and included in the delineation of the hippocampus in the hippocampal volumetric studies ŽWatson et al., 1992; Van Hoesen, 1995.. 6.1.4. Parietal lobe 6.1.4.1. Identification of the PISJ. The definition and identification of the PISJ is of importance since it determines the border between the SMG and AG on the lateral inferior parietal gyrus. Following the description by Duvernoy Ž1991., we have defined the PISJ as the most anterior downward-projecting sulcus that commences from the IPS. Nevertheless, due to the variability in down-

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ward side branches of the IPS and in the course of the PISJ ŽOno et al., 1990., we strongly recommend checking transaxial and sagittal planes to localize the inferior extreme of the PISJ. It is of note that when the inferior extreme of the PISJ is anterior to plane E1, the SMG is not subdivided into caudal and rostral portions. If this is the case, only the rostral SMG is defined. 6.1.4.2. Definition of parieto-occipital boundary on the lateral surface. No clear-cut boundary distinguishes the occipital lobe from the neighboring parietal lobe on the lateral surface of the brain ŽDuvernoy, 1991.. An imaginary line connecting the point where the POS cuts into the dorsal hemisphere margin and the pre-occipital notch has been defined as the posterior border of the parietal lobe ŽCritchley, 1953.. However, the preoccipital notch is not easily identified in the adult brain ŽCritchley, 1953.. Therefore, on each coronal slice, we defined the lateral parieto-occipital boundary by telegraphed points on the lateral surface of the brain situated at the same level as the deepest points of the POS. Thus, a parallel line to the POS is defined as the parieto-occipital boundary on the lateral surface of the brain. These landmarks constitute a reliable and reproducible border. Previous parcellation methods have defined the orthogonal plane drawn passing through the point where the POS cuts into the dorsal hemisphere margin as the border between the parietal and the occipital lobes on the lateral surface ŽRademacher et al., 1992..

and the ILOcG on the lateral surface, and the CuG and the LG on the medial surface of the brain constitute the most posterior portion of the occipital lobe. However, the lack of clear anatomical boundaries at this posterior portion of the brain, particularly on the ventral surface of the brain, makes it difficult to establish a reliable set of anatomical landmarks. The fact that the reliability score for the left FG ŽICC s 0.60. is the lowest ICC for any of the cortical subregions analyzed may reflect this difficulty.

6.1.5. Occipital lobe 6.1.5.1. Occipital pole definition. We sought to parcel the posterior aspect of the occipital lobe that has been defined more generally as the occipital pole ŽOP. in previous parcellation methods. The OP was arbitrarily defined as the caudal 10% of the Y axis extent through the hemisphere on the lateral and the ventral brain surfaces ŽRademacher et al., 1992.. We felt a more detailed approach to parcel this subregion was necessary to investigate possible abnormalities in specific occipital areas and to enhance the validity of the remaining occipital subregions that have been defined. Thus, the posterior aspects of the LG and the FG on the ventral surface, the SLOcG

The present study was performed at the University of Iowa, Iowa City, IA, USA, with the following grant support: MH31593, MH40856 and MHCRC43271.

7. Conclusion In conclusion, the current study indicates that by utilizing topography-based guidelines as described above, the entire human cortex can be parcelled successfully and reliably. We believe this new method will help characterize the subtle gross structural anomalies in specific cortical subregions that might reflect underlying neuropathological processes in neurological and mental illnesses. Additionally, the development of accurate parcellation systems of the human cortex based on MR images will permit investigators to achieve a better spatial localization, and in turn a better understanding, of the complex activation patterns observed in functional neuroimaging studies.

Acknowledgements

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