INFORMATION TO USERS
This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer.
The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, prim bleedthrough, substandard margins, and improper alignment can adversely affect reproduction.
In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note wiQ indicate the deletion.
Oversize materials (e.g^ maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand comer and continuing from left to right in equal sections with small overlaps. Each original is also photographed in one exposure and is included in reduced form at the back of the book.
Photographs included in the original manuscript have been reproduced xerographically in this copy. Higher quality 6" x 9" black and white photographic prints are available for any photographs or illustrations appearing in this copy for an additional charge. Contact UMI directly to order.
A Beil & Howell Information Company 300 North ZeeD Road. Ann Arpor. Ml 48106-1346 USA 313/761-4700 800:521-0600
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. MRI STUDIES OF THE BRAIN: APPLICATION OF THREE-DIMENSIONAL SURFACE-RENDERING TECHNIQUES TO QUANTITATIVE MORPHOMETRY OF THE SUPRATEMPORAL
CORTEX ty Jennifer Jeryl Kulynych submitted to the Faculty of the College of Arts And Sciences of The American University In Partial Fulfillment of the Requirements for the Degree
of Doctor of Philosophy in
Psychology
SIGNATURES OF COMMITTEE : CHAIR: ^
DEAN OR THE COLLEGE
DATE 1993
THE AMERICAN UNIVERSITY WASHINGTON, D.C. 20016 THE AMERICAN UNIVERSITY LIBRARY
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. UMI Number: 9608812
UMI Microform 9608812 Copyright 1996, by UMI Company. All rights reserved.
This microform edition is protected against unauthorized copying under Title 17, United States Code.
UMI 300 North Zeeb Road Ann Arbor, MI 48103
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. MRI STUDIES OF THE BRAIN: APPLICATION OF
THREE-DIMENSIONAL SURFACE-RENDERING TECHNIQUES TO QUANTITATIVE MORPHOMETRY OF THE SUPRATEMPORAL
CORTEX
by Jennifer Jeryl Kulynych ABSTRACT
New techniques for MRI surface-rendering morphometry were developed to yield more reliable and valid measurements of
supratemporal cortical structures. Asymmetry of the planum temporale
(PT), a supratemporal region of language-related association cortex, was then investigated in 10 schizophrenics and 10 age-matched controls, and
in a larger sample of 12 normal females and 12 age-matched normal males. All subjects were strongly right-handed (Edinburgh Inventory >
+.70). Surface area was also assessed for Heschl’s gyrus (HG), a
supratemporal region of primary auditory cortex. While numerous postmortem studies have documented pronounced asymmetry of the PT, no similar lateralization has been described for HG. Results indicate an interaction between gender and hemisphere for area of the PT, with
males having a significantly larger left versus right PT. Left-right differences in PT area were not significant among females.
ii
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. No main effect of gender was found for total (left + right) PT area. No
main effects of gender or hemisphere and no interactions were detected
for the area of HG. No effect of diagnosis was found for PT or HG, as male schizophrenics showed a normal supratemporal configuration, with a
significant left>right asymmetry for PT and no significant lateralization of
HG. This result does not confirm reports of reduced PT laterality in schizophrenia. The finding of sexual dimorphism in PT area, however, is
consistent with neuropsychological evidence for gender differences in the lateralization of language functions attributable to the supratemporal cortex.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ACKNOWLEDGMENTS
This project was supported by a NIMH pre-doctoral Intramural Research and Training Award. My thanks to the many staff and research
fellows at the Clinical Brain Disorders Branch who assisted with data collection, analysis, and advice, including Drs. Jeffrey Zigun, Kate Vladar, and Zorica Llajavic. Many thanks as well to Dr. Daniel Weinberger and
Dr. Burton Slotnick for serving as committee members, and for offering their comments and criticisms of this manuscript. Lastly, I extend
particular thanks to my committee chair, Dr. Bryan Fantie, and to my
fourth committee member, Dr. Doug Jones, without whose unwavering
support and enthusiasm this project could not have been completed.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. TABLE OF CONTENTS ABSTRACT...... ii
ACKNOWLEDGMENTS...... i v LIST OF TABLES...... vii
LIST OF FIGURES...... viii CHAPTER 1. GENERAL INTRODUCTION...... 1
2. STUDY 1. COMPARISON OF SERIAL SLICE AND SURFACE-RENDERING MORPHOMETRY: INTRODUCTION...... 8
3. METHODS FOR STUDY 1...... 12
4. RESULTS OF STUDY 1...... 19
5. DISCUSSION OF STUDY 1...... 22
6. STUDY 2. APPLICATION OF MRI SURFACE-RENDERING MORPHOMETRY TO A COMPARISON OF PLANUM TEMPORALE ASYMMETRY IN NORMAL FEMALES, NORMAL MALES, AND MALE SCHIZOPHRENICS: INTRODUCTION...... 28
7. METHODS FOR STUDY 2 ...... 36
8. RESULTS OF STUDY 2 ...... 50
9. DISCUSSION OF STUDY 2...... 53
APPENDIX A ELEMENTS OF MRI: TISSUE CHARACTERIZATION WITH RF PULSE...... 64
v
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. APPENDIX B TECHNICAL AND METHODOLOGICAL ISSUES IN IMAGE PREPARATION...... 71
APPENDIX C NORMAL ASYMMETRIES OF SUPRATEMPORAL GYRAL STRUCTURES: POSTMORTEM, ANGIOGRAPHIC, CYTOARCHITECTONIC AND ELECTROPHYSIOLOGICAL STUDIES...... 81
APPENDIX D MRI STUDIES OF THE SUPRATEMPORAL CORTEX...... 95
APPENDIX E TABLES...... 101
APPENDIX F FIGURES...... 107
REFERENCES ...... 134
vi
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LIST OF TABLES
TABLE PAGE
1. STUDY 1. MEAN PLANUM TEMPORALE AREAS...... 102
2. STUDY 1. PLANUM TEMPORALE ASYMMETRY COEFFICIENTS...... 103
3. STUDY 2. MEAN AGE AND HANDEDNESS...... 104
4. STUDY 2. MEAN PLANUM TEMPORALE AND HESCHL'S GYRUS AREAS...... 105
5. STUDY 2. PLANUM TEMPORALE ASYMMETRY COEFFICIENTS...... 106
vii
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LIST OF FIGURES
FIGURE PAGE
1. UNDERESTIMATION OF THE DIMENSION OF BRAIN STRUCTURES RESULTING FROM THICK-SLICE MRI MORPHOMETRY STUDIES...... 109
2. COMPARISON OF SURFACE RENDERINGS PRODUCED BY SEGMENTATION IN ONE VERSUS THREE PLANES OF SECTION...... I l l
3. ON-COMMAND RESLICING OF MRI DATASET INTO ORTHOGONAL PLANES OF SECTION...... 113
4. EXPOSURE OF SUPRATEMPORAL SURFACE FOLLOWING SEGMENTATION OF MRI DATASET...... 115
5. MEASUREMENT OF THE PLANUM TEMPORALE IN A SUPRATEMPORAL SURFACE RENDERING VERSUS SERIAL SAGITTAL SECTIONS...... 117
6. IMPACT OF POSTERIOR MARGIN CRITERIA ON APPARENT PLANUM TEMPORALE ASYMMETRY...... 119
7. UNDERESTIMATION OF LATERAL PLANUM TEMPORALE AREA RESULTING FROM MEASUREMENT IN SERIAL SECTIONS...... 121
8. PROCEDURE FOR DEMARCATING ANTERIOR HESCHL'S GYRUS BOUNDARY ON A SUPRATEMPORAL SURFACE RENDERING...... 123
9. GENDER-BY-HEMISPHERE INTERACTION FOR PLANUM TEMPORALE AREAS...... 125
10. CONTRAST VARIATION IN RAW MRI DATA...... 127
viii
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 11. COMPARISON OF HISTOGRAM EQUALIZATION PARAMETERS FOR RAW MRI DATASET...... 129
12. IMPACT OF VARYING THRESHOLD VALUES ON SURFACE RENDERINGS PRODUCED BY THE DIP STATION MODULE...... 131
13. "NORMATIVE" SUPRATEMPORAL ANATOMY, AS DESCRIBED BY GESCHWIND AND LEVITSKY (1968) ...... 133
ix
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. CHAPTER 1
GENERAL INTRODUCTION The development of high-resolution "volume" magnetic
resonance scans, coupled with high-fidelity surface-rendering techniques,
permits a novel approach to the in-vivo study of gross brain structure. This research encompasses many aspects of morphometry - the measurement of normal brain structures and diagnostically significant structural abnormalities - with the eventual goal of describing the relationship between brain morphology and cognitive functioning.
Historically, while the development of morphometric techniques has paralleled those of postmortem examination, pneumo
encephalography, and computerized tomography (CT) (Zigun &
Weinberger, 1992), magnetic resonance imaging represents a significant
advance for cerebral morphometric applications. Neuropathological studies of postmortem brain structure frequently involve older subjects whose brains are subject to the effects of aging, significant medical
pathology, and tissue shrinkage or deformation from formalin fixation.
CT scans expose subjects to a substantial dose of ionizing radiation and
produce images of limited resolution, with some structures obscured by bone artifacts (Partain, Price, Patton, Stephens, Stewart, & James, 1983;
Pfefferbaum & Zipursky, 1991). By comparison, MRI offers a non-
1
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2
invasive glimpse of the living brain with unequalled soft-tissue contrast (Bielke, Meves, Meindl, Bruckner, Seelen, Rink, et al., 1984)
uncomplicated by postmortem distortions and minus ionizing radiation
exposure (See Appendix A for a discussion of MRI scanning and image reconstruction). Technological advances in scanner design and the
enhanced flexibility of MRI’s scanning parameters continue to
dramatically improve image resolution since the first reported human
scan, a crude cross-sectional image created in 1977 (Damadian, 1983). The integration of computerized surface-rendering techniques with these high-resolution MRI scans has advanced the study of gross neuroanatomy beyond the stereotactic atlas of the "average" brain, leading to a new appreciation of both individual variation and
normative configuration, particularly with respect to the cerebral cortex. Despite the promise of this imaging technique, the use of MRI in brain morphometry was initially hampered by the limitations of
conventional MRI scans that produce non-contiguous "slices" of the brain spanning up to a centimeter of tissue. Such slices yield cross-
sectional images of relatively poor resolution that blur the contours of many brain structures and obscure their tissue boundaries.
Measurements made with these thick or non-contiguous slices can only crudely approximate the dimensions of an anatomical region of interest.
A large body of MRI morphometry studies in the psychiatric literature
contain data derived from older MRI scanning techniques, yet even the more consistent findings in this literature, such as ventricular
enlargement (ventriculomegaly) in schizophrenia, have not been
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 3
invariably replicated (Zigun & Weinberger, 1992). Persistent technical difficulties related to image resolution, anatomical localization and the
reliability of existing morphometric techniques have previously limited
the utility of measuring brain structures with MRI. Currently, a new generation of MRI scanners and pulse sequences permit what is termed "volume imaging" (Prorok & Sawyer, 1992). Very thin (approx. 1mm) images or "slices" are acquired in a contiguous
sequence. The resulting MRI dataset contains voxels (the three- dimensional representation of a volume element of data) that are
essentially isotropic (equivalent along all axes). Where conventional MRI images present data only in the plane acquired from the scanner, volume
datasets can be "resliced" to present data in any desired plane of section,
standard or oblique, from a single scan. This feature of volume imaging allows aspects of brain structure to be analyzed from multiple viewpoints
within the same dataset. Equally important, tissue of interest can be accurately segmented out of the dataset, and processed with computerized surface-rendering algorithms to create three-dimensional images of the entire surface of a structure. These techniques have been successfully
applied to create surface renderings of the ventricular system, the cortex, the hippocampal formation, and the superior surface of the temporal lobe
(Damasio & Frank, 1992; Falk, Hildebolt, Cheverud, Kohn, Figiel, &
Vannier, 1991; Levin, 1989; Shenton, Kikinis, Jolesz, Poliak, LeMay,
Wible, et al., 1992; Vladar, 1992).
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 4
Cerebral Morphometry
Morphometry of brain structures as seen with MRI was initially attempted through area measurements produced with planimetry
devices, and later, computer-aided image analysis (Zigun & Weinberger, 1992). Investigators traced the boundary of a structure in the few slices in
which relevant borders could be clearly determined. While interrater
reliability could frequently be achieved in studies relying on area
measurements of a relatively few thick, poor-resolution MRI slices, the technical validity of such measurement data was often questionable. For example, an approximation of the variable shape of a complex mesial
temporal structure such as the hippocampus cannot be obtained from a few thick, non-contiguous slices through the widest point (Figure 1). Despite these limitations, researchers publishing morphometric findings
relied upon these as the best available methods at the time (e.g., Suddath , Casanova, Goldberg, Daniel, Kelsoe &Weinberger, 1989; Suddath,
Chritison, Torrey, Casanova & Weinberger, 1990).
In subsequent attempts to improve the accuracy of MRI morphometry, the volumes of structures were estimated; area measurements were multiplied by the thickness of the slices. In
comparison to area measurements, volume estimations were shown to
increase sensitivity to patient-control differences in a CT study of the
lateral ventricles (Raz, Raz, Weinberger, Boronow, Pickar, Bigler, et al., 1987), and the implications for MRI studies are the same. Volume
estimates improve validity by allowing increasingly accurate
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. measurements of smaller, more complex structures (Zigun & Weinberger, 1992).
Even when this methodological improvement in validity is considered, it can be demonstrated that any measurement made in one
cross-sectional view or plane falls short of assessing the true contours of a
cortical or subcortical structure. Here the implications of three- dimensional surface rendering for improved morphometry are
significant. Surface rendering can be used to provide a simple illustration of this problem. In Figure 2A, a surface rendering of the lateral ventricular system has been produced with segmentation decisions made
only in the original coronal dataset. The boundaries chosen during segmentation to produce a surface rendering correspond to those that
would serve as regions of interest (ROIs) for an estimation of ventricular
volume. A surface rendering of the ventricles of a second subject (Figure
2B) has been made following additional editing of ROIs in transverse and
sagittal views generated by reslicing the original MRI dataset. This rendering, produced from data segmented in three orthogonal views, closely reconstructs the complex contours seen in a textbook illustration of the ventricular system (Figure 2C); thus, the final rendering more
closely reproduces the complex contours of in vivo anatomy and should
provide a more accurate assessment of lateral ventricle volume (Vladar, 1992). The use of surface renderings has been limited largely to the
qualitative evaluation of the cerebral cortex, in particular, for the
planning of neurosurgery (Hu,Tan, Levin, et al., 1990). Recently,
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 6
improvements in segmentation and surface-rendering techniques have produced images of the cortex of a quality suitable for quantitative purposes, due to their lack of artifacts and the presence of distinct, realistic
gyri and sulci. One quantitative application of these surface renderings has been the use of a cross-correlation algorithm to analyze the gyral patterning of the cerebral cortex. The cross-correlation procedure
generates a similarity measure scaled from -1.0 to 1.0, based upon the
position of maximal similarity in a two-dimensional map of similarity coefficients calculated at all possible superimpostions of two images (Jones, 1992b). Such computerized analysis of gyral patterning was shown
to be superior to the ratings of trained neurologists in discriminating the
members of monozygotic twin pairs from unrelated subjects (Bartley, Jones, & Weinberger, 1992b).
Cross-correlation analysis of gyral patterning is one exploratory
approach to a quantitative use of surface-rendered images. A more
obvious application is suggested, however, by the observation that images
of the quality produced by the techniques developed at the Clinical Brain Disorders Branch of the NIMH (CBDB) resemble the photographs of
postmortem brains that formed the basis for many classic morphometry
studies. The use of in vivo MRI images in morphometric measurement, especially in the study of hidden cortical surfaces, has been hindered in
the past only by the lack of effective scanning and image-processing
techniques for the creation of accurate, lifelike representations of the
brain.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 7
This dissertation describes the development of a novel methodology for deriving morphometric measurements from surface renderings. Technical and methodological issues considered in the the
development of these procedures are discussed in detail in Appendix B.
Improved segmentation and rendering techniques were applied to volume MRI data to expose and analyze quantitatively the hidden cortical surface of the temporal lobe. The temporal lobe was chosen in view of the significant emphasis placed on this region by researchers seeking evidence of structural brain changes in schizophrenia. Study 1 describes new segmentation and rendering techniques that reveal the
superior surface of the temporal lobe with a clarity seen previously only in postmortem dissection. These techniques are shown to greatly improve morphometric reliability when compared to a conventional
serial-section approach (see Appendix D). Study 2 applies surface-
rendering morphometry to an examination of the effects of gender and
schizophrenia on the normal patterns of asymmetry reported in
postmortem for a the supratemporal gyral structure the planum
temporale.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. CHAPTER 2. STUDY 1. COMPARISON OF SERIAL SLICE AND SURFACE
RENDERING MRI MORPHOMETRY: INTRODUCTION
The application of computerized surface-rendering techniques to volume MRI datasets has greatly facilitated the study of the human
cerebral cortex in vivo (Falk, Hildebolt, Cheverud et al., 1991; Levin, Hu,
Tan & Galhotra, 1989; Steinmetz & Huang, 1991). Three-dimensional renderings of cortical surfaces assist the planning of neurosurgery
(Damasio & Frank, 1992; Hu, Tan, Levin et al., 1990) and may also permit the exploration of cognitive functions attributed putatively to specific cortical regions (Steinmetz, Volkman, Jancke, & Freund, 1991). These technological advances may be particularly relevant to morphometric
studies of the structural anatomy of the cerebral cortex, where postmortem research is known to be complicated by tissue deformation
and volume changes (Steinmetz, Furst, & Freund, 1989), and where
conventional serial MRI sections have proven unreliable for the precise identification of gyri and sulci (Hu, 1990; Jernigan, Zisook, Heaton,
Moranville, Hesselink, & Braff, 1991a). The suggested utility of surface- rendering methods for morphometry, however, has not previously been examined in detail, systematically tested, or applied to actual
8
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 9
neuroanatomical measurements. Utilization of surface renderings in MRI morphometry would
provide a novel approach that more fully exploits the three-dimensional
quality of volume MRI acquisitions. This aspect of volume MRI datasets is oftendisregarded or, at best, poorly appreciated in morphometric studies that rely on serial sections. Most suchstudies make no attempt to
examine the slice-to-slice contiguity of a region of interest (ROI); each slice is typically analyzed without reference to adjacent serial sections of the dataset. Thus, these studies have ignored the anatomical reality of smooth structural contours in planes orthogonal to the slices containing
ROIs.
Morphometry of the Planum Temporale
A feature of the cortical surface that is particularly well-suited for an exploration of the morphometric utility of renderings is the planum
temporale (PT) (Geschwind & Levitsky, 1968). The PT is a triangular
region of the posterior supratemporal surface that has been described as exhibiting "the best-defined asymmetries in the gross configuration of the human cerebral cortex" (Galaburda, LeMay, Kemper, & Geschwind, 1978)
(A detailed discussion of normal asymmetries of the supratemporal cortex may be found in Appendix C). The functional significance of this area has been inferred from neuropsychological and cytoarchitectonic studies that suggest a portion of the neuroanatomical substrate of
language may be localized to the PT (see Galaburda et al., 1978). Yet
morphometry of this cortical region is complicated by the great variability
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 10
exhibited within and across individual brains. Postmortem studies have revealed patterns of supratemporal cortical configuration where the number of transverse gyri present may range from none to as many as
five in either hemisphere (Campain & Minkler, 1976). As a result, delineating the borders of the planum is a significant
problem in serial sections. The sulcus corresponding to the prominent
Heschl's gyrus (HG) is commonly described as an anterior demarcation of the planum (Geschwind, Galaburda, and LeMay, 1979); yet, when viewed in serial slices, the identification of the full lateral extent of HG may itself
be ambiguous. This ambiguity results when Heschl's sulcus posterior to HG terminates short of the lateral boundary of the temporal lobe, and is
no longer discernible in the remaining serial slices. Cortical surface
renderings from volume MRI data provide an invaluable aid for the visualization of such variable gyral structures (Kulynych, Vladar, Jones,
& Weinberger, 1993). In the absence of such visualizations, the difficulty
of boundary discrimination in serial section has led some researchers to
identify the most anterior transverse gyrus (HG), and to include all transverse gyri posterior to it in planum measurements (Larsen,
Odegaard, Grude, & Hoien, 1989; Steinmetz, Rademacher, Huang, H., Zilles, Thron, et al., 1989) while postmortem studies have often included
only the region posterior to all transverse gyri (Chi, Dooling, & Gilles,
1977; Wada, Clarke, & Hamm, 1975; Witelson & Kigar, 1988). Attempts to adapt this latter definition to MRI studies have been confounded by unacceptable interrater variability in determining even the number of
cortical elevations that constitute individual gyri in serial section
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 11
(Steinmetz, Rademacher, Huang, Zilles, Thron, et al., 1989). MRI surface
renderings present a viable solution to this problem by providing an in
vivo visualization of the cortical surface that closely mimics postmortem appearance.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. CHAPTER 3. METHODS FOR STUDY 1
MRI surface renderings and traditional morphometry techniques were
employed to determine the area of the PT in order to quantitatively assess
the utility of the rendering method. Implementation of the traditional (serial slice alone) approach follows previously published work (Larsen, et al., 1989; Rossi, Stratta, Mattei, Cupillari, Bozzao, Gallucci, et al., 1992; Steinmetz, et al., 1989; Steinmetz, Rademacher, Jancke, Huang, Thron, & Zilles, 1990; Steinmetz, et al., 1991): the investigator uses a mouse to direct a cursor that outlines ROIs on MRI slices displayed individually on the
computer screen. One significant modification to this traditional
approach is a visualization enhancement developed in the CBDB
laboratory (Jones, 1992a) that allows the researcher to view, upon command, the orthogonal axial and coronal slices intersecting any chosen
point in the primary sagittal MRI dataset. These secondary cross-sections
are obtained by reslicing the primary MRI volume (a process requiring less than five seconds). Each cross-section is automatically marked to indicate the exact location of the chosen voxel. Generating these resliced orthogonal views increases accuracy and interrater reliability by allowing
ROI placement to be evaluated from multiple perspectives. Figure 3 illustrates an example of this on-command reslicing capability.The
12
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 13
sagittal volume MRI datasets studied were obtained from seven
normalmale volunteers who were classified as strongly right-handed (mean score 0.93, range 0.70 to 1.00) by means of the Edinburgh Handedness scale (Oldfield, 1979). All MRIs were acquired on a GE Signa
1.5T scanner with a spoiled GRASS sequence (TR=24ms, TE=5ms) as a set of 124 contiguous sagittal slices with 1.5 mm slice thickness and in-plane
field of view of 240 mm across a 256x256 pixel matrix for each slice.
Although these MRI datasets are not truly isotropic volumes, the slice density is sufficiently great to produce resliced image planes with a resolution and clarity that is difficult to distinguish from the original
slices, as is also evident in Figure 3. Exploiting this ability to reslice
volume MRI data along orthogonal planes increases the accuracy of extracerebral tissue segmentation, thereby greatly improving the overall
quality and clarity of gross cortical surface renderings (Bartley, Jones, &z Weinberger, 1992a), and thus this capability was applied to the
quantitative morphometry of MRI datasets.
All procedures were developed on Apple Macintosh Ilci and Quadra 950 computers with the public-domain NIH Image program (Rasband,
1992). Wherever possible, repetitive sequences of commands were
automated by means of the simple macro language that is a component of
NIH Image. Surface renderings were generated by the commercial software
package DIP Station (HIPG Inc.). Three-dimensional views created with this software result from a volumetric ray-tracing algorithm that
produces depth and gradient images. In a comparison of approaches to
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 14
surface rendering, Bomans et al. (Bomans, Hohne, Tiede, & Riemer, 1990) suggest that semi-transparent displays produce superior visualizations of
complex neuroanatomical surfaces. Therefore, an integral shading
option, where ray casting slightly penetrates the image surface to compute the gradient across a small depth of voxels, was selected for the processing of MRI datasets (HIPG, 1990). Artifacts are reduced in the resulting image, and quality of the cortical surface rendering is comparable to that of
postmortem photographs (Bomans, et al., 1990). Prior to tissue segmentation, all MRI datasets were aligned according
to the stereotaxic axes described by Talairach and Tournoux (1988). This procedure ensures that differences in anatomical angle or orientation
reflect true intra- and inter-subject deviations from a standard orientation. Briefly, this process entails rotating and shifting the "stack"
of slices so that a line connecting the anterior and posterior commissures
lies centered on a predefined horizontal axis. Successively reslicing this sagittally-oriented stack, first ccronally and then axially, enables orientation of the interhemispheric fissure along the standard axes. Macros written for NIH Image facilitate this process. The investigator
uses the mouse-driven cursor to draw a line segment connecting the
appropriate anatomy (intercommissural or interhemispheric) and the macros then proceed to rotate and shift the MRI stack, automatically orienting the line segment to the appropriate position on the screen. Extracortical tissues are then removed using a semiautomated
segmentation procedure developed in the CBDB laboratory. With the assistance of macros written for NIH Image, the original sagittal MRI
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 15
dataset is resliced transversely, and ROIs are generated via thresholding the cortex/CSF boundary in each slice. Each of these ROIs is then
homomorphically expanded until it overlays primarily the layer of CSF
between cortex and cranium; the investigator observes this
semiautomatic procedure and may selectively make corrections. Tissue exterior to these ROIs is erased, leaving a set of slices that are predominantly brain tissue. To ensure 3-dimensional contiguity of this
segmentation, additional semiautomatic editing is executed on coronal and, finally, sagittal reslicings. This procedure results in smooth cortical contours in all views of the brain. Surface renderings produced by this
technique have proven to display few artifacts such as spurious gyral bridges and sulcal expansions (Bartley, Jones & Weinberger, 1992a). Similar procedures were used to expose the supratemporal surface.
The approach was analogous to that described by Geschwind and Levitsky (1968), in that investigators endeavored to "cut off' the frontal lobes that
overly and obscure the insular cortex. ROIs were manually drawn along
the Sylvian fissure in each sagittal slice to remove the overlying frontal lobes (Fig. 4A). Segmentation in each slice allows the hemispheres to be disarticulated independently, ensuring that interhemispheric variations
in the morphology of the Sylvian fissure are reflected in the final resected dataset. The posterior limit of the PT was chosen to exclude tissue along the ascending ramus of the Sylvian fissure (this posterior boundary was
determined in serial sagittal sections). Surface renderings of the seven
computer-resected brains were generated from the front with a 45° pitch
using DIP Station. As illustrated by the renderings in Figure 4 (B and C),
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 16
this orientation displays the entire supratemporal gyral configuration well, particularly the PT.
Two important methodological questions pertaining to the
morphometric use of surface renderings were also examined. The first concerns the impact on PT area of variations in the angle of temporal
plane orientation. Variations in orientation of the temporal plane were
compared within and between subjects following alignment of all brains
to the standard stereotaxic axes. To determine orientation of this plane within each hemisphere, the angle formed by the horizontal plane and the supratemporal surface was measured on left and right lateral renderings of each subject. The second, related question entails consideration of foreshortening
effects in a two-dimensional surface projection. In these temporal surface
renderings the direct line of sight falls 45° from the horizontal plane. To
assess the impact of foreshortening, the angle formed by the temporal
plane and a plane perpendicular to this line of sight was determined.
Apparent foreshortening of surface measurements may be analyzed by taking the cosine of this angle. The resulting number yields the relative
magnitude of surface area reduction attributable to apparent foreshortening.
Planum Tempornle Measurements
ROIs were drawn manually on renderings of the supratemporal surface to measure the area of the PT. Each ROI included the entire
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 17
exposed supratemporal surface posterior to Heschl's sulcus (HS), the
sulcus following the most anterior transverse gyrus. The lateral boundary
of the PT was taken to be the visual edge of the rendering (Fig. 5A). From
these area measurements an "asymmetry coefficient", 5 = (R-L)/[(R+L)/2], (Galaburda, Corsiglia, Rosen, & Sherman, 1987) was determined for each
individual brain. This coefficient provides a dimensionless measure of
lateral asymmetry ranging from -2 to +2.
Traditional serial-slice measurements were performed in the sagittal volume MRI datasets in accordance with established criteria (Steinmetz, Rademacher, Jancke, Huang, Thron, et al., 1989; Steinmetz, Volkman,
Jancke & Freund, 1991). A line-of-interest (LOI) conforming to the same boundary criteria used in making the surface rendering measurements
(except for the lateral extent) was traced along gyral contours in each sagittal MRI section (Fig. 5B). Investigators attempted to replicate previously defined boundary criteria for the PT in sagittal sections
(Steinmetz, et al., 1989). According to these criteria, HG is located mesially
at its retroinsular origin, and its position is followed laterally through
progressive slices until the termination of HS. The lengths of LOIs were summed and multiplied by the slice spacing to obtain the area of the PT as determined by this method, and a corresponding asymmetry coefficient
calculated. Two raters made independent measurements of the PT by both methods described above in all seven subjects. To fully assess interrater variability, the two raters performed all segmentation procedures,
surface-rendering measurements, and area measurements
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 18
independently. The agreement between the area measurements of the
two raters was assessed using Pearson's r and the unbiased intraclass correlation coefficient, ICC(U), as suggested by Bartko and Carpenter
(1976).
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. CHAPTER 4
RESULTS OF STUDY 1
Table 1 summarizes the PT area measurements for all subjects as
obtained by both raters and methods. The two raters agreed very closely on area measurements made by the surface-rendering method (Pearson's r = 0.90 p < 0.0001; ICC(U) = 0.78 p < 0.0001). While statistically significant,
the level of correlation between the raters was lower on area
measurements derived from serial slices (Pearson's r = 0.77 p < 0.01; ICC(U) = 0.60 p < 0.003). The distinction between the two methods of measurement is even more apparent when one considers the asymmetry
coefficients displayed in Table 2. The surface-rendering method resulted in a significant correlation between raters (Pearson's r = 0.96 p < 0.0006;
ICC(U) = 0.76 p < 0.003), while the serial-slice method did so only on the ICC (U) (Pearson’s r = 0.68 p > 0.05; ICC(U) = 0.52 p < 0.03). If the asymmetry coefficients in Table 2 are used to categorize laterality as suggested by Galaburda (Galaburda, et al., 1987), i.e., "Right” if 8 > +0.05,
"Left" if 5 < -0.05, and "None" -0.05 > 8 < +0.05, then additional differences appear between the methods. Whereas the surface-rendering
method shows almost complete agreement between the two raters for
each subject, the serial-slice method shows substantial disagreement. Using the rendering method, raters agreed on the direction of planum
19
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 20
asymmetry for 6 of 7 subjects, versus only 4 of 7 subjects when usingserial
slice measurements. Moreover, the expected asymmetry, i.e., left greater
than right (Geschwind & Levitsky, 1968), is moreconsistently achieved
with the surface-rendering approach.While serial-slice and surface- rendering measurements were significantly correlated for both raters
(Pearson’s r = 0.51 p <0.006; ICC(U) = 0.34 p < 0.02), in the surface- rendering measurements the degree and direction of lateral (PT)
asymmetry were uniformly larger and more consistent. The surface- rendering method yielded a greater value for leftward asymmetry (mean
5 = -0.40 ± 21% s.e.m.) with lower variance across subjects than was obtained by the serial-slice method (mean 5 = -0.204 ± 57% s.e.m.).
Consistent with the report of Steinmetz et al. (1990) is the finding
that if datasets are resected to include the ascending posterior ramus of
the Sylvian fissure, rather than conforming to the Geschwind and Levitsky (1968) criterion of "a cut made in the plane of the Sylvian
fissure", then the apparent asymmetries become less obvious (Figure 6). This observation underscores the importance of segmenting the dataset
to include only posterior temporal cortex located "in the plane" of the supratemporal surface. The angles formed by the temporal planes of both the left and the
right hemispheres were compared in all subjects. The mean angle for the
left temporal plane was 27.4° ± 1.14° s.e.m.; and for the right temporal
plane, 28.8° ± 0.45° s.e.m. Within-subject differences between the
orientation of left and right temporal planes ranged from 0.9° to 5°, with an average deviation of 1.3° ± 1.06° s.e.m. A paired t-test indicated no
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 21
significant angular difference between the orientation of left and right temporal planes. A sign test also demonstrated a random distribution of
difference scores in positive and negative directions. These results suggest
that orientation of MRI datasets to standard stereotactic axes substantially
reduces the likelihood that systematic differences in temporal plane
orientation might affect the laterality apparent in two-dimensional surface projections of the PT.
For supratemporal renderings at a 45 degree pitch, a systematic reduction ranging from 3% to 6% (mean = 4.38% ± 0.31% s.e.m.) of absolute surface area was found to result from the effects of
foreshortening. Within-subject left-right differences in temporal plane
angles generated deviations of less than 3% of absolute surface area (mean = 0.75% ± 0.54% s.e.m.).
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. CHAPTER 5 DISCUSSION OF STUDY 1
This study has explored the possibility of enhanced morphometry
through a more complete incorporation of three-dimensional MRI information. A frequently-studied supratemporal structure, the planum temporale, illustrates well the difficulties of measurement in two-
dimensional serial slices without a view of the corresponding cortical surface. This comparison indicates that, for measurements of gyral
structures such as the PT, cortical renderings present a viable
morphometric alternative to serial slices with several distinct advantages. Cortical surface rendering measurements yielded both greater
interrater reliability and more consistent evidence of the planum
asymmetry than would be predicted for a sample of normal, strongly right-handed men (Galaburda, Rosen, & Sherman, 1990). Interrater
reliability appears to be greatly improved when a gyral structure can be
viewed in the cortical context of a surface rendering. In contrast to
previous MRI serial-section studies of the PT, where interrater reliability was poor (Larsen, Odegaard, Grude & Hoien, 1989), in the surface-
rendering analysis equivalent boundary criteria were applied and highly consistent agreement was obtained. An additional advantage of utilizing
22
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 23
surface renderings in MRI morphometry is that validation is often
simple and direct; the asymmetries reported in this study are obvious
upon visual inspection of the surface rendering itself. A lesserdegree of interrater agreement and less consistent asymmetry findings resulted
from serial-slice measurements, where considerable ambiguity in tissue discrimination complicated the identification of gyri and the delineation
of PT boundaries. The techniques described can be implemented in a practical and efficient manner on relatively modest desktop computer systems and do not require custom software development. This type of computerized
image-processing configuration lies within the means of most
laboratories and performs all aspects of the techniques described
accurately and efficiently. For quantitative purposes high-quality surface
renderings are certainly a prerequisite, and the renderings generated by this system are more than sufficient for the application presented. While these techniques offer a rapid and reliable method of
observing and quantifying the presence of PT asymmetries, certain technical limitations inherent in the analysis of three-dimensional
surface reconstructions must be considered. Surface renderings, by their
nature, reveal only those cortical areas that have been exposed by segmentation. Thus, segmentation decisions will unavoidably influence
apparent surface area. In the case of the PT, a priori decisions regarding the posterior extent of the Sylvian fissure were found to have a dramatic
impact on both the appearance and the size of the rendered PT surface. In
addition, visual parallax effects make the apparent dimensions of a
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 24
rendered surface a function of the projection angle, although the cosine
dependence of these angular deviations lessens their impact on surface- area measurements. Nonetheless, it is essential that all brain MRIs be
aligned in a common stereotactic frame of reference, as in this study. Utilization of an accepted standard orientation, such as that described by Talairach and Tournoux (1988), will also facilitate comparison of data and results.
Due to the problems of cortical tissue hidden within sulci, and the
possible systematic foreshortening of the rendered PTs, surface rendering
measurements were anticipated to underestimate those obtained from
serial slices. It was, therefore, unexpected that total (left + right) PT area measurements from surface renderings (mean = 1009.2 ± 68.9 mm^
s.e.m.) were significantly larger (t = 5.6 p < 0.001, two-tailed, paired sample) than corresponding serial-slice measures (mean = 785.9 ± 53.6
mm^ s.e.m.). This observation suggests that lateral portions of the PT that could not be discerned in serial slices (but are evident in surface
renderings) contribute significantly to the PT area. Figure 7 A illustrates the PT area visible in serial slices. A surface rendering of the LOIs from
serial-slice measurement of this dataset was created, and superimposed onto the corresponding surface rendering. Only the extreme boundaries of the LOIs have been shown on the rendering, in order to reveal the
gyral structures encompassed by sagittal-section measurements. Omission
of lateral PT area by serial-slice regions is evident when LOI areas are compared to PT areas measured directly on the surface rendering (Fig. 7B). A diminished impact of cortical folding on PT area is further
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 25
supported by the conclusion of Zilles et al. that states, in the absence of
lateralized gyrification index (GI) differences in the dorsal temporal lobe,
planum asymmetry reflects "an absolute enlargement in cortical surface
not caused by a difference in the degree of folding" (Zilles, Armstrong, Schleicher, & Kretschmann, 1988).
The inevitable difficulty of clearly delineating the PT all the way to the lateral edge of the supratemporal surface in serial sections is particularly unfortunate. Omissions in serial sections occur at the broadest extent of the PT, the very region where Geschwind and Levitsky
(1968) originally observed asymmetries in the length of the lateral
boundary. The surface rendering method circumvents this difficulty by allowing inclusion of the entire lateral extent of the PT in the area
measurement. Conclusions about the accuracy of measurement on cortical renderings must be qualified by recognition of the loss of
curvature resulting from a two-dimensional projection of a three-
dimensional surface. Yet for a relatively "flat” region such as the PT, the
area obscured in surface renderings by curvature and cortical infolding apparently plays little role in determining asymmetry. Prior comparisons of serial-section measurements to those made on postmortem
photographs have detected no impact of cortical folding on PT asymmetry (Steinmetz, Rademacher, Jancke, Huang, Thron et al., 1990). Clearly, the
very small systematic contribution of foreshortening to measurement
error is outweighed as well by the greater area variance resulting from random slice-to-slice deviations in the serial-section measurement.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 26
This study offers a simple alternative to existing MRI methods for
assessing asymmetry of the planum temporale. In the tradition of most postmortem and MRI studies, particularly those utilizing only linear
measurements, emphasis was placed on the determination of the relative degree of PT asymmetry within subjects. A further integration of surface- rendering and serial-slice techniques would yield increased
morphometric accuracy of actual area measurements. For example,
editing of LOIs in three views may aid difficult boundary discriminations in serial section, and ensure that LOI contours describe a smooth three- dimensional surface. The transfer of boundaries from surface renderings
back to serial slices would also serve to "map" regions of interest onto the dataset, where cortical area can be measured with no loss of curvature to
surface projection. The techniques developed here to create an in vivo analog of postmortem photographs are readily adaptable to more complex
gyral and subcortical structures, where the additional investment of time required to integrate morphometric techniques may substantially
improve accuracy and reliability of measurement. The examination of lesions and asymmetries of the superior
surface of the temporal lobe has received renewed attention in studies of
language disorders such as developmental dyslexia (Galaburda, Sherman, Rosen, et al., 1985; Humphreys, Kaufmann, & Galaburda, 1990) Postmortem research, however, has demonstrated that individual
variability limits the utility of standard brain atlases in localizing lesions, describing the asymmetry of the PT, or representing the number of
transverse temporal gyri (Hu, Tan, Levin et al., 1990; Jernigan, et al.,
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 27
1991a; Steinmetz & Huang, 1991; Steinmetz, Rademacher, Huang, Zilles,
Thron et al., 1989). In order to quantify differences in gyral volume,
Sylvian fissure length, planum temporale asymmetry, or any of a number of cortical features of morphometric interest, it must be possible to reliably identify these structures. A surface-rendering approach realizes this goal.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. CHAPTER 6 STUDY 2. APPLICATION OF MRI SURFACE RENDERING
MORPHOMETRY TO A COMPARISON OF PLANUM TEMPORALE
ASYMMETRY IN NORMAL FEMALES, NORMAL MALES AND MALE
SCHIZOPHRENICS: INTRODUCTION
Schizophrenia has been conceptualized as the collision of normal
brain maturational processes with a preexisting, static, and probably developmental brain "lesion" - i.e., neuropathological insult or
abnormality (Weinberger, 1987). A lack of increased glial-cell ratios in the
cortex of schizophrenics, even when neuronal loss is present, suggests that the neuropathological process is of early developmental origin (Benes, Davidson, & Bird, 1986; Falkai & Bogerts, 1986). Due to the
commonly observed heterogeneity of clinical symptoms, schizophrenia
has been likened to an "umbrella term" for multiple disease processes. It is possible that a broad spectrum of schizophrenic disorders result from
the interaction of nervous system development with multiple regions of atrophy and histopathological change (Berman & Weinberger, 1989). The
prefrontal cortex has been proposed as one locus for such a "lesion" in
schizophrenia (Zee & Weinberger, 1986), with psychosis resulting from regional hypofunction or the disconnection of prefrontal dopamine projections from other brain regions (Weinberger, 1992; Weinberger,
28
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 29
1991).
In addition to focal brain lesions, abnormal patterns of cerebral
asymmetry might be consistent with a developmental model of
schizophrenia, or at least implicate an early developmental
neuropathological insult. Indeed, initial reports of lobar widths as measured from CT scans indicated a reversal of common frontal and
occipital asymmetries (Luchins, Morihisa et al., 1981; Luchins, Weinberger et al, 1982). These results were not consistently replicated, however (Andreasen, Dennert et al., 1982; Jernigan, Zatz et al, 1982,
Weinberger et al, 1982; Luchins and Meltzer, 1983).
The temporal lobe has been suggested as a possible locus of abnormal asymmetry in schizophrenic psychosis, where a lesion would
manifest itself through a disorder of a hypothetical "laterality" gene,
producing unilateral morphological reductions in size and/or aberrant
asymmetries of temporal lobe structures (Crow, Ball, Bloom, Brown, Bruton, Colter, et al., 1989a; Roberts, 1991). The suggestion that
schizophrenia results from arrested growth of brain structures that develop relatively late - namely those of the left temporal lobe, thought
to lag the right in prenatal development by several weeks (Chi, Dooling & Gilles, 1977a; 1977b)- was advanced by Crow et al in 1989. These researchers sought to explain their finding of temporal horn ventricular enlargement in schizophrenia that was "highly, significantly selective to
the left hemisphere" (Crow, et al., 1989a; Crow, Colter, Frith, Johnstone, &
Owens, 1989b). Chronic changes in ventricular size are of interest largely as a reflection of a possible reduction in surrounding cortical and
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 30
subcortical tissue; thus such a lateralization theory would predict positive findings for morphological change in the temporal lobes of
schizophrenics. Specifically, the "temporal lobe hypothesis" hinges upon the findings of "diagnosis-by-side interactions" in matched-group MRI studies (Weinberger, Suddath, Casanova, Torrey, & Kleinman, 1991).
Attempts to detect lateralized morphometric changes specific to schizophrenia have produced contradictory results for areas or volumes
of the whole temporal lobe and of mesial temporal lobe structures. In normals, however, it is the supratemporal neocortex that has been shown in classic postmortem studies to exhibit the most striking asymmetries of the human brain (Galaburda, LeMay, Kemper & Geschwind, 1978;
Geschwind & Levitsky, 1968; Pfeifer, 1936; von Economo & Horn, 1930;
Wada, Clarke & Hamm, 1975) (See Appendix C). Of late, the
supratemporal cortex and other temporal lobe gyral structures have aroused the interest of researchers seeking regions where schizophrenia
might disrupt the normal process of lateralization.
Although their functional complexity has led to a description of the temporal lobes as among "the least-known regions of the brain" (Sedat & Duvernay, 1990), the "lateralization" hypothesis and its prediction of
temporal lobe structural change in schizophrenia can be systematically examined through the use of magnetic resonance scanning of carefully
controlled patient and comparison groups. Such in vivo studies are a necessary complement to existing postmortem data, in view of the
previously discussed limitations of postmortem research. While a body of MRI literature is emerging that bears upon the temporal lobe in
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 31
schizophrenia, the variability of existing morphometric techniques and the presence of methodological confounds cloud the interpretation of many such studies. Emphasizing these limitations, Pfefferbaum and
Zipursky, in a 1991 review of the literature, described MRI studies of the temporal lobe as "in their infancy."
A review of neuropathological and imaging research indicates the
variable nature of the structural change that has been linked to
schizophrenia. Mesial temporal lobe and anteromedial limbic abnormalities have been noted in the brains of schizophrenics (Weinberger, 1991), most commonly in the size of the hippocampus and parahippocampal gyri, with several postmortem studies noting gross
cytoarchitectonic abnormalities in these regions (Brown, Colter, Corsellis, & al, 1990; Jacob & Beckman, 1986; Roberts, 1991). MRI and postmortem
reports have described volume reductions of the entire limbic complex (Bogerts, Meertz, & Schonfeldt-Bausch, 1985; DeLisi, Dauphinais, &
Gershon, 1988), or the left portion (Bogerts, Falkai, Haupts, & al., 1990; Shenton, et al., 1992) and bilaterally in the anterior hippocampus (Suddath, Christison, Torrey, Casanova, & Weinberger, 1990), or the entire hippocampal formation (Falkai & Bogerts, 1986). A consistent trend
toward a focal, lateralized mesial temporal lesion, however, has not yet emerged.
Lateralized reductions have been reported in MRI studies of
schizophrenia in the area, volume, and/or gray matter content of the entire temporal lobe, either on the right (Barta, Pearlson, Powers,
Richards, & Tune, 1990) or the left side (Crow, Colter, Frith, Johnstone &
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 32
Owens, 1989b; Johnstone, Owens, Crow, Frith, Alexandropolis, Bydder, et al., 1989; Rossi, Stratta, D'Albenzio, & al., 1990; Rossi, Stratta, Di Michele,
& al., 1991; Bogerts, Falkai, Haupts, et al., 1990), although several studies also noted a significant asymmetry of temporal lobe volume in control subjects. For example, Suddath et al. reported a larger right temporal lobe
in both normal and schizophrenic subjects, coexistent with a bilateral reduction in temporal lobe gray matter among schizophrenics (Suddath Casanova, Goldberg, Daniel, Kelsoe, & Weinberger, 1989).
A near equivalent number of studies have failed to detect a lateralized temporal lobe reduction in schizophrenia (DeLisi, Stritzke,
Riordan, Holan, Boccio, Kushner, et al., 1992; Kelsoe, Cadet, Pickar, &
Weinberger, 1988; Shenton, Kikinis, Jolesz, Poliak, LeMay, et al, 1992;
Swayze, Andreasen, Randall, Alliger, Yuh, & Ehrhardt, 1992; Young, Blackwood, Roxborough, & al., 1991) The limitations of existing
methodology may have contributed substantially to the conflicting nature of these findings. The majority of these MRI studies drew conclusions
from measurements made in three or fewer slices through the region of interest. The impact of slice positioning and partial volume artifacts may be exacerbated by such a limited sampling of the dimensions of large
structures such as the temporal lobe, or those of complex shape within
the limbic system.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 33
The Lateralization Hypothesis and the Supratemporal Cortex
Researchers studying aberrant development of the temporal lobe
must distinguish the likely foci of abnormality from among multiple
cortical and subcortical candidates. Studies of temporal lobe areas,
volumes, and mesial temporal lobe structures have yielded no conclusive verdict with regard to abnormal lateralization in
schizophrenia. By comparison, the neocortex of the temporal lobe has received less scrutiny. In 1986, Jacob and Beckman noted abnormal temporal lobe gyral patterning in the postmortem examination of a
sample of schizophrenic brains, especially in the left hemisphere (Jacob & Beckman, 1986). Two recent studies have examined this possibility, with both reporting volume reductions in the left superior temporal gyrus of
schizophrenics (Barta, Pearlson, Powers, Richards, & Tune, 1990; Shenton, Kikinis, Jolesz, Poliak, LeMay, et al, 1992).
A reduction in Sylvian fissure asymmetry, implying alterations in
perisylvian gyri, has also recently been reported in schizophrenia, (although findings were based on a postmortem sample with no
handedness data available). Among the perisylvian cortical structures
that might exhibit this altered lateralization, the surface of the superior temporal gyrus that lies in the plane of the Sylvian fissure is unique in the extent of its interhemispheric asymmetry, often clearly visible to the
naked eye. This pronounced lateralization has prompted repeated study in normals, yet the impact of the schizophrenic disease process on the
supratemporal cortex is relatively under explored (See Appendix D). If a
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 34
relationship between schizophrenia and disrupted lateralization is to be
identified in the temporal lobe, the supratemporal cortex requires careful examination.
Crow (1989a; 1989c) has proposed that abnormal lateralization in
schizophrenia is linked to an aberrant "cerebral dominance gene" in the pseudoautosomal region of the Y chromosome, with mutations of this
gene significantly affecting asymmetry of the temporal lobe. Although we do not directly address the genetic nature of schizophrenia in this research, our objective is to detect an indication of Crow's predicted abnormal temporal lobe lateralization among schizophrenics. The use of
MRI morphometry permits concurrent versus retrospective
determination of diagnosis and handedness, allowing a better match
between patient and control groups. The volume MRI datasets employed in our morphometric studies may also be "re-dissected" to examine multiple brain structures, while avoiding postmortem complications of tissue distortion, shrinkage and atrophy.
While a single study has examined abnormal lateralization in schizophrenia with respect to the planum temporale (Rossi, Stratta, Mattei, Cupillari, Bozzao, et al., 1992), unanswered questions about the
impact of gender on structural lateralization, as well as methodological
shortcomings, render the results difficult to interpret. In the following study, planum temporale asymmetry is examined in right-handed, age
and gender-matched normals and schizophrenics, using a novel surface-
rendering technique that demonstrably improves measurement validity
and interrater reliability (Kulynych, Vladar, Jones, & Weinberger, 1993).
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 35
Although a properly matched sample of female schizophrenics was
unavailable at the time of this study, the design permits gender-based
comparisons within normal subjects, and diagnosis-related comparisons
among male subjects. In addition, this study reports what would appear,
on the basis of computerized literature searches, to be the first quantitative analysis of the primary transverse temporal (Heschl’s) gyrus,
using MRI techniques.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. CHAPTER 7
METHODS FOR STUDY 2
Issues Related to Experimental Design and Subject Selection
Slice Positioning Artifacts DeLisi et al. describe a methodological problem that may complicate
MRI morphometry studies of the temporal lobe and mesial temporal
structures. These authors follow the common practice of measuring temporal lobe volume in coronal sections, due to the clearly identifiable boundaries of the anterior temporal lobe. They also note, however, the
inevitable underestimation of the temporal lobe size due to an inability to measure the posterior portion, where lobar boundaries become
indistinct in coronal sections (DeLisi, Stritzke, Riordan, Holan, Boccio, et al., 1992). This ambiguity becomes evident when moving caudally
through coronal MRI views of the brain: a point is reached beyond which
the temporal lobes become visually indistinguishable from the occipital
lobes (Sedat & Duvernay, 1990). A persistent underestimation of the posterior temporal lobe across
studies may interact with lateralized petalias or "torque" effects (Kertesz, Polk, Black, & Howell, 1990; LeMay, 1992) where a normal greater left hemisphere protrusion in the posterior direction is balanced by greater
36
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 37
right hemisphere protrusion anteriorly (LeMay, 1976). A coronal slice
through a brain with pronounced torque effects might intersect a right
temporal lobe that was shifted anteriorly relative to the left, resulting in a greater right area measurement for each slice. The posterior portions of
the left temporal lobe would be undersampled with respect to
corresponding points on the right, leading to the underestimation of the relative volume of the left lobe and possibly of left mesial temporal lobe
structures. Techniques for rendering three-dimensional images of temporal lobe anatomy, such as those described in Study 1, are applied in
Study 2 to avoid these possible serial-section artifacts.
Diagnostic Subtyping in Schizophrenia
Certain schizophrenia researchers have distinguished between
"positive" and "negative" symptoms (i.e., hallucinations, delusions, thought disorders, and bizarre behavior versus apathy, flattened affect, anhedonia and cognitive impairment) (Andreasen, 1982; Andreasen and
Olsen, 1982). Based upon this distinction, discrete subtypes of the disorder
have been proposed (Crow, 1985). Classification of schizophrenic subtypes according to clinical symptomology has been criticized, however, due to
low interrater reliability, lack of a relationship between diagnosis and
treatment response, and little evidence for discrete neuropathological
etiologies that might correspond to subtypes of the disorder (Jeste,
Kleinman, Potkin, Luchins and Weinberger, 1982). Recently a large-scale longitudinal study found little evidence for the stability of such
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 38
diagnostic subtyping. Marneros, Deister and Rohde (1992) reported a "bimorphous" course of illness (both positive and negative symtoms) for 76% of patients studied, with an increase in the proportion of negative
symptoms over time. The schizophrenic sample in the current study consisted young adult males with a predominance of positive symptoms, although the majority received an undifferentiated diagnosis due to clinical
hetereogeneity. While the small-n nature of this study precluded any differentiation of possible subtypes, clinical evidence did not suggest that these patients constituted a sample biased toward "negative" symptoms
or the predominance of frontal versus temporal involvement (Crow,
1985) (J. Gold, Ph.D., 1993, personal communication).
Gender
Complicating the limitations of existing morphometric methodology is the widespread neglect of subject variables that may bear a systematic relationship to structural lateralization (Hynd & Semrud-
Clikeman, 1989). For example, gender may have a significant impact upon normal structural lateralization. In a 1988 review, Witelson and Kigar describe the significant confound introduced in the literature by a
disregard for the effects of gender in morphometric research. Few of the
previously cited temporal lobe morphometry studies examined this
factor, and, when it was considered, gender generally was controlled by limiting samples to male subjects. In one notable exception, when data
were analyzed by gender, a significant sex-by-hemisphere interaction was
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 39
found for the temporal lobe size of bipolar females (Svvayze, Andreasen,
Randall, Alliger, Yuh, et al., 1992).
Raine et al. noted a similar lack of analysis by gender in a review of
ten morphometric studies of the corpus callosum. When these authors
reanalyzed their own callosal data on schizophrenics and normals, they
observed a significant gender-by-diagnosis interaction (Raine, Harrison, Reynolds, Sheard, Cooper, & Medley, 1990). The morphometric significance of gender with regard to the corpus callosum is supported by the observation of Zilles that commissural size relative to cortical area is 10% larger in females (Zilles, 1990). Additionally, sexual dimorphism has
been observed with regard to the absolute cell numbers of the
hippocampus (Falkai & Bogerts, 1986), and Witelson has reported an
interaction of age and gender indicating reduced size of the corpus callosum with increasing age in men but not women (Witelson, 1991).
While the sexes have an equivalent volumetric proportion (46%) of
cortical to whole brain area (Zilles, 1990), significant gender differences in
brain weight (male brains heavier) have been consistently reported in postmortem study (Ankey, 1992). The impact of gender in detailed morphometric imaging studies of whole and regional brain widths, areas
or volumes is largely unexplored. It is unclear whether sexual dimorphism in brain weight translates to a significant gender-related difference in CT or MRI morphometry. Dauphinais et al. reported no
significant effect of gender on cerebral size in a two-slice study of normals and schizophrenics (Dauphinais, DeLisi, Crow, Alexandropolous, Colter, Tuma, et al., 1990). Similarly, Kersetz et al. have found that, when lobar
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 40
measurements of brain regions are normalized to correct for individual variations in brain size, previously statistically significant gender effects
disappear, although these results are based on a single-slice MRI study (Kertesz, Polk, Black & Howel, 1990). On the whole, these two studies
offer only slight evidence for an absence of gender effects on brain
dimensions. By contrast, gender differences have been noted where the
relative asymmetry of brain regions is assessed; trends among females toward more symmetric frontal and occipital widths relative to males have been reported in CT studies (Koff, Naeser, Pieniadz, Foundas, &
Levine, 1986; LeMay & Kido, 1978). Clarification of the impact of gender as
a factor in MRI morphometry awaits methodologically sound studies that carefully examine this issue. The research presented in this dissertation has been structured to provide such data. Sex differences in functional organization and/or brain structure
have been hypothesized on the basis of gender-related variability in rates
of recovery from brain trauma (McGlone, 1980), and in performance on certain neuropsychological tests (McGlone, 1977). The interaction between gender and lateralization now appears more complex than earlier
conceptions of functional asymmetry that ascribed superiority in linguistic skills to females and greater visual-spatial ability to males
(Maccoby & Jacklin, 1974). In current models, gender differences interact with functional asymmetries in a global view of hemispheric specialization. Across both sexes the left hemisphere is regarded as
superior for processing where temporal order is salient, and the right hemisphere as subserving processing demands for synthesis and
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 41
integration (Witelson, 1983). Men and women may differ in their relative reliance on or efficient use of one or the other hemispheric processing strategies (Flor-Henry, 1980). Alternately, Kimura has hypothesized that
functional gender differences reflect a different infrahemispheric organization, with speech and verbal functions more dependent on anterior regions in females (Kimura & Harshman, 1984).
In a frequently-cited review of the literature, McGlone (1980) concluded that converging lines of evidence point to greater functional symmetry (and by implication, reduced anatomical asymmetry) among
females, with several caveats: 1) the use of analysis of variance and the
demonstration of sex-by-hemisphere interactions in carefully-controlled
studies are critical to discerning the extent of gender differences in functional lateralization, 2) many women, particularly right-handers,
may show patterns of asymmetry typical of right-handed males, and 3) atypical lateralization of non-right-handed subjects may override and obscure sex differences in the many studies where handedness is not well
controlled. McGlone's conclusions regarding gender effects merit consideration in any study of the relationship between lateralization of either structure or function in the brain. Although divergent functional
lateralization may not be incontrovertibly linked to gender differences in
brain structure, the possible morphometric implications of sexual
dimorphism for morphometry cannot be ignored.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 42
Handedness and Lateralization
The weight of existing evidence supports McGlone's conclusion
that handedness must be carefully controlled when gender differences in
lateralization are examined. Handedness, one of the most clearly evident
functional asymmetries, is particularly salient where studies of the temporal language cortex are concerned (LeMay, 1992). Right-handedness has been linked to left hemispheric localization of speech, and left- handedness to more atypical localization based upon sodium amytal testing for speech dominance (Branch, Milner, & Rasmussen, 1964).
Annett (1964) has described a model for homozygous and heterozygous
genotypes with respect to handedness, resulting in overlapping distributions of the degree of left or right manual preference. She
theorized that the genetic predisposition toward lateralization exists among the majority of right-handers, with the absence of this "right-shift
factor" resulting otherwise in randomly distributed handedness. More
recently Annett (1992) has detailed similarities in the distribution of asymmetries in praxic skill and asymmetries of the planum temporale, implying a link between mechanisms of both structural and functional lateralization.
An anatomical substrate of the "right-shift factor” is similarly implied by evidence that the majority of the population, namely right
handers, is more likely to have speech functions lateralized to the left hemisphere (Branch, Milner & Rasmussen, 1964; Kimura, 1987).
Corresponding to this functional variation is evidence of gross
neuroanatomical differences between left and right handers. Reduced or
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 43
reversed normal asymmetry of the Sylvian fissure (based upon the position of Sylvian vasculature within each hemisphere) has been noted
in arteriographic study of left-handers (Hochberg & LeMay, 1975) and a recent MRI study of normal subjects found a significantly lesser degree of
the typical asymmetry of the temporal language cortex (PT) among left
handers (Steinmetz, Volkman, Jancke & Freund, 1991). Unfortunately,
while both male and female subjects were included in the latter study,
data were not analyzed for the interaction of handedness and gender. Morphometric studies of cerebral asymmetry may also be confounded by the inadequate assessment of handedness. Where
handedness is evaluated, a single question regarding hand preference or
"writing hand" has often formed the basis for subject classification. This
dichotomous criterion is clearly inadequate in light of the current conceptualization of handedness as a continuously distributed variable,
and one that is more accurately assessed using an inventory of observed
hand preferences for a variety of tasks (Geschwind & Galaburda, 1985; Hynd & Semrud-Clikeman, 1989; LeMay, 1992).
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 44
Experimental Design of Study 2 As previously described, the factors relevant to this morphometric study of supratemporal lateralization were diagnosis (normal versus
schizophrenic), gender, and handedness. Additionally, the impact of age on morphological measures must be considered, due to evidence of age- related variability in cortical volume, and findings of slow degenerative
brain changes with increasing age, and greater age-related cortical atrophy
among males (Gur, Mozley, Resnick, Gottlieb, Kohn, Zimmerman, et al., 1991; Jernigan, Archibald, Berhow, Sowell, Foster, & Hesselink, 1991b).
Systematic examination of the relationship of each of these factors to
supratemporal laterality would be impractical in view of the sample size required to achieve sufficient statistical power. Therefore, pertinent
factors were isolated and the remaining factors carefully controlled as
follows: Due to the unavailability of a sufficiently large female
schizophrenic sample, diagnosis could only be examined in a two-way
comparison of male normals and male schizophrenics. Age was
controlled across all comparisons by the selection of young adult subjects. Handedness was similarly controlled by the restriction of all samples to
strongly right-handed (Edinburgh L.Q. >.70) subjects. Although controlled in the diagnosis comparison, gender was systematically examined as a
factor in the supratemporal laterality of normal subjects. As a result, this design addressed two specific research questions: 1) Does the lateralization of supratemporal gyral structures differ between right-handed, adult male
schizophrenics and their normal male counterparts? 2) Do patterns of
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 45
supratemporal laterality differ between normal, right-handed adult males
and females?
Subject Selection Criteria
MRI datasets were obtained from ten male schizophrenics, twelve normal males, and twelve normal females between the ages of 20 and 35
(a subset of the normal males served as subjects for Study 1).
Sample size was an important consideration, given the cost of MRI scanning (>$1,000 per subject) and the labor-intensive nature of three- dimensional MRI morphometry. Samples in the present study, however,
are equivalent to prior MRI explorations of the PT (Larsen,Odegaard,
Grude & Hoien, 1989; Rossi, Stratta, Mattei, Cupillari, Bozzao, et al., 1992) with the added advantage of both careful control of handedness and a
gender comparison group. The effect size (Cohen, 1988; Cohen, 1992) of PT laterality in the postmortem literature is quite large, with the left PT
averaging one third larger than the right, and asymmetries of this
structure often are visible to tne naked eye (Geschwind & Levitsky, 1968). Given the magnitude of anatomical PT asymmetry and the successful
detection of PT lateralization in more methodologically limited studies,
sample size in the current study was considered sufficient for between- group comparisons.
Schizophrenics selected for this study were among inpatients at the NIMH Neuropsychiatric Research Hospital. All were diagnosed as
schizophrenic on the basis of DSM-III-R criteria, and classified as strongly
right-handed (mean score 85.7) by means of the Edinburgh Handedness
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 46
Scale (Oldfield, 1979). Normal male volunteers were selected on the basis of strong right-handedness (mean E.I. score=94.8), and matched as closely
as possible by age to the schizophrenic patients. A third sample of strongly
right-handed normal female volunteers (mean E.I. score=94.0) were also age-matched to the normal male sample. Two-sample t-tests revealed no significant differences between male and female normals, or between schizophrenics and male normals with regard to age or scores on the
Edinburgh Handedness Inventory (See Table 3). Normal controls were screened for a history of head injury, substance abuse, neurological, and
psychiatric disorders. All subjects gave informed consent.
MRI Aquisition
Sagittal volume MRIs were acquired on a GE Signa 1.5 T scanner
(SPGR, TR=24, TE=5) as 124 contiguous 1.5 mm slices (FOV 240 mm,
256x256 pixel matrix). Image analysis was performed on Apple Macintosh
Ilci and Quadra 950 computers using the NIH Image program. Surface renderings were generated by the commercial software package DIP Station (HIPG Inc.).
SegmentatiQn_and„Surface_Rendering Procedures Details of both extracortical tissue segmentation and surface rendering morphometry of the PT are described elsewhere (Kulynych, Vladar, Jones & Weinberger, 1993). Using macros written in-house for the
NIH Image software, the original sagittal datasets were first rotated so that
a line connecting the anterior and posterior commissures becomes the
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 47
horizontal axis of each slice. Datasets were then resliced axially and the interhemispheric fissure similarly defined as the horizontal axis. This procedure was repeated once again in the coronal plane, with the
horizontal axis passing through the interhemispheric fissure. These
successive realignments are critical to establishing a uniform orientation
of each brain to a standard 3-D reference space, the Talairach and Tournoux (1988) atlas. Procedures for segmentation of brain tissue developed in the CBDB laboratory involve the semi-automatic removal of extracortical tissue
with the dataset resliced to the transverse plane. Additional semi automatic editing is performed in both the coronal and sagittal planes to
insure smooth cortical contours that will produce high-fidelity surface
renderings. Following whole-brain segmentation, the supratemporal
surface is exposed in each sagittal slice: a region of interest (ROI) is drawn
to encircle brain tissue above the Sylvian fissure, then frontal lobe tissue contained in this ROI is automatically "cut off" in a manner analogous to
the Geschwind and Levitsky (1968) postmortem study of the planum temporale. The posterior limit of the PT is chosen in serial sagittal
sections so as to exclude tissue of the ascending ramus of the Sylvian fissure. Surface renderings of the resected sagittal datasets are generated as
frontal views with a 45 degree pitch in order to optimally expose
supratemporal gyral structures.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 48
Planum Temporale Measurement
The PT was measured bilaterally in all subjects. Prior to
measurement all surface-rendered supratemporal images were assigned numerical codes, allowing the investigator to remain blind to sex and
diagnosis. To eliminate the possibility of a systematic left or right bias in
the size of PT ROIs, half of the surface renderings of the resected datasets were randomly "flipped", using an NIH Image macro that creates an
identical picture in which left-right orientation is transposed. The investigator thus remained blind to the true right-left orientation of each
supratemporal rendering. ROIs of the PT surface were drawn manually on these
supratemporal renderings. Each ROI included the entire exposed supratemporal surface posterior to Heschl's sulcus (HS). Heschl's sulcus
was identified according to the criteria of Steinmetz et al. (1991) as the sulcus immediately caudal to the most anterior transverse gyrus. As a result of the resection of the sagittal dataset to exclude the posterior
ascending ramus of the Sylvian fissure, the posterior boundary of the PT became a clearly demarcated border in the supratemporal surface rendering. The lateral boundary of the PT was determined by the visual edge of the surface rendering.
Heschl’s Gyrus Measurement
As viewed in a supratemporal surface rendering, Heschl’s gyrus
(HG) follows a diagonal course across the temporal plane, merging with
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 49
the rostral superior temporal gyrus near the temporal pole. In order to measure Heschl's gyrus on a surface rendering it became necessary to establish a consistent anterior border for this structure. A procedure was
developed for defining an anterior boundary in sagittal sections that would remain visible in a subsequent surface rendering. NIH Image tools
allow a black line to be drawn at a 45 degree angle to the temporal surface,
intersecting at a point immediately anterior to HG in each slice where the gyrus is present. In those datasets where HG does not reach the edge of the supratemporal surface, the boundary point can be projected laterally
through the remaining slices. When the resulting dataset is processed with the rendering module DIP Station, an anterior boundary for HG
appears as a dark line on the rendered supratemporal surface (see Figure
8). Procedures identical to those used to measure areas of the PT were applied to measurements of HG. Supratemporal renderings were coded and randomly "flipped". ROIs were drawn to make bilateral
measurements of the exposed surface of HG for each subject. As described, anterior HG borders for each supratemporal surface rendering resulted
from a prior delineation of the boundary in serial sections. Heschl's sulcus served as the posterior boundary of the HG, and again the visual edge of the rendering established the lateral boundary.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. CHAPTER 8 RESULTS OF STUDY 2
Prior to measurement of PT and HG areas, the agreement of two independent raters was evaluated for the surface-rendering technique.
Previously described agreement for the surface-rendered PT measurements in a subset of this sample was high (Pearson's linear
correlation coefficient r=0.90, p.<.0001, unbiased intraclass correlation
coefficient ICC(U)=0.78, p.<.0001)(See Study 1, Chapter 2). Agreement
between two independent raters for measurements of HG was also
evaluated and found to be excellent (Pearson's r=.87, p.c.OOOl, ICC(U)=.81, p.<0001).
PlanumTemporale
Mean areas for left and right PT are presented by group in Table 4. PT data for all subjects were first analyzed by two two-way ANOVAs, with
group (female, male, or male schizophrenic) as independent variables and side (left and right PT areas) as a repeated measure. For the
comparison of control males and females, there was no significant main effect of gender and only a slight trend (F=3.384, p<0.073) toward a main effect of side. The gender-by-side interaction, however, was significant
50
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 51
(F=5.62, p<0.03) (Figure 9). Post hoc tests indicated that while the left planum (mean=7.05 cm2, ± 0.52 s.e.m) was significantly greater than the
right planum in males (mean=5.36 cm2, ± 0.30 s.e.m.) (Tukey’s HSD, p<0.036) in females there was no such difference (Tukey's HSD, p>0.98).
Moreover, male left planums were significantly larger than female left planums (5.30 cm2 ± 0.61 s.e.m.) (Tukey's HSD, p<0.03), while no size difference was detected between males and females for right PT areas. The comparison between schizophrenics and ten age-matched normal males revealed a significant effect of side (F=11.17, p<0.004), and
no main effect of diagnosis or diagnosis-by-side interaction. A post-hoc
test indicated that, across both groups, left planums were significantly larger than right planums (Tukey's HSD, p<0.0038).
Asymmetry Coefficients
A dimensionless, directional measure of asymmetry was determined for each subject by applying the formula 5PT=(R-L)/.5*(R+L).
Using this coefficient, subjects were classified according to the Galaburda et al. (1987) criteria as exhibiting leftward asymmetry of the PT (5PT<- 0.05), symmetry of the PT (-.05<5PT<0.05), or rightward asymmetry of the
PT (5PT>.05) (See Table 5). Among females, asymmetries were evenly distributed with 5/12 subjects leftward, 6/12 subjects rightward, and 1/12
subjects showing symmetry of the PT. The distribution of 8PT among normal men was skewed leftward, with 10/12 subjects leftward, 1/12
rightward, and 1/12 showing symmetry of the PT. Fisher’s exact test
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 52
indicated a significant gender difference between the distribution on non-
symmetric SPTs (p < 0.03). Schizophrenic 8PT distribution was also skewed to the left, with
8/10 subjects leftward, 1/10 rightward, and 1/10 exhibiting symmetry of the PT. For the comparison of schizophrenics and matched male controls, no difference was detected between the distribution of lateralization
coefficients (SPT) for the two groups.
Heschl’s_Gyxus Mean areas of the left and right HG for each group are shown in
Table 4. Two-way ANOVAs for HG data revealed no significant effect of
group or side, and no significant interactions in the comparison of
normal men and women or between schizophrenics and matched
controls. Paired t-tests detected no significant difference between
lateralization indices (5HG) in females versus males, or in schizophrenics
versus matched controls.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. CHAPTER 9 DISCUSSION OF STUDY 2: GENDER AND SCHIZOPHRENIA
COMPARISONS OF HESCHL'S GYRUS AND PLANUM TEMPORALE
AREAS
As a test of the laterality hypothesis (Crow, Ball, Bloom, Brown, Bruton, et al., 1989a) this carefully controlled MRI study offers no evidence for the involvement of the supratemporal cortex in schizophrenia. Although a study of unrelated singletons cannot address the hypothesis that schizophrenia is related to a mutation of the "cerebral
dominance gene”, the present results do not support Crow’s prediction of
lateralized temporal lobe abnormalities, insofar as no diagnosis-by-side interaction was observed for areas of the planum temporale. Schizophrenic males did not differ from healthy controls in areas of the left, right or combined PTs, and the entire sample demonstrated a
significant leftward lateralization of PT area. While the surface-rendering
method detected clear asymmetries in regard to lateralization of the PT, there was a marked absence of lateralization in HG. This lack of
asymmetry in contrast to that of the PT suggests that no systematic bias resulting from temporal plane orientation or two-dimensional surface
projection accounted for the observed left-right area differences in the PT.
While these results contradict the Rossi et al. report of reduced PT
53
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 54
asymmetry in schizophrenia (Rossi, Stratta, Mattei, Cupillari, Bozzao, et
al., 1992), methodological limitations and the absence of analysis by
gender in the Rossi et al. study provide little basis for comparison with the present results. The lack of an effect by diagnosis in the present
sample of right-handed schizophrenics is not a refutation of the laterality
hypothesis, however, particularly when the heterogeneous nature of schizophrenia is considered. To the extent that schizophrenic psychosis may result from the interaction of CNS maturation with a number of different brain lesions (Weinberger, 1987), brain abnormalities may vary
between patient groups. Thus the distribution of regional structural
volumes may overlap between patients and normals, increasing the difficulty of detecting reliable group differences (Pfefferbaum & Zipursky,
1991). The sample in the present study, consisting of strongly right- handed schizophrenics and controls, may represent overlapping tails of two such distributions with regard to temporal lobe lateralization.
Reports of an increase in left or mixed handedness exist in the
schizophrenia literature (Flor-Henry, 1979), and confirmed right-handers might compose a distinct subgroup within the broader spectrum of
schizophrenic patients.
This study offers the first in vivo evidence of gender differences in
the asymmetry of the planum temporale. Left planums were significantly larger than right planums among normal males; by comparison no
significant difference between left and right areas was present among
females. The lack of a significant main effect of group indicates no
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 55
difference in overall (left + right) planum size, although left planums alone were significantly larger in men than in women.
These data correspond remarkably well to the recent report of Witelson
and Kigar (1992) concerning asymmetries of the horizontal portion of the Sylvian fissure, the posterior extent of which reflects PT length. Over a period
of thirteen years, these authors dissected 67 brain specimens of patients who
received detailed examination of manual preference prior to death from a terminal illness. Postmortem analysis of Sylvian fissure length revealed diverging patterns of asymmetry among men and women analogous to those
we describe for the entire PT. The horizontal Sylvian fissure (HSF) was defined by Witelson and Kigar
(1992) as extending from Heschl’s sulcus to the point where the Sylvian
fissure bifurcates into the posterior ascending and descending rami. This
boundary is a linear equivalent of the PT area measurement used in the present study. Few postmortem or MRI studies to date have systematically examined the effects of gender on asymmetries of the perisylvian region.
Among those few, only that of Witelson and Kigar (1992) has adequately
controlled for handedness. Their data, coupled with the results of the present study, illustrate the significant impact of both variables on the lateralization of the temporal language cortex.
Witelson and Kigar (1992) report a significant gender-by-hemisphere interaction in the length of the HSF, with multiple comparisons indicating men had a larger HSF in the left, but not the right hemisphere, although both sexes did show a statistically significant PT asymmetry. A
trend towards a handedness-by-gender interaction was detected for HSF
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 56
(p<0.08), with post hoc tests suggesting a relationship between HSF length and handedness in men but not in women. A corresponding relationship of handedness to PT area is suggested by the results of the present study,
where 11/12 right-handed men had larger left planums, while the
direction of planum asymmetry was evenly distributed among right- handed females. These findings indicate a relationship between gender
and lateralization of the supratemporal cortex is present only among
right-handed males. While females as a group show reduced laterality, it cannot be inferred from these data that the plana of individual women
are less asymmetric. A bimodal distribution of leftward and rightward Pt asymmetries among women is equally possible.
In contrast to findings for the planum temporale, the present results
indicate that the area of Heschl's gyrus is quite consistent, both between
hemispheres, and across sexes. This lack of asymmetry may reflect a more bilateral distribution of those tonotopically organized cortical zones with
the greatest specificity for particular sound frequencies (Kolb & Whishaw, 1990; Webster & Garey, 1990), although such a detailed mapping of the primary auditory cortex has not been accomplished. While certain
postmortem studies have reported asymmetries favoring the right hemisphere in the number of Heschl's gyri (Chi, Dooling & Gilles, 1977b;
Geschwind & Levitsky, 1968), areal measurements in the present study were restricted to the first transverse temporal gyrus. To facilitate
comparison with existing MRI studies of the planum temporale, all
cortex caudal to the posterior sulcus of the first Heschl’s gyrus was
included in the current PT measurements. HG regions of interest (ROIs)
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 57
should therefore reflect an area of primary auditory cortex distinct from the region defined as the planum temporale. Equally important,
combined cytoarchitectonic and electrophysiological evidence suggests that the core of primary auditory cortex can be localized to the
anteromedial portion of the first transverse gyrus.
To establish that structural asymmetry of the PT reflects more than
mere differences in the relative position of gyri, the composition and
function of the asymmetrical region must be examined (Galaburda, Sanides & Geschwind, 1978). Any attempt to relate gross anatomy to
cognitive function requires that gyral and sulcal boundaries be chosen to conform as nearly as possible to unique microanatomic and
electrophysiological characteristics of a tissue region. This requirement remains unmet for the posterior border of the planum, where existing
evidence suggests that auditory association cortex stretches, to a variable
extent, beyond the convenient morphometric boundary of the Sylvian point (Galaburda & Sanides, 1980). In view of the reversal of left-larger
asymmetry in the posterior ascending ramus of the Sylvian fissure, compensatory increases in other cortical association areas may actually
balance asymmetry of the planum temporale. For example, Eidelberg and Galaburda (1984) have described a divergence of asymmetries in
association cortex of the inferior parietal lobule and the planum, although as in most such cytoarchitectural studies the variables of sex and
handedness were not considered. Future MRI studies of groups (well
controlled for these variables) might expand morphometric analysis to multiple cortical regions such as the asymmetrically-positioned
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 58
supramarginal gyrus (Witelson & Kigar, 1992), in order to discern the full range of asymmetries of the Sylvan fissure.
The present results are also consistent with earlier neuropsychological reports of gender differences in patterns of functional asymmetry. Kimura and Harshman (1984) describe two lines of evidence for gender divergence in functional lateralization, based primarily upon
studies of speech impairment in neurological populations, and less conclusively upon investigations of verbal processing (dichotic listening) in normal subjects. Among patients with lateralized lesions, reports
indicate a rate of left hemisphere aphasia up to three times higher in men
than women (McGlone, 1977; Kimura, 1983), more severe left
hemisphere lesion-induced verbal memory deficits among men (McGlone, 1978); and a pattern of lateralized Verbal and Performance IQ
deficits following unilateral temporal lobectomy or vascular lesion
among men that was not evident among women (Inglis & Lawson, 1981;
Inglis, Ruckman, Lawson, Maden, & Monga, 1983). Data from neurological populations are commonly interpreted as an indication of greater language lateralization among males, possibly resulting from
greater lateralization of language-related cortex. Gender differences in the language lateralization of normal subjects
have been reported in several dichotic listening investigations, where larger and more significant right-ear advantage (REA) scores were found
among right-handed males versus right-handed females (Harshman, Remington, & Krashen, 1983; Springer & Searleman, 1978). The majority
of dichotic listening studies have not reported gender differences, possibly
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 59
due to large within-sex variability and the small magnitude of gender
effects (Harshman, Remington & Krashen, 1983; Kimura &l Harshman, 1984). Yet support for a normal gender-related dichotomy in verbal processing is also offered by a study reporting sex differences in the amplitude of anterior versus posterior event-related potentials (ERPs)
recorded in response to verbal and spatial memory tasks (Taylor, Smith, & Iron, 1990). Although the evidence for differing patterns of functional
lateralization remains somewhat controversial, positive findings have tended to converge in the direction of reduced language lateralization
among women (Strauss, Wada, & Goldwater, 1992), a trend that is
consistent with the present report of less consistent structural asymmetry of language-related cortex among females.
Etiology of Structural and Functional Lateralization
In her review of gender influences on brain asymmetry, McGlone
(1980) asks two fundamental questions regarding sex differences: "Why do they exist?", and "Do (they) matter?" Neither of these issues can be
considered unequivocally resolved even with respect to purely
anatomical asymmetries. For the planum temporale, theories about the
origins of asymmetry range from genetically-linked lateralized patterns of growth in the parietal/occipital areas (Witelson & Kigar, 1992), possibly
coupled with unilateral developmental pruning of cortical neurons (Galaburda, Rosen & Sherman, 1990), to the degree of exposure to testosterone in utero (Geshwind & Behan, 1982). The latter theory.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 60
known as the "Geschvvind Hypothesis", postulates the existence of a fixed
amount of a cortical language substrate that exhibits asymmetry as a
result of normal developmental processes. Exposure to testosterone or
any delaying influence in the intrauterine environment is predicted to differentially retard the growth of the left PT, accompanied by a compensatory increase in the area of the right PT. The model predicts a greater degree of PT symmetry among males, in association with
increased incidence of left-handedness, developmental disorders, and autoimmune disturbances.
An alternative etiology has been proposed in which lateralization
results from greater variability in the size of the smaller (usually right)
planum temporale. This theory diverges from the Geschvvind hypothesis
in rejecting the notion of a fixed amount of language substrate. Rather, the authors suggest that, where symmetrical plana are found, a
teratogenic agent such as excessive testosterone has acted to reduce
normal, asymmetrical neuronal loss, thus limiting the developmental involution of the smaller PT. Galaburda et al. (1987; 1990) have advanced this hypothesis, maintaining that asymmetry of the PT results from a normal reduction in neurons of the right temporal cortex, with greater
asymmetry predicted among women, presumably as a consequence of
lessened exposure to testosterone in utero. In support of this theory
Annett (1992) has proposed a related model of handedness in which the
degree of asymmetry in praxis depends upon the skill of the non
preferred hand. Data from the present study, however, as well as that of Witelson and Kigar, support a conclusion of greater /e/f—hemisphere
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 61
variability with respect to the growth of the planum temporale. Notably,
among our subjects the right PT did not differ in area between the sexes.
Reductions in PT asymmetry appear to result from decreased size of the
left PT, more commonly among women, although the coexistence in
both sexes of bilaterally symmetric Heschl's gyri suggests no global
retardation of left temporal lobe growth can account for observed
asymmetries. Geschwind and Galaburda (1985) have described the lateralized brain as providing a larger complement of those varying talents and skills that
contribute to greater diversity within the species. Anthropological
evidence establishing the presence of structural asymmetries during the evolution of the species is seen in Neanderthal skull castings, thirty to fifty thousand years old, that reveal a steeper, more sharply curving
Sylvian fissure (LeMay, 1976). An evolutionary basis for the development of gender differences in asymmetry is fertile ground for speculation, but
Flor-Henry (1980) has suggested that the increased efficiency of spatial
analysis as conveyed by a lateralized brain offers a selective advantage to males in pursuit of females during mate selection.
Theories that link functional and anatomical asymmetries tend to equate greater absolute size with functional superiority. Larger cortical areas generally subserve more complex functioning in the visual and
somatosensory systems, establishing a precedent for the attribution of this
property to the auditory cortex (see discussion in Kolb & Whishaw, 1990; Witelson, 1983). Irrespective of this evidence, a danger exists that the
study of sexual dimorphisms may become politicized by unquestioned
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 62
adoption of this assumption, given the widely-reported gender disparities
in brain weight and verbal/spatial skills (Harris, 1980; Maccoby & Jacklin, 1974). Differences between the sexes may ultimately be found to lie not in
the magnitude but in the distribution of complementary asymmetries of size and function across the entire cortex.
A final consideration of the meaning of neuroanatomical sexual
dimorphism is prompted by the work of Waber, who has questioned the dichotomous male/female categorization of the brain. Her neuropsychological findings indicate that early maturers have superior verbal skills relative to the increased spatial skills of late maturers, regardless of sex (Waber, 1976). Given that the organization of cortical function may be linked to rates of maturation within the brain, the variable distribution of asymmetry may result from a continuum of
hormonally-induced "maleness" or "femaleness". This continuum model suggests that researchers should examine the correlates of structural laterality within one gender - perhaps investigating whether
greater asymmetry among females correlates with increased visuospatial skills.
The planum temporale has been the focus of laterality research in
the studies presented due to its dramatic asymmetry, relative to other brain regions, and existing anatomic, electrophysiological, and neuropsychological evidence clearly linking this region to speech
function. Improvements in neuroimaging techniques and the careful
control of relevant subject variables have revealed a previously
undocumented interaction of gender and hemispheric asymmetry of the
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 63
planum temporale, lending credence to longstanding theories of sex differences in the lateralization of speech and language. Yet for males
asymmetry of the planum temporale region appears so fundamental a
phenomenon of cortical development that within-sex patterns, at least
among right-handers, reflect no impact of schizophrenic psychosis. Finally, the gender divergence in patterns of PT laterality detected in this
study indicates that sexual dimorphism should be considered in any
investigation of the relationship between psychopathology and abnormal cerebral asymmetries.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. APPENDIX A
ELEMENTS OF MRI: TISSUE CHARACTERIZATION WITH RF PULSE
The theoretical basis of magnetic resonance imaging (MRI) stems
from the observation that groups of protons (hydrogen nuclei) that are stimulated by a radio frequency (RF) pulse will emit signals that can be
detected by the RF receiver component of a MRI scanner, and that the
amplitude of these signals reflects the chemical structure of the
environment in which the protons are embedded (Straughan, Spencer, &
Bydder, 1983). Through mathematical transformation these signals are reconstructed to create an anatomically meaningful image of the composition of living tissue (Prorok & Sawyer, 1992) The resulting MRI
image is an anatomical representation in which certain physiological tissue characteristics have been decoded from an array of RF signal amplitudes (Maudsley, 1983).
This matrix of numbers, each represented by a shade of gray
corresponding to the signal intensity emitted by a particular perturbed
(stimulated) tissue, is translated into a computerized image by the MRI
scanner. The visual appearance of the reconstructed image, however, is a
function of multiple variables related to properties of the MRI scanner, the RF pulse (the pulse sequence) and the tissue of interest. As a result,
64
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 65
the same tissue can appear dramatically different as imaging parameters
are altered. Of particular concern for brain morphometry, both image
contrast and spatial resolution are directly influenced by the interaction of
these variables.The phenomenon of nuclear magnetic resonance, including the behavior of the hydrogen proton in an external magnetic
field, was described independently by Bloch et al. and Purcell et al, in 1946 (Bloch, Hanson, & Packard, 1946; Purcell, Torrey, & Pound, 1946) Briefly, the hydrogen nucleus is composed of a single proton which spins on its axis, with a magnetic pole that is normally randomly directed. On
average, a group of protons tend to align with and precess about the axis
of an external magnetic field (Mallard, 1983). Due to the proton's characteristic nuclear spin this alignment will be either parallel or antiparallel to the external field, with the net alignment of the proton
group favoring the lower-energy parallel state (House, 1983) If a RF pulse
of the appropriate resonant frequency is applied (the Larmor frequency)
in such a magnetic field, then the group of protons "flip" into the higher energy parallel state. The result is a "resonance condition" in which protons dissipate this absorbed energy by emitting radiowaves as they
precess back to a more relaxed configuration (James, Pickens, Rollo,
Stephans, Erickson, Patton, et al., 1983; Pfefferbaum, Lim, Rosenbloom, & Zipursky, 1990). The strength of the radio signal emitted by these relaxing
protons characterizes the type of tissue perturbed, with areas of high
signal intensity appearing bright in the computerized MRI image, and
areas of low signal intensity appearing as relatively darker shades of gray.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 66
In 1973, Lauterbur described a method of constructing 2-
dimensional images of a biological object that would reflect the spatial distribution of a stable isotope such as hydrogen. He proposed combining
the multiple projections that could be formed by the rotation of an object within a gradient magnetic field. This principle applies in the modern
MRI scanner, although here the field gradient is rotated as the subject lies
stationary (Holland, Hawkes, & Moore, 1983). Linear gradients of magnetic field strength are applied along the body, then repeated in step wise fashion within the plane of each "slice" or cross-section. Protons resonate within the slice at frequencies corresponding to the different
gradient field strengths, allowing the spatial encoding of individual
volume elements (voxels) of tissue (Oldendorf & Oldendorf, 1988). This spatial encoding is achieved through a Fourier transform of the detected
signal (Maudsley, 1983). Lauterbur was the first to describe this use of
linear gradients to localize the source of nuclear magnetic resonance
(NMR) signal within a plane, although subsequent modifications were required to adapt this technique to biomedical imaging (Andrew, 1983). It is important to note that the three-dimensional tissue voxels are actually represented on the computer screen as the two-dimensional
picture elements (pixels) of the MRI image. Slice thickness of the cross- sectional image forms the third dimension of the voxel. In non contiguous serial MRI sections a "gap" of several millimeters occurs between the end of one voxel and the beginning of another. Tissue
contained in this gap is not imaged, although these omissions are not
obvious from the inspection of consecutive image slices. Tissue
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 67
distinctions within a voxel are also masked by partial volume effects, because the overall signal intensity of the corresponding pixel represents
the average signal intensity of all tissue contained within the voxel,
obscuring within-voxel heterogeneity (Kelly, 1987)
Grayscale levels in the MRI image is in part a function of intensity
differences in signal emitted by tissues of different physiological
composition. These differences in signal intensity do not reflect simple tissue properties such as density (imaged in X-ray and CT techniques). Instead MRI images reflect the complex interaction of three tissue "relaxation" times, commonly referred to as Tl, T2, and T2 star, that characterize the behavior of hydrogen nuclei in the tissue environment.
For example, intensity differences detected immediately following RF perturbation reflect the rate of tissue magnetization, i.e., the ease with which protons can exchange energy with their environment (termed the
lattice). The Tl (spin-lattice) relaxation time is the time by which
magnetization of 63% of a particular proton sample is achieved, and
varies according to the interaction of nuclei with their molecular tissue environment (House, 1983). Relatively homogenous substances with
widely dispersed molecules such as water or CSF have comparatively long Tl times, and changes in magnetization are "sluggish". These
regions appear dark when the initial signal is sampled, in comparison to the brighter appearance of more compact, complex brain tissue, where a greater proportion of hydrogen in the form of tissue water is bound in macromolecules and cellular structures, and tissues magnetize and
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 68
demagnetize more rapidly, as reflected in shorter Tl times (Brandt- Zawadzki, 1987; Straughan,Spencer, & Bydder, 1983).
Signal decay of a proton group is accelerated by dephasing effects that
result from random thermal motion and fixed magnetic inhomogeneity in the tissue environment, and which hasten the loss of observable
magnetization within a voxel of tissue. T2 (transverse relaxation time) and T2-star constitute dephasing effects due to random fluctuations from thermal noise and constant non-uniformity of magnetic field across the voxel, respectively (Oldendorf & Oldendorf, 1988). A primary source of T2
relaxation or dephasing effects is the interaction between nuclear spins in a proton group (House, 1983). With time, signal intensity dissipates at a
greater rate in a more complex tissue environment. When sampled at
later timepoints, more homogeneous substances (water or CSF) reflect
less signal loss from dephasing than surrounding brain tissue. In an MRI image based on such a delayed sampling, contrast effectively reverses.
More aqueous tissues appear relatively brighter due to delayed dephasing effects resulting from this T2 (transverse-relaxation) time (Brandt- Zawadzki, 1987).
The choice of Tl of T2 weighting (or alternate imaging parameters)
bears a direct relationship to the visual appearance of MRI images. Tl-
weighted images such as the ones used in Studies 1 and 2 are based on a
more immediate sampling of signal, where rapidly magnetized tissues
appear as the brightest pixels in the image. Volume imaging with both short aquisition times (approximately 12 minutes) and good gray
matter/white matter/ CSF contrast becomes possible using these Tl-
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 69
weighted scans.The high contrast of Tl images reflects in part the large variations in Tl time that result from very small differences in water
content across tissues (Straughan, Spencer & Bydder, 1983). The pulse
sequence, or timing and grouping of the RF pulses, can be varied to enhance Tl or T2 effects, by altering the parameters TR (repetition time, between pulse sequences) and TE (echo time, between initial and "refocusing" pulses) (Oldendorf & Oldendorf, 1988).
Unfortunately, the visual appearance of an MRI image is also subject to a number of undesired artifactual influences resulting from
physiological complications such as head movement and blood flow, as
well as hardware and software limitations. "Noise" or random RF
interference also accompanies signal and may obscure images in a manner analogous to the "snow" seen with poor television reception.
The ratio of signal to noise (SNR) can be increased with the use of a high
field strength - i.e., a 1-Tesla or greater magnet, which evokes stronger signal from tissue (Prorok & Sawyer, 1992). With sophisticated pulse
sequences such a scanner can create three-dimensional volume scans, with small, nearly isotropic contiguous voxels. Fine resolution and high
SNR make Tl-weighted volume MRI scans the technique of choice for
and "reslicing" along secondary planes and reconstructing brain surfaces. Of additional concern in MRI image analysis are scan artifacts. Artifacts as manifest in a MRI scan can be described as "highly unintuitive effects on the image intensity (causing) blurring and spatial
distortion or mislocation"(Wendt, Murphy, Ford, Bryan, & Burdne, 1984). These unwanted effects include "ghost" images caused by head motion
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 70
and partial volume averaging. Movement effects are often a consequence
of patient anxiety coupled with lengthy scan time, which may be ameliorated with fast pulse sequences such as the SPGR (Spoiled Gradient
Recall Acquisition in the Steady State) used in the present studies. Partial volume averaging is of particular concern in older, thick-slice studies, where a voxel may encompass a tissue span of more than a centimeter
(extremely non-isotropic). The averaging of gray values across greater depth results in a pixel intensity that may be unrepresentative of any single component tissue in the voxel. This averaging or blurring may obscure tissue borders and cause a significant loss of anatomical detail.
State of the art volume scans produced by increasingly powerful magnets
and improved RF detection techniques reduce partial voluming effects
and provide more veridical characterization of the tissue of interest.
Relative to other noninvasive imaging techniques such as CT, MRI is frequently viewed as lacking harmful biological effects that might limit the length or number of studies performed upon a single subject. It
would be more accurate to suggest that no such risks are presented within the safety limits established for the strength of the static magnetic field or exposure to RF pulse (Andrew, 1983). In very high fields (much greater than existing 2-3 Tesla clinical limits) cardiovascular effects and damage
to nerve or muscle tissue may be observed. Likewise, excessive heating of
tissue may result from exposure to high-frequency RF pulses, placing a
practical upper limit on the design of pulse sequences (Saunders & Orr, 1983).
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. APPENDIX B TECHNICAL AND METHODOLOGICAL ISSUES IN IMAGE PREPARATION
A number of technical and methodological considerations were
central to the processing of MRI images used in the previously described studies. Procedures for the preparation of image data included aligning MRI "stacks" with a set of standard stereotactic axes, optimizing techniques for segmentation of raw MRI datasets, maximizing and
standardizing gray-white contrast within the raw image data,
determining the correct value for thresholding functions within the surface rendering module, and assessing interrater reliability. Alignment of images to the Talairach and Tourneaux axes (1988)
was considered an essential first step, as it standardized head positioning across subjects. This procedure orients the brain with reference to the
midsagittal and bicommissural planes. The bicommissural plane,
bisecting the anterior and posterior commissures of the corpus callosum, bears the most constant relationship to intracerebral structures and, therefore, provides the best "baseline” for stereotactic orientation
(Steinmetz & Huang, 1989). Macros written for NIH Image (Jones, 1992a) allow a line connecting the anterior and posterior commissures in the
71
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 72
original sagittal dataset to define the horizontal plane, with a corresponding shift and realignment of each image in the sagittal MRI stack. Similar procedures are applied with the dataset resliced in
transverse and coronal planes, to align the interhemispheric fissure to the standard axes and orient each brain in 3-dimensional space. While
torque effects and petalias (LeMay, 1976) are unaltered by this
standardization, rotational artifacts such as those resulting from head tilt
or orientation in the scanner should be substantially reduced. Approaches to "segmenting" brain tissue, or isolating tissues of
interest within an MRI image, vary in accordance to the degree of
procedural automaticity claimed by proponents of a given technique, as well as in the accuracy with which tissues are discriminated. In general,
manual procedures produce the most accurate classification of pixels (Andreasen, Cohen, Harris, Ciszadlo, Parkkinen, Rezai, et al., 1992), while
requiring the greatest amount of time, morphometric experience, and
knowledge of anatomy. Hohne and Hanson (1992) have described the significant role of intuition in such manual segmentation of MRI stacks into meaningful parts, a task where the skill required of a human expert
is further taxed by partial voluming effects (i.e., where individual voxels
contain signals averaged across different tissues). Even those "automatic"
techniques employing edge detection, where the operator plants a "seed" that traces the pixel border of a structure, frequently require manual
editing to correct the undesired boundary resulting when the seed fails to detect the intersection of two structures in the same intensity range
(Cohen, Andreasen, Alliger, Arndt, Kuan, Yuh, et al., 1992).
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 73
Currently, computer algorithms cannot rival the human eye in performance of the complex pattern recognition required to discriminate
obscure anatomical boundaries. Semi-automated approaches to segmentation vary from simple thresholding to sophisticated
multivariate discriminant analysis of multiple MRI scans from images
differently weighted to enhance particular tissue boundaries (Jernigan, et
al., 1991b; Jernigan, Salmon, Butters, & Hesselink, 1991c; Pfefferbaum, Lim, Rosenbloom & Zipursky, 1990). While these techniques have proved successful for simple procedures, such as excluding skull tissue or segmenting the ventricles, smaller subcortical structures and the more
complex gyral surface of the cortex cannot be accurately thresholded or their pixels automatically classified on the basis of differences in signal
intensity (Kikinis, Shenton, Jolesz, Gerig, Martin, Anderson, et al., 1992). The segmentation techniques developed in the CBDB laboratory
for use with NIH Image (Jones, 1992a) employ a semi-automated
approach to segmentation of whole-brain from CSF, skull, and meninges,
followed by additional manual editing in orthogonal planes resliced from the original dataset. Initially, extra-cerebral tissues are segmented from
datasets in the transverse plane as follows: A thresholding function is used to mask and surround the brain tissue with a region of interest. Extra-cerebral tissues can be automatically erased from the image,
although occasional manual editing of the thresholded ROI is required when the boundary "bleeds" beyond the desired anatomical border.
While this first pass through the dataset segments a large portion of brain
tissue, certain boundary decisions, particularly regarding image editing
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 74
around venous sinuses and the orbits of the eyes, are accomplished more accurately when the dataset is resliced into orthogonal (i.e., coronal and
sagittal) planes. Additionally, CBDB macros allow an unedited version of
the original dataset to be used to "repair" errors in the segmented MRI stack. Such errors are often difficult to discern in one particular plane, yet
become readily apparent as jagged "tears" when the MRI dataset is "resliced" in another plane. These segmentation errors may result in significant artifacts when a cortical surface rendering is generated; thus their repair is an important step in the segmentation procedure (Bartley,
Jones & Weinberger, 1992a).
Contrast Enhancement
Image contrast in the raw MRI dataset is determined by the
combined effect of field strength, pulse sequence, image reconstruction parameters, variations in tissue, (particularly water content) and miscellaneous scanner and motion-related artifacts (Pfefferbaum & Zipursky, 1991). The complicated interaction of these factors across a
diverse population of subjects produces MRI datasets with considerable
variability in signal intensity and image contrast between individuals (Figure 10). Traditional radiologic use of MRI images has required only
within-scan consistency for diagnostic purposes. The quantitative
application of MRI images requires a greater level of contrast consistency
across individuals. Pilot studies for this dissertation revealed that such a
range of contrast variability has a direct impact on the quality of resulting
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 75
cortical surface renderings. When gray-white contrast was low in a raw image dataset, the resulting cortical surface rendering exhibited relatively indistinct gyral patterning (Figure 11A, level I).
A systematic method of compensating for this contrast variation
was developed by utilizing the characteristic shape of MRI pixel intensity
histograms in a manner similar to that of DeCarli et al. (1992). Such preprocessing techniques incorporating histogram equalization have
been suggested as a means of enhancing image contrast without a concomitant increase in image noise (Austin, Tsui, Strickland, Pizer, Staab, & Partain, 1984). In our procedure a histogram of pixel values was produced for an axial slice that bisects the anterior and posterior
commissures in each dataset. This slice was chosen as one representing a
wide range of values for cortical and subcortical tissue, while containing a minimum of extracerebral skin, muscle, fat, or cranium that might bias
adjustment toward higher signal values.
Each MRI histogram consists of overlapping distributions of gray
matter, white matter, and CSF pixels (Figure 11C). Inspection of
histograms corresponding to the same anatomy across individuals (axial transverse slice) indicated a characteristic curved distribution of pixel
values that varied largely in terms of peak position (brightness) and
width (contrast). The uniformity of histogram shapes suggested that simple linear adjustments to the positions of white matter, gray matter, and CSF peaks could be applied to standardize contrast and brightness across individuals. If the positions of the extreme white matter and CSF
values within the brain are located, the histogram can be "stretched" so
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. that these points coincide with the maximum (255) and minimum (0) pixel values. This histogram equalization minimizes the systematic error that might result from the stripping of dark versus light images, or from
varying amounts of grey matter penetration in the surface rendering m odule. To establish objective criteria for the appropriate degree of contrast
adjustment, two neurologists were asked to evaluate the surface
renderings and to select the contrast level that most accurately
represented in vivo cortical tissue. After weighing the advantage of distinct gyral patterning against artificially-widened sulci, each
neurologist independently chose contrast level III (Figure 11A).
Histograms for the raw data of all subjects were therefore adjusted to distribute pixel values within the dataset along a contrast range approximating that of level HI. Rendering Module Parameters
The 3D DIP Station Rendering Module uses a volumetric ray-tracing algorithm that produces depth and gradient images. The integral shading
option that computes the gradient across a slight penetration of surface
voxels was chosen in accordance with the recommendation of Bomans et al. regarding surface rendering of the brain (Bomans, Hohne, Tiede &
Riemer, 1990). This integration algorithm is optimal for medical imaging
of complex, irregular surfaces like the cortex - artifacts are reduced and the resulting image is more "life-like", despite a marginal reduction of the 3-
dimensional effect. The DIP Station Module requires the user to specify
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 77
two important parameters: aspect ratio and thresholding value. The aspect ratio correction for an MR image is a straightforward computation
of slice spacing in units of in-plane pixels. In this case the deviation of CBDB scans from true isotropic voxels (depth of 1.5mm versus an isotropic depth of 0.9375 mm) results in an aspect ratio of 1.6. Specifying
the appropriate aspect ratio ensures that the surface rendering will reflect
anatomically correct proportions in three dimensions. Specifying the second parameter, thresholding value, required a
systematic comparison analogous to the previously described procedure
for establishing the correct adjustment of raw image contrast and brightness. Thresholding values determine the degree of surface
penetration applied in the rendering computation, as the algorithm seeks to discriminate CSF from tissue. The appearance of the resulting surface rendering is visibly altered by the threshold selected in the rendering module. To obtain a representative range of thresholding values, renderings of the same brain were generated from an extremely high penetration, where a significant amount of cortical gray matter had been "thresholded" away (Figure 12, level 50), then with successively
decreasing penetration in equal increments until the point where gyral
patterning became blurred (Figure 12, level 25), as the CSF/gray-matter
boundary was no longer distinguished by the threshold level. Again, the
independent judgment of two neurologists produced a consensus opinion that thresholding level 35 (Fig 12) reflected the best balance
between the distinctiveness of gyral patterning and correct gyral/sulcal
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 78
widths. This thresholding level, therefore, was applied throughout in the
production of cortical and supratemporal surface renderings.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 79
Interrater Reliability
An important methodological concern for any morphometry study
is the demonstration of interrater reliability. Customarily morphometric
measurements are repeated by a second "rater" to demonstrate the
reproducibility of data obtained according to particular a priori boundary criteria. As might be argued from the results of single-slice studies, interrater reliability does not speak to the validity of measurement criteria. Yet the existence of many sources of variance in morphometry, ranging from scan artifacts to difficult boundary discrimination, dictates a
prerequisite requirement that investigators demonstrate their measurements meet some standard of consistency when data are
reported. The analysis of interrater reliability merits careful consideration.
The actual agreement between ratings must be distinguished from a
simple correlation between raters, even though the latter statistic is
frequently reported as the sole indication of agreement. For quantitative data, the ANOVA Intraclass Correlation Coefficient (ICC) has been
proposed as an additional indication of the variance within sets of
measurements (Bartko, 1976). The Pearson Product Moment correlation (r), while often reported as a demonstration of reliability, is insensitive to
the presence of additive or multiplicative biases in ratings. A second
rater’s measurements may agree well in rank order with those of the first rater, although the actual data points might be of consistently greater or lesser magnitude. The ICC equals unity only when raters have identical
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 80
ratings, and this stricter criterion may fail to reach statistical significance
even when Pearson's r=l, given sufficient systematic disparity in the
actual ratings (Bartko & Carpenter, 1976). In Studies 1 and 2, the unbiased
version of the ICC, ICC(U), is reported. This method of computation corrects for a slight positive bias in the original ICC.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. APPENDIX C NORMAL ASYMMETRIES OF SUPRATEMPORAL
GYRAL STRUCTURES: POSTMORTEM, ANGIOGRAPHIC,
CYTOARCHTTECTONIC, AND ELECTROPHYSIOLOGICAL STUDIES
Anatomical Asymmetry of the Supratemporal Cortex
Gross anatomy of the superior surface of the temporal lobe, a cortical region normally concealed by the overlying frontal lobes, was first
explored through postmortem dissection. Neuroanatomists of the 1930s
noted asymmetries of the posterior supratemporal cortex upon removal
of the frontal lobes (Pfeifer, 1936; von Economo & Horn, 1930). Predating these neuroanatomical observations was evidence of asymmetry of cognitive functioning such as the lateralized disruption of speech
following left frontal lesions, reported by Paul Broca in the 1860s (Geschwind, 1979; Kolb & Whishaw, 1990). Asymmetry of function was
also clearly evident in the "fluent” aphasias described by Wernicke during the same era as resulting from localized lesions of the left temporal lobe (Hecaen, 1979). Despite coexistence in the medical literature of postmortem and
neuropsychological reports of lateralization, the pursuit of relationships
81
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 82
between asymmetry of structure and function was impeded for almost a century by a paucity of quantitative anatomic data (Witelson & Kigar, 1988). Scattered observations of anatomical asymmetry were difficult to reconcile with what Von Bonin in 1962 termed "astonishing differences"
in the lateralization of cognitive functions such as speech. Skepticism
regarding the significance of anatomical lateralization prevailed until
1968, when Geschwind and Levitsky published a large-sample (n=100 brains) postmortem study of the superior temporal cortex. The cortical
structure of interest to Geschwind and Levitsky, the planum temporale, is located in the region known as Wernicke's area, where left-side lesions
differentially impair speech comprehension. The authors, who reported
that the outer border of the left planum was up to a third longer than the right in 65% of their sample, were led to speculate that the commonly ascribed lateralization of speech to the left hemisphere might indeed be related to structural brain differences.
This finding focused attention on the supratemporal cortex as the
nexus of a demonstrable brain-behavior relationship (Figure 13 illustrates an example of supratemporal anatomy). The region is classically demarcated as follows:
"The planum temporale is the superior surface of the posterior part of the superior temporal gyrus and is situated within the Sylvian fissure. It is a relatively flat surface and lies posterior to the transverse temporal gyrus (Heschl's gyrus) or gyri which contain primary auditory sensory cortex. The planum is within the general region described as Wernicke's on the left side, crucial for the comprehension of language." (From Witelson and Kigar, 1988).
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 83
When the frontal lobes are removed, one or more gyri, known as
Heschl's or transverse gyri, are visible as they cross the superior surface of
the temporal lobe. Heschl's gyrus has been described as "a strongly developed convolution on the supratemporal plane (Steinmetz, Rademacher, Huang, Zilles, Thron, et al., 1989)" sometimes appearing
divided into an anterior and posterior portion by an incomplete
transverse sulcus, the sulcus intermedius of Beck (von Economo & Horn,
1930). The triangular planum temporale lies posterior to either the first or the last transverse gyrus according to alternate definitions (Witelson &
Kigar, 1988). A "textbook" conception of supratemporal gyral configuration, based upon the landmark Geschwind and Levitsky study,
would depict two Heschl’s gyri on the right and one on the left, although
opinions vary throughout the literature regarding the labeling of the transverse gyri (Witelson, 1983).
Subsequent postmortem analysis of normal brains has revealed
much greater variability in supratemporal gyral configuration, with multiple transverse gyri potentially appearing in either hemisphere. In
an examination of 16 adult brains, Witelson and Pallie (1973) reported
that two Heschl's gyri appeared with equal frequency in both the left and
the right hemispheres. While numerous postmortem studies have replicated findings of PT asymmetry in adult and fetal brains (Chi, Dooling & Gilles, 1977b; Falzi, Perrone, & Vignolo, 1982;
Galaburda,Sanides & Geschwind, 1978; Wada,Clarke & Hamm, 1975;
Witelson & Palie, 1973) (see Witelson and Kigar, 1988 for an extensive
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 84
review) it should be noted that anterior boundary definitions that include
one or more of the transverse gyri may alter the apparent PT asymmetry. PT area and asymmetry are also directly linked to posterior boundary definitions, and postmortem studies have used criteria varying from
dissection across the plane of the Sylvian fissure (Steinmetz, Rademacher, Jancke, Huang, Thron, et al., 1990), excluding posterior
ascending rami, to cuts "dorsal to the Sylvian fissure and any ascending rami"(Witelson, 1983; Witelson & Palie, 1973). Reubens et al. have suggested, however, that PT "asymmetry" results largely from the
steeper, more anterior angle formed by the posterior ascending ramus of
the right Sylvian fissure (Reubens, Mahowald, & Hutton, 1976). In this case, laterality effects should hinge on exclusion of the ascending rami. Steinmetz et al. (1990) have demonstrated that inclusion of cortex lining
the ascending and descending rami negates findings of PT asymmetry,
lending support for the original boundary convention of Geschwind and Levitsky (1968), who note the contribution of the posterior border to their asymmetry effect.
In contrast to aduits, infant brains do not consistently demonstrate mature patterns of asymmetry. In 44/85 infant and fetal brains studied by
Wada, Clarke, and Hamm (1975) the right planum was equal to or greater
than the left, versus the same pattern in only 18/100 adults. The authors
interpret this finding as an indication that the left planum continues to develop beyond the point when right planum growth has been
completed. This and other postmortem studies of the planum temporale
in fetal brains have addressed the question of lateralized differences in
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. rates of PT development. At issue is whether anatomical asymmetry is biologically predetermined, or alternately, is subject to the influence of postnatal environmental experience or learning effects (Witelson & Palie,
1973). One line of evidence for "hard-wired", genetically-based structural
lateralization is suggested by asymmetry of the posterior Sylvian fissure
(reflecting differences in supratemporal anatomy) among higher primates (LeMay & Geschwind, 1975). Yeni-Komshian and Benson (1976) have measured significantly longer left Sylvian fissures in approximately 80% of samples of both great apes (gorillas and orangutans) and humans,
versus only 44% of a sample of chimpanzees. In suggesting an evolutionary role for anatomic asymmetry, the authors predict that
functional asymmetry may not be restricted to humans. Recently Hopkins et al. (1993) have documented such lateralization of function,
namely the "left-hemisphere" spatial rotation of images, in baboons.
Among humans, progressive increase with gestational age gives a
clear indication of the development of anatomical asymmetry in utero. While the primary temporal lobe is visible at 7-10 weeks, the temporal
gyri continue to grow and differentiate through the final trimester, and
beyond (Sedat & Duvernay, 1990). Witelson and Pallie (1973) reported a leftward asymmetry of the PT in two-thirds of a sample of 14 neonatal
brains (average age 12 days), a percentage roughly equal to the adult
population, while in a younger subsample (mean age 6.6 days) left-right differences were not significant. Wada, Clarke and Hamm (1975) found the PT was first measurable at 29 weeks gestation. Again, these
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 86
investigators discovered that leftward lateralization of the PT was much
less frequent in a younger versus more mature fetal and neonatal brains. Similar findings were reported in two studies of 207 fetal brains age 10-44 weeks gestation, where Chi, Dooling and Gilles (1977a; 1977b) noted that the transverse temporal gyri were visible by 31 weeks. In two-thirds of the
sample these gyri were detected 1-2 weeks earlier on the right side. Fifty- four percent of the sample displayed a leftward planum asymmetry, with
symmetry reported for 28% of fetal brains. An asymmetry was also
reported for the number of HG, with multiple gyri occurring on the right
in 54% of the fetal brains. Obviously, any analysis of functional lateralization was precluded
by the developmental status and postmortem nature of these samples. Irrespective of this limitation, studies of immature brains are frequently
cited as evidence that 1) temporal lobe development, particularly
gyrification, occurs later in the left hemisphere, and 2) lateralization of the PT occurs prior to language learning experience.
Interaction of Gender and Anatomic Asymmetry
The report of left-larger planum asymmetry across 60-80% of
postmortem samples (Aboitiz, Scheibel, & Zaidel, 1992) may often have been confounded by the influence of gender. One large scale study (100
adults and 85 infants and fetuses) that did analyze planum data by gender
reported that adult subjects who showed reversals of normal asymmetry (L>R) were significantly more likely to be female (Wada, Clarke &
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 87
Hamm,1975). In the few subsequent instances when gender effects have
been systematically examined, differences in lateralization have not been
invariably detected, although methodologies for determining PT size vary widely. Aboitiz, Scheible and Zaidel (1992) found no interaction of
gender and hemisphere in a linear measurement (length of the lateral
boundary) of the PT in postmortem brains. The authors reported no
criteria for the determination of handedness, however, which is ambiguous at best in their retrospective reports. PT measurements in this study also appear to have included the posterior ascending ramus (PAR),
complicating a comparison to other planum results.
By contrast, a retrospective study of gender differences in temporal plane asymmetry that was particularly well-controlled was recently reported by Witelson and Kigar (1992). Postmortem analysis of Sylvian fissure (SF) length revealed diverging patterns of asymmetry between
men and women, with a significant sex-by-hemisphere interaction
revealed in the length of the horizontal SF across the temporal plane. Since the anatomy of the SF directly reflects that of adjacent gyri, inferences can be drawn as to the dimensions of the underlying planum
temporale. Witelson and Kigar point to the remarkable fact that even
with measurements adjusted for cerebral weight and length, gender differences remained in the extent of the left, but not the right horizontal Sylvian fissure. The authors speculate that the cortex of the left temporal
lobe (i.e., Heschl’s gyri and the planum temporale) varies in response to fetal hormones, resulting in anatomical and possible functional sexual differentiation.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 88
Carotid Angiography
In vivo asymmetries of the supratemporal cortex were first indicated by the quantification of data obtained from carotid angiography. This procedure involves visualization of the brain's vasculature through
X-rays, preceded by the injection of a contrast medium into the arterial
blood stream (Friel, 1974). The carotid arteriogram combined with amytal
testing established an initial link between lateralization of structure and function.
The most posterior branches of the middle cerebral artery are known to create a landmark angle as they cross the SF, forming a characteristic
loop around Heschl's gyrus (Liegeois-Chauvel, Musolino, & Chauvel,
1991; Ratcliff, Dila, Taylor, & Milner, 1990). Ratcliff, Dila, Taylor and
Milner (1990) examined the carotid arteriograms of patients undergoing amytal testing for the functional localization of speech and reported a greater degree of asymmetry in this arterial angle among patients with left-hemisphere speech. Hochberg and LeMay (9175) also identified a relationship between handedness and the asymmetric height of the
Sylvian point (the end of the Sylvian fissure at the temporoparietal
point) on carotid arteriograms. The effect of gender on reported asymmetries was not systematically examined in either study.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 89
Cvtoarchitecture of the Supratempoml Cortex
Cytoarchitectonics, the arrangement of cells through the depth of the cortex (Witelson & Kigar, 1988), refers to the description of brain regions
based upon cellular structure and organization, versus gross anatomical boundaries such as gyri and sulci (Friel, 1974). During prenatal development neurons migrate from germinal zones of the lateral and third ventricles to cortical locations, where differentiation into pyramidal and stellate cells is accompanied by the organization of neurons into
horizontal layers and vertical columns (Barkovich, Gressens, & Evrard, 1992). In a postmortem study of the posterior temporal cortex, Galaburda
and Sanides (1980) describe how functional regions of the cortex can be differentiated based upon the number and width of cell layers and the
density and size differences of cells within each layer.
The cerebral cortex can be divided on a cytoarchitectonic basis into allocortex and isocortex. Allocortex, the more primitive subtype, varies
greatly in laminar organization and occurs within the temporal lobe on the surface of the amygdala and hippocampus. Isocortex is common to primary, secondary, motor, and association cortex, and covers a large extent of the supratemporal surface. Transitional or mesocortex can also
be identified at the boundaries of isocortical and allocortical regions (Zilles, 1990). While the number of distinct cellular layers in the cerebral cortex may vary, neocortical areas are typically characterized by six layers
collectively forming the isocortex. Within the isocortex, primary sensory
fields are known as konicortex - Greek for "dusty" cortex due to the
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 90
extreme density of the layer IV granular cells that are visible as dark bands in Nissl stain preparations (Nauta & Feirtag, 1986).
Early cytoarchitectonic studies of von Economo and Horn (1930) identified a granular primary sensory form of cortex in the HG region,
roughly equivalent to Brodman's area 41 (Brodman, 1909). This
koniocortex has many granular and few pyramidal cells, and electrical stimulation of the area results in simple auditory perceptions of buzzing
or humming (Ong & Garey, 1990; Penfield & Perot, 1963). A replication of Von Economo’s original parcellation localized a central core of koniocortex, or granular primary sensory cortex, to the posterior portion
of the first transverse (Heschl’s) gyrus (Galaburda & Sanides, 1980).
Existing maps vary, however, in the positioning of cytoarchitectonic boundaries. Braak (1978) has restricted this primary auditory core only to the rostral portion of Heschl’s gyrus.
Human auditory cortex is distinguished by highly myelinated fibers and a vertical "organ pipe" columnar arrangement (Seldon, 1981) that
may form the basis for functional units in auditory processing (Zilles, 1990). In the primary koniocortical region, the columnar organization
appears to map the auditory spectrum, with columns of cells responding to particular sound frequencies (Nauta & Feirtag, 1986). Most
cytoarchitectonic parcellations find the primary auditory cortex to be surrounded by concentric belts of parakonio-, or auditory association
cortex, occuring in Brodman's area 42 (Zilles, 1990). Stimulation of this
region is reported to produce complex acoustic phenomena (Ong & Garey, 1990; Penfield & Perot, 1963).
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 91
Galaburda and Sanides describe a third region, termed area TPT, corresponding roughly to the boundaries of the planum temporale, and
located posterior to the belt of auditory association cortex. The
cytoarchitecture of TPT is identified by a poorly defined layer IV, distinct columnar organization in layer HI, and a wide, dense layer VI
(Armstrong, 1990). This region has been found to encompass a
proportionately larger area in humans than in other species (Penfield &
Roberts, 1959). TPT extends from the caudal portion of Heschl's gyrus to the posterior supratemporal plane, and in some brains upward along the
Sylvian fissure into the parietal operculum. While area TPT was found to resemble integration cortex of the parietal lobe, as a cytoarchitectonic region TPT retained a distinct appearance, and Galaburda and Sanides
hypothesized that it serves as a transition between specialized auditory neocortex and parietal integration cortex.
Notably, asymmetries in the amount of cortex containing area TPT
were detected in another postmortem study (Galaburda, Sanides &
Geschwind, 1978). In three of four brains studied, area TPT was larger in the left hemisphere, a lateralization that matched morphological asymmetry of the planum temporale, defined in these subjects as the region posterior to the first transverse gyrus. As Reubens et al. (1976) have noted, the spill of auditory association cortex into the
supramarginal gyrus and PAR suggest that morphological asymmetry of the PT may be an insufficient index of the extent of auditory association cortex in each hemisphere. Parcellation of an area of the inferior parietal
lobule, region PG, has also revealed cytoarchitectonic asymmetries that
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 92
are inversely correlated with asymmetries of the planum temporale (Eidelberg & Galaburda, 1984). Asymmetry in the columnar organization of neurons has also been identified in histopathological study of the temporal language cortex. Seldon (1981) noted smaller neural column width in the right temporal
lobe. Ong and Garey (1990) reported that, in an area from the caudal HG to the posterior SF (Brodman's 42), neurons arranged in radial columns showed a general increase in columnar organization in Wernicke's area
(posterior PT). This columnar organization was greatly reduced in the right hemisphere, leading the authors to hypothesize that greater
columnar spacing on the left may allow increased synaptic interaction,
thus facilitating left hemisphere language functioning.
Hlectrophysiological Studies
While temporal lobe lesion data and the study of aphasias have long suggested certain language processes are associated with the temporal cortex, study of the brain's electrical response to auditory stimulation
provides additional evidence of the auditory functions of Heschl's gyrus and the planum temporale (Bloom & Lazerson, 1988). The auditory cortex
has been extensively studied in this manner in cats and monkeys.
Among these animals, core auditory fields contain a number of cells
"highly tuned" to respond to certain frequencies, with a rostral-caudal arrangement of high and low tones that may be reversed in adjacent fields. Other cells in the auditory cortex are believed to act as "feature
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 93
detectors" for complex sounds in the environment (Webster & Garey, 1990).
Functioning of the auditory cortex is less well defined in humans,
due to limits on direct cortical stimulation and ablation in human
subjects. An understanding of cortical organization was gained initially
through recordings from the exposed temporal cortex during surgery (Celesia, 1986). The classic neurosurgical studies of Penfield and Roberts
described simple auditory hallucinations resulting from direct stimulation of Heschl's gyrus, and defined regions where stimulation led
to aphasic errors (Penfield & Perot, 1963; Penfield & Roberts, 1959). In a
summary of hundreds of cases, Penfield and Perot note that stimulation of Heschl's gyrus led only to simple auditory percepts, and never the
perception of speech that was noted in surrounding areas. Subsequently
Celesia found that auditory evoked potentials recorded from depth probes
of HG during surgery were constant, reproducible, and of short latency. By contrast, evoked potentials (EPs) from surrounding areas in the superior
temporal gyrus and parietal operculum were smaller and variable, with longer latency, possibly indicating polysensory function in these regions
(Celesia, 1986). A tonotopic organization within the temporal cortex has
also been suggested by a positron emission tomography (PET) study that identified greater response to high frequency tones medially and
posteriorly, versus an anterolateral response to low tones (Lauter,
Herscovitch, Formsby, & Raichle, 1985). These findings must be viewed as preliminary due to the limitations of neuroanatomical localization with PET.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 94
Precise delineation of primary auditory cortex has been aided by the
integration of depth electrode studies and individualized methods of
electrode localization. In a depth electrode study of 15 epileptic patients awaiting surgery, Liegeois-Chauvel et al. (1991) used stereotactic angiography to obtain a three-dimensional reconstruction of electrode
lead positions. Data from these recordings suggest that the source of
auditory evoked potentials can be localized to the medial tip of Heschl’s gyrus, corresponding to the konicortex (granular sensory cortex) fields identified by Galaburda and Sanides (1980). Congruent with the concept of unidirectional transfer of information from sensory to association cortical
areas (Kolb & Whishaw, 1990) stimulation of the medial HG in the
Liegeois-Chauvel et al. study evoked responses in hypothesized areas of
association cortex (i.e., the lateral HG, the PT, and the anterior superior temporal gyrus), while no response in the medial tip of HG was recorded
as a result of stimulation of any other region (Liegeois-Chauvel, Musolino, & Chauvel, 1991).
In a preliminary electrophysiological examination of the temporal speech cortex, auditory evoked potentials localized with MRI have also
been compared between schizophrenics and normals. While different recording environments may have contributed to group differences,
Reite, Teale, Zimmerman, Davis, Whalen, and Edrich (1988) found that
normal lateralized interhemispheric differences in source location (left hemisphere sources higher and more posterior in the temporal lobe)
were absent in the schizophrenic sample.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. APPENDIX D MRI STUDIES OF THE SUPRATEMPORAL CORTEX
As Witelson and Kigar (1988) note, conventional MRI studies of the
supratemporal surface are hampered by persistent methodological
problems. Of primary concern is the difficulty of capturing a temporal lobe structure bilaterally within any single MRI slice, when the gyri of interest may vary in position and dimension between the hemispheres.
The choice of plane of section also poses a vexing dilemma: while the use of coronal slices may cause omission of posterior portions of the temporal
plane (Larsen, Odegaard, Grude & Hoien, 1989) and sagittal sections the underestimation of lateral areas (Kulynych, Vladar, Jones & Weinberger,
1993), transverse slices are most sensitive to interhemispheric differences in temporal plane position. Such plane- of- section artifacts are only compounded by partial volume averaging (Kelly, 1987), which in older,
thick-slice studies may significantly obscure fine anatomical detail. Witelson and Kigar conclude on this basis that 3-dimensional imaging techniques may be required in order to adequately visualize the
supratemporal cortex. Larsen et al. (1989) proposed the first approach to studying the PT
with MRI. They evaluated thirteen postmortem brains by direct
measurement of the lateral margin and then remeasured from a series of
95
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 96
coronal MRI sections (3 mm slices with a 0.3 mm gap). An attempt was
made to reconstruct the size of the PT based upon tracings in the coronal plane, although he impossibility of following the upward curve of the Sylvian fissure in thick coronal sections reduced accuracy and led to the
omission of the posterior region of the PT. Variability in the number of
transverse gyri observed by this method led to difficulty in establishing anatomical landmarks. Investigators were forced to exclude more than 20% of the original sample whose supratemporal landmarks could not be
identified. The MRI procedure was successful only in the sense that the
direction of PT asymmetry was reproducible for 9/10 brains utilizing both
techniques; when MRI tracings were compared to postmortem
measurements of the lateral PT boundary there was no significant correspondence between actual areas measured. Steinmetz et al. (1989) explored a different approach to MRI
evaluation of the PT by utilizing volume MRI datasets (contiguous
sagittal slices 1.17mm thick), and assessing PT areas visible in an oblique slice lying approximately in the plane of the Sylvian fissure. Due to inter observer difficulty in distinguishing between the transverse gyri of the
temporal lobe, planum measurements were made inclusive of all the area posterior to the first transverse gyrus. The authors defend these
boundary criteria by noting that cytoarchitectonic studies have localized
primary auditory cortex primarily to an anteromedial region on the first
HG. Therefore, supratemporal cortex caudal to HG1 may be presumed to subserve auditory associative functions. While anatomic and MRI measurements of Steinmetz et al. were significantly correlated, this
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 97
single-slice technique remains sensitive to any interhemispheric
variation in the position of the PT. In view of the inevitable differences
in the posterior boundary of PT that reflect asymmetries in the angle of
the posterior Sylvian fissure (Witelson & Kigar, 1988), it is difficult to envision a single slice at any oblique angle that could include the caudal
portions of both the left and right planum temporale. Steinmetz et al. revised their MRI methodology in a 1990 study of
the planum that compared the impact of cortical folding on apparent PT asymmetry (Steinmetz,Rademacher, Jancke, Huang, Thron, et al., 1990). The authors address the hypothesis of Reubens et al. (1976) that PT asymmetry depends upon a boundary convention that excludes tissue in
the ascending ramus of the Sylvian fissure. The brains of 7 women and 3
men were examined, although the effects of gender and handedness were
not considered in data analysis. Volume datasets (128 contiguous sagittal
slices 1.17mm thick) of postmortem brains were compared to photographic planimetry of the PT as it was exposed in postmortem dissection. Surface areas derived from tracings of the PT in sagittal section were predicted to account for variable degrees of cortical folding, or gyrification, (Zilles, Armstrong, Schleicher & Kretschmann, 1988) to a greater extent than areal measurements made on photographs of the exposed postmortem surface. Such a comparison examines the proposition that the "convoluted surface area of the PT' (Steinmetz et al.,
1990) exhibits a pattern of asymmetry that differs from the superficially exposed area, a finding that might invalidate numerous postmortem
studies based on photographic tracings. The relative asymmetry of the PT
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 98
was also assessed with the inclusion of tissue buried in the posterior
ascending and descending rami of the Sylvian fissure (area PT+).
Steinmetz et al. found that cortical folding did not differ between
hemispheres. The direction of PT asymmetry was the same for surface area and sagittal slice tracings, possibly, the authors note, a result of the relatively smooth "plane" of the structure’s surface. Yet tissue of the
posterior Sylvian rami (combined ascending and descending) was found
to exhibit a significant rightivard asymmetry that countered leftward planum asymmetry. When considered together (area PT+), the combined
cortical areas showed no significant left-right asymmetry. In sum, these
findings suggest that while posterior boundary criteria deserve careful consideration, measurement of the exposed surface of the PT does
accurately assess cortical asymmetry of this structure.
MRI Examination of Structure-Function Relationships in the Planum
Temporale
Although existing serial section approaches to MRI measurement of the PT are subject to previously mentioned shortcomings (underestimation of posterior or lateral boundaries, for example), such methodologies have been used to study the relationship between neuroanatomical asymmetries and cognitive functioning. Steinmetz et
al. examined the impact of handedness upon planum temporale asymmetry in a sample of 52 normal volunteers, relying upon
morphometric measurements made in sagittal volume MRIs (Steinmetz,
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 99
Volkman, Jancke & Freundl991). The investigators wished to characterize the functions of the temporal cortex by determining whether sinistrality produced a different pattern of PT lateralization, based upon
evidence that left-handers have a greater incidence of anomalous language dominance (Hecaen, De Agostini, & Monzon-Montes, 1981). Steinmetz et al. found that when handedness was determined on the
basis of "hand preference" tasks, left-handers had a significantly smaller degree of leftward lateralization when compared to right-handers.
Division of subjects on the basis of self-described handedness, however, yielded no significant difference in lateralization. Unfortunately, the impact of gender on planum asymmetry was not examined in this sample.
Larsen et al. applied their previously described methodology to a
study of the PT in cases of developmental dyslexia (Larsen, Hoien, Lundberg, & Odegaard, 1990). Limitations of the method resulted in
exclusion of some subjects, and results were expressed only in laterality
ratios, yet the authors reported replication of a postmortem finding of
greater PT symmetry in dyslexia (Galaburda, Sherman, and Rosen, 1985). Interestingly, although all subjects were right-handed, disregard for gender may have introduced a confound, as all female subjects in the dyslexic group were among those classified as "symmetrical" in PT area.
A preliminary study of the impact of schizophrenia on normal lateralization of the planum temporale yielded results that are also difficult to interpret due to the neglect of the impact of gender as a subject
variable, as well as a reliance upon planum measurements in thick (3mm
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 100
with 1mm gap) coronal slices. Rossi et al. (1992) compared PT areas in 20
schizophrenics and 12 controls using the Larsen et al. (1989) methodology, encountering the difficulty faced by the method's originators: 3 schizophrenics and 1 control in the Rossi et al. study could not be
evaluated by this method. Among the subjects who were assessed, a significant diagnosis-by-hemisphere interaction was reported (Rossi,
Stratta, Mattei, Cupillari, Bozzao, et al., 1992). The authors interpret their
findings as a lack of PT asymmetry in schizophrenia, as left planums were significantly larger than rights in the control but not the schizophrenic
group. While the difference in the laterality quotient L-R/L+R was
statistically significant between the groups, schizophrenics actually demonstrated greater mean lateralization in the opposite (rightward)
direction (mean laterality quotient for schizophrenics =-0.07 versus 0.05 for the normal group). This curious reversal of asymmetry was not noted by Rossi et al. in their discussion of results.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. APPENDIX E. TABLES
101
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 102
TABLE 1. STUDY 1. MEAN PLANUM
TEMPORALE AREAS
AREA MEASUREMENTS IN mm*
Surface Render Serial Section
Rater #1 Rater #2 Rater #1 Rater #2
Subject L R L R LR L R
1 733 424 660 417 534 347 392 386
2 644 444 494 379 456 432 517 445
3 660 443 562 467 345 383 369 385
4 662 331 612 315 623 298 724 375
5 399 393 391 444 362 288 438 445
6 450 312 357 260 283 303 364 w/JtX'XAA
7 714 455 532 418 462 385 333 395
MEAN 609 400 515 386 438 348 448 396
S.EM ±53 ±24 ±45 ±30 ±48 ±22 ±56 ±15
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 103
TABLE 2. STUDY 1. PLANUM TEMPORALE ASYMMETRY
COEFFICIENTS
ASYMMETRY COEFFICIENTS 8
Surface Render Serial Section
Subject Rater #1 Rater #2 Rater #1 Rater #2
l -0.534 -0.452 -0.425 -0.013
2 -0.367 -0.262 -0.055 -0.150
3 -0.394 -0.184 +0.104 +0.043
4 -0.667 -0.640 -0.705 -0.635
5 -0.016 +0.125 -0.229 +0.016
6 -0.362 -0.316 +0.067 -0.055
7 -0.442 -0.239 -0.182 +0.170
MEAN -0.397 -0.281 -0.204 -0.089
S.E.M. ±0.082 ±0.097 ±0.117 ±0.106
Right 0 1 2 1
N one 1 0 0 3
Left 6 6 5 3 . i
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 104
TABLE 3. STUDY 2. MEAN AGE AND HANDEDNESS
MEAN AGE AND HANDEDNESS
GROUP AGE HANDEDNESS (YEARS) (El)
FEMALE
m ean 25.0 94.8 s.e.m. 1.07 2.78
MALE
m ean 25.9 94.0 s.e.m. 1.24 3.03
SCHIZ.
m ean 29.7 85.7 s.e.m. 1.94 4.23
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 105
TABLE 4. STUDY 2. MEAN PLANUM TEMPORALE AND HESCHL'S GYRUS AREAS
PLANUM TEMPORALE (PT) AND HESCHL'S GYRUS (HG) AREAS (cm2)
GROUP LEFT PT RIGHT PT LEFT HG RIGHT HG
FEMALE
m ean 5.3 5.5 5.0 4.6 s.e.m. 0.61 0.37 0.35 0.39
MALE
m ean 7.0 5.4 5.4 5.1 s.e.m. 0.52 0.30 0.40 0.39
SCHIZ. m ean 7.1 5.5 5.9 5.7
s.e.m. 0.49 0.73 0.38 0.27
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 106
TABLE 5. STUDY 2. PLANUM TEMPORALE ASYMMETRY COEFFICIENTS
TABLE 5. CLASSIFICATION OF 5PT ASYMMETRY COEFFICIENTS
GROUP 5PT LEFT RIGHT SYMMETRIC SPT < -0.05 SPT >0.05
FEMALE
m ean 0.09 N=5 N=6 N=1
s.e.m. 0.125
MALE m ean -0.25 N=10 N=1 N=1 s.e.m. 0.082
SCHIZ.
m ean -0.31 N=8 N=1 N=1
s.e.m. 0.13
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. APPENDIX F. FIGURES
107
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Figure 1. Underestimation of structural dimensions resulting from thick*
slice morphometry studies.
Vertical lines define the intersection of three coronal slices with
the hippocampal formation. It is evident that a substantial portion of this complex subcortical structure is omitted when morphometric
measurements of the hippocampus are obtained from relatively few,
widely spaced slices.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 109
SLICE
I vl k<««
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Figure 2. Comparison of Surface Renderings Produced by Segmentation
in One Versus Three Planes of Section.
Three visualizations of the lateral ventricular system are presented. The first, containing three-dimensional view of the lateral ventricles, was rendered following segmentation in only the coronal
plane in a series of 2mm thick slices (A). The serrated edges of the
ventricles in (A) correspond to regions of interest that would define
morphometric measurement of the ventricles when measured in coronal
sections. The surface rendering of the lateral ventricles in (B) follows segmentation of a second subject’s dataset in coronal, transverse, and sagittal sections. The smooth contours in this rendering more closely resemble a medical artist’s depiction of the ventricular system (C), and
the additional editing performed in three orthogonal views will produce
regions of interest which more accurately capture the true volume of the structure.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. I l l
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Figure 3. On-command reslicing of MRI dataset into orthogonal planes of section.
An illustration of on-command reslicing. The top portion of the
figure displays a slice from the primary sagittal dataset. The arrow (A)
indicates the position of the mouse-controlled cursor. Coronal and axial slices are generated with a vertical line on each indicating the position of
the sagittal slice being analyzed. The position of the chosen voxel is
marked by a gap in the vertical line, as denoted by arrows (B) and (C) added in this figure.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 113
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Figure 4. Exposure of supratemporal surface following segementation of
MRI dataset
A white line has been traced on a lateral surface rendering (A) to illustrate where serial slices of the primary dataset were segmented. The supratemporal surface renderings are created by removing all tissue
above this level. An oblique view of the resulting surface rendering (B) reveals the gyral configuration of previously hidden temporal regions. A
front view of the same brain rendered at a 45° pitch (C) is representative of the orientation of renderings used in the quantitative morphometry of the planum temporale.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 115
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Figure 5. Measurement of the planum temporale in a supratemporal
surface rendering versus serial sagittal sections.
White lines, thickened in this illustration to improve visibility,
demarcate regions of interest (ROIs) encircling the planum temporale on
a typical supratemporal surface rendering (A). Arrows identify the
location of both Heschl’s gyri (HG). A white line was also drawn on a representative slice from the primary sagittal dataset (B) to illustrate one of the lines of interest (LOI) used in measuring the planum temporale in serial sections.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 117
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Figure 6. Impact of posterior margin criteria on apparent planum temporale asymmetry.
This figure illustrates how the posterior extent of resection impacts the apparent asymmetry of the planum temporale. If the ascending posterior ramus of the Sylvian fissure is included (A), then there is little
apparent PT asymmetry in the resulting surface rendering. If the dataset is resected along the plane of the Sylvian fissure, according to the criteria of
Geschvvind and Levitsky (Geschwind & Levitsky, 1968), then a substantial PT asymmetry is revealed.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 119 i t V t
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Figure 7. Underestimation of lateral planum temporale area resulting from measurement in serial sections.
The underestimation of lateral PT area in serial slice measurement is illustrated (A) by superimposition of the boundary of the surface-
rendered sagittal LOIs onto the corresponding supratemporal rendering.
Arrows indicate PT regions omitted in serial slice measurements, when compared to PT ROIs drawn directly on surface renderings (B).
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 121
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Figure 8. Procedure for demarcating anterior Heschl's gyrus boundary on
a supratemporal surface rendering
This figure illustrates a methodology for measuring the surface
area of the primary transverse (Heschl’s) gyrus. In sagittal sections, a black
line is drawn anterior to HG in each slice (A). When the anterior
boundary is no longer discernible, this point is extended laterally to the final slice. After processing with the surface rendering module, a dark
boundary appears on the supratemporal rendering, defining the anterior boundary of Heschl's gyrus.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 123
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Figure 9. Gender x Hemisphere interaction for planum temporale areas.
This figure illustrates the interaction of sex and hemisphere in PT
area measurements, as well as the lack of a significant gender or side effect for the area of HG.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 125
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Figure 10. Contrast variation in raw MRI data.
This figure illustrates the range of image contrast present in the raw MRI datasets of three subjects in this sample (above), and the
uniform intensity of image contrast following histogram adjustment
(below).
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Figure 11. Comparison of histogram adjustment parameters for raw MRI dataset
Image contrast, pixel distribution and a surface rendering reflecting varying degrees of contrast adjustment are presented for a single MRI
dataset. In (A) surface renderings of the same brain are created from the
raw segmented dataset (I) across increasingly truncated grayscale
distributions (II,III, IV). (B) represents the contrast visible in the same dataset across levels of contrast adjustment. (C) displays histograms for the pixel values of the raw dataset (I), and each enhanced dataset.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 129
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Figure 12. Impact of varying threshold values on surface renderings
produced by the DIP Station module.
This figure illustrates surface renderings of the same MRI dataset
with increasing threshold values within the DIP Station surface
rendering module. Image contrast has been held constant across all renderings.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 131
25 30 35
4 # % ™
v ■>'. . v A v j * r .t * . "‘--S'_»I'»JL'».*^3*5-. _ % w ; -, — ->
40 45 50
I p m ,
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Figure 13. "Normative" supratemporal anatomy, as described by Geschwind and Levitsky (1968).
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 133
II fT RIQHT
REPRODUCED FROM N.GESCHWIND ANDD. LEVITSKY (I* * ) IN SOSNCS. VOL..P.186.
Sl-HESCHL'SSULCUSl TG1TKAM3VERSECYRIB1 S?-HESCHL'SSUI£US2 TG2-TRAKSVERSEGYRIE? F I-HAMUMTlMrOKAlE PT - 1 TAM U24 TEMPORALE ru KismaaRMAKaN ru -rasiaaoRMARON TT-TEMFOKALtOU: OP-OCOnTAUOLE
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. REFERENCES
Aboitiz, F., Scheibel, A. B., & Zaidel, E. (1992). Morphometry of the
Sylvian fissure and the corpus callosum, with emphasis on sex differences. Brain. 115.1521-1541.
Andreasen, N.C. (1982) Negative symptoms in schizophrenia: Definition and reliability. Arch. Gen. Psychiatry 39. 784-788.
Andreasen, N.C. & Olsen, S. (1982) Negative versus positive schizophrenia: Definition and validation. Arch. Gen. Psychiatry.
29,789-794. Andreasen, N .C ., Dennert, J.W. et al. (1982) Hemispheric asymmetries and schizophrenia. Am. T. Psychiatry. 147.1457-1462.
Andreasen, N. C., Cohen, G., Harris, G., Ciszadlo, T., Parkkinen, J., Rezai, K., & Swayze, V. W. (1992). Image processing for the study of brain structure and function: Problems and programs. Journal of Neuropsychiatry. 4.125-133.
Andrew, R. E. (1983). Perspectives in MNR imaging. In L. C. Partain, A. E. James, D. F. Rollo, & R. R. Price (Eds.), Nuclear Magnetic
Resonance Imaging Philadelphia: W.B. Saunders.
Ankey, C. D. (1992). Sex differences in relative brain size: The mismeasure of woman, too? Intelligence. 16. 329-336.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 135
Annett, M. (1992). Parallels between asymmetries of planum temporale and hand skill. Neuropsvchologia. 30. 951-962.
Annett, M. A. (1964). A model of the inheritance of handedness and cerebral dominance. Nature. 204. 59-60.Armstrong, E. (1990).
Evolution of the brain. In G. Paxinos (Eds.), The Human Nervous
System New York: Academic Press.
Austin, J. D., Tsui, B. M. W., Strickland, D. C., Pizer, S. M., Staab, E. V., & Partain, C. L. (1984). Three-dimensional display of NMR images. In P. D. Esser & R. E. Johnston (Eds.), Technology of Nuclear Magnetic
Resonance New York: The Society of Nuclear Medicine, Inc.
Barkovich, A. J., Gressens, P., & Evrard, P. (1992). Formation, maturation,
and disorders of brain neocortex. ATNR. 13.423-446. Barta, P. E., Pearlson, G. D., Powers, R. E., Richards, S. S., & Tune, L. E. (1990). Auditory hallucinations and smaller superior temporal
gyrus volumes in schizophrenia. Am I. Psychiatry. 147.1457-1462.
Bartko, J. (1976). On various intraclass correlation reliability coefficients.
Psychplogictd.Pylletin, 762-765. Bartko, J. J., & Carpenter, W. T. (1976). On the methods and theory of reliability. The Tournal of Nervous and Mental Disease. 163151. 307- 317.
Bartley, A. J., Jones, D. W., & Weinberger, D. R. (1992a). Improved surface renderings of the brain using orthogonal MRI slices. Biol Psychiatry Abst.. 31.121A.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Bartley, A. J., Jones, D. W., & Weinberger, D. R. (1992b). A quantitative
technique for comparison of gyral and sulcal patterns from MRI brain surface renderings. Soc Neurosci Abs. IS(Pt2), 1595. Benes, F., Davidson, J., & Bird, E. D. (1986). Quantitative cytoarchitectural
studies of the cerebral cortex of schizophrenics. Arch. Gen Psychiatry. 43.31-35. Berman, K. F., & Weinberger, D. R. (1989). Brain structure and function in schizophrenia. In H. I. Kaplan (Eds.), Comprehensive Textbook of Psychiatry. Fifth Edition Baltimore: Williams and Wilkins.
Bielke, G., Meves, M., Meindl, S., Bruckner, A., Seelen, W. V., Rink, P., &
Pfannenstiel, P. (1984). A systematic approach to optimization of
pulse sequences in NMR imaging by computer simulation. In P. D. Esser & R. E. Johnston (Eds.), Technology of Nuclear Magnetic
Resonance New York: The Society of Nuclear Medicine, Inc.
Bloch, F., Hanson, W., & Packard, M. (1946). Nuclear induction. Phvs Rev. . 69.127.
Bloom, F. E., & Lazerson, A. (1988). Brain. Mind and Behavior. New York: W.H. Freeman and Co. Bogerts, B., Ashtar, M., et al. (1990). Reduced temporal limbic structure volumes on magnetic resonance images in first episode schizophrenia. Psychiatry Res.. 35.1-13. Bogerts, B., Falkai, P., Haupts, M., & al., e. (1990). Postmortem volume
measurements of limbic system and basal ganglia structures in chronic schizophrenics: Initial results from a new brain collection. Schizophrenia Res.. 3. 295-301.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Bogerts, B., Meertz, E., & Schonfeldt-Bausch, R. (1985). Basal ganglia and limbic system pathology in schizophrenia: A morphometric study of brain volume and shrinkage. Arch Gen Psychiatry. 42. 784-791. Bomans, M., Hohne, K.-J., Tiede, U., & Riemer, M. (1990). 3-D
segmentation of MR images of the head for 3-D display. IEEE
Transactions on Medical Imaging. 9(2), 177-183. Braak, H. (1978). The pigment architecture of the human temporal lobe. Anat. Em bryol-150. 229-250.
Branch, C., Milner, B., & Rasmussen, T. (1964). Intracarotid sodium amytal for the lateralization of cerebral speech dominance. X& Neurosurgery. 21. 399-405.
Brandt-Zawadzki, M. (1987). Magnetic resonance imaging principles: The bare necessities. In M. Brandt-Zaswadzki & D. Norman (Eds.),
Magnetic Resonance Imaging of the Central Nervous System. New York: Raven Publishing. Brodman, K. (1909). Vergleichende Lokalisationslehre der
Grosshirnrinde. Leipzig: Barth. Brown, R., Colter, N., Corsellis, J. A. N., & al, e. (1990). Postmortem
evidence of structural brain changes in schizophrenia: Differences
in brain weight, temporal horn area and parahippocampal gyrus compared with affective disorder. Arch Gen Psychiatry. 43.36-42.
Campain, R., & Minkler, J. (1976). A note on the gross configurations of the human auditory cortex. Brain Lang. 2, 318-323.
Celesia, G. G. (1986). Organization of auditory cortical areas in man. Brain.
22,403-414.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 138
Chi, J. G., Dooling, E., and Gilles, F.H. (1977). Gyral development of the human brain. Annals of Neurology. 1, 86-93.
Chi, J. G., Dooling, E. C., & Gilles, F. H. (1977). Left-right asymmetries of
the temporal speech areas of the human fetus. Arch Neurol. 34. 346-348.
Cohen, G., Andreasen, N. C., Alliger, R., Arndt, S., Kuan, J., Yuh, W. T. C.,
& Ehrhardt, J. (1992). Segmentation techniques for the classification of brain tissue using magnetic resonance imaging. Psychiatry Research: Neuroimaging. 45. 33-51.
Cohen, J. (1988). Statistical.Power Analysis for the Behavioral Sciences.
Hillsdale, N.J.: Lawrence Erlbaum Associates. Cohen, J. (1992). A power primer. Psychological Bulletin. 112.155-159.
Crow, T.J. (1985) The two-syndrome concept: Origins and current status. Schizophrenia Bull. 11. 471-486.
Crow, T. J., Ball, J. B., Bloom, S. R., Brown, R., Bruton, C. J., Colter, N.,
Frith, C. D., Johnstone, E. C., Owens, D. G., & Roberts, G. W. (1989a). Schizophrenia as an anomoly of the development of cerebral asymmetry. Arch Gen Psychiatry. 46.1145-1150.
Crow, T. J., Colter, N., Frith, C. D., Johnstone, E. C., & Owens, D. G. C.
(1989b). Developmental arrest of cerebral asymmetries in early
onset schizophrenia. Psychiatry Research. 29. 247-253.
Crow, T. J. (1990). The continuum of psychosis and its genetic origins: The sixty-fifth Maudsley lecture. British I. Psychiatry. 156. 788-797.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Damadian, R. (1983). NMR scanning for medical diagnosis: A historical
perspective. In L. C. Partain, A. E. James, D. F. Rollo, & R. R. Price (Eds.), Nuclear Magnetic Resonance Imaging Philadelphia: W.B.
Saunders. Damasio, H., & Frank, R. (1992). Three-dimensional in vivo mapping of
brain lesions in humans. Arch Neurol. 49. 137-143.
Dauphinais, I. D., DeLisi, L. E., Crow, T. J., Alexandropolous, K., Colter,
N., Tuma, I., & Gershon, E. (1990). Reduction in temporal lobe size in siblings with schizophrenia: A magnetic resonance imaging study. Psychiatry Research: Neuroimaging. 25,137-147.
DeCarli, C., Maisong, J., Murphy, D.G., Teichberg, D., Rapoport, S.I., &
Horwitz, B. (1992) Method for quantification of brain, ventricular, and subarachnoid CSF volumes from MRI images. TCAT. 2. 274-
284. DeLisi, L. E., Dauphinais, I. D., & Gershon, E. S. (1988). Perinatal
complications and reduced size of brain limbic structures in
schizophrenia. Schizophrenia Bulletin. 14.185-191. DeLisi, L. E., Stritzke, P., Riordan, H., Holan, V., Boccio, A., Kushner, M., McClelland, J., Van Eyl, O., & Anand, A. (1992). The timing of brain morphological changes in schizophrenia and their relationship to clinical outcome. Biological Psychiatry. 31. 241-254.
Eidelberg, D., & Galaburda, A. M. (1984). Inferior parietal lobule:
Divergent architectonic asymmetries in the human brain. Arch Neurol. 41. 843-852.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Falk, D., Hildebolt, C., Cheverud, J., Kohn, L., Figiel, G., & Vannier, M.
(1991). H um an cortical asymmetries determined with 3D MR technology. T Neurosci Methods. 39.185-191.
Falkai, P., & Bogerts, B. (1986). Cell loss in the hippocampus of schizophrenics. European Arch, of Gen..Psychiatry, 236.154-161. Falkai, P., Bogerts, B., Greve, B., Pfeiffer, U., Machus, B., Folsch-Reetz, B.,
Majtenyi, C., & Ovary, I. (1992). Loss of sylvian fissure asymmetry in schizophrenia. Schizophrenia Res. 7, 23-32. Falzi, G., Perrone, P., & Vignolo, L. A. (1982). Right-left asymmetry in anterior speech region. Arch Neurol. 39. 239-240.
Flor-Henry, P. (1979). Laterality, shifts of cerebral dominance, sinistrality
and psychosis. In J. Gruzelier & P. Flor-Henry (Eds.), Hemispheric
Asymmetries Qf Function in Psychopathology Amsterdam:
Elsevier Science Publishers.
Flor-Henry, P. (1980). Evolutionary and clinical aspects of lateralized sex differences (Commentary). Behavioral and Brain Sciences. 2, 215- 263. Friel, J. P. (Ed.). (1974). Dorland's Illustrated_Medical Dictionary (Twenty- fifth ed.). Philadelphia: W.B. Saunders.
Galaburda, A., & Sanides, F. (1980). Cytoarchitectonic organization of the hum an auditory cortex. T. Comp. Neurology. 190. 597-610.
Galaburda, A. M., Sanides, F., and Geschwind, N. (1978). Human brain: Cytoarchitectonic left-right asymmetries in the temporal speech
region. Arch .N m ol, 25,812-17.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Galaburda, A. M., Corsiglia, J., Rosen, G. D., & Sherman, G. F. (1987).
Planum temporale asymmetry, reappraisal since Geschwind and Levitsky. Neuropsvchologia. 25. 853-868. Galaburda, A. M., LeMay, M., Kemper, T., & Geschwind, N. (1978). Right-
left asymmetries in the brain: Structural differences between the
hemispheres may underlie cerebral dominance. Science. 199. 852-
856. Galaburda, A. M., Rosen, G. D., & Sherman, G. F. (1990). Individual variability in cortical organization: Its relationship to brain
laterality and implications to function. Neuropsychologia. 28(6).
529-546. Galaburda, A. M., Sherman, G. F., Rosen, G. D. (1985). Developmental
dyslexia: Four consecutive patients with cortical abnormalities. Ann Neurol. 1& 222-233.
Geschwind, N., Galaburda, A. and LeMay, M. (1979). Morphological and
physiological substrates of language and cognition. In R. Katzman (Eds.), Developments in Congenital and Aquired Cognitive Disorders New York: Raven Press.
Geschwind, N., & Galaburda, A. M. (1985). Cerebral lateralization:
Biological mechanisms, associations and pathology: 1. A hypothesis and a program for research. Arch. Neurology. 42. 428-
459.
Geschwind, N., & Levitsky, W. (1968). Human brain- Left-right
asymmetries in the temporal speech region. Science. 161.186-7.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Geshvvind, N., & Behan, P. (1982). Left-handedness: association with immune disease, migraine and developmental learning disorder. Proc. Natl. Acad. Sci.. 79. 5097-5100.
Gur, R., Mozley, D., Resnick, S. M., Gottlieb, G. L., Kohn, M., Zimmerman, R., Herman, G., Atlas, S., Grossman, R., Berretta, D.,
Erwin, R., & Gur, R. E. (1991). Gender differences in age effect on brain atrophy measured by magnetic resonance imaging. Proc. Natl. Acad. Sci USA. 28, 2845-2849.
Harris, L. J. (1980). Lateralized sex differences: substrates and significance. Behavior and Brain Science. 2, 215-263.
Harshman, R. A., Remington, R , & Krashen, S. D. (1983). Sex, language and the brain. Part III. Evidence from dichotic listening for adult sex differences in verbal lateralization. Dept. Psychol. Res Bull..
Univ. Western Ontario. 558.
Hecaen, H. (1979). Aphasias. In M. S. Gazzaniga (Eds.), Handbook of Behavioral Neurobiologv (pp. 239-292). New York: Plenum Press.
Hecaen, H., De Agostini, M., & Monzon-Montes, A. (1981). Cerebral organization in left-handers. Brain and Language. 12. 261-284.
HIPG (1990). PIP Station User Reference Manual.
Hochberg, F. H., & LeMay, M. (1975). Artereographic correlates of handedness. Neurology. 25. 218-222.
Hohne, K. H., & Hanson, W. A. (1992). Interactive 3D segmentation of
MRI and CT volumes using morphological operations. Tourn. Comp Assist. Tom ogr, 16. 285-294.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Holland, G. N., Havvkes, R. C., & Moore, W. S. (1983). A tomographic NMR brain scanner. In L. C. Partain, A. E. James, D. F. Rollo, & R. R. Price (Eds.), Nuclear Magnetic Resonance Imaging Philadelphia:
W.B. Saunders. Hopkins, W. D., Vauclair, J., & Fagot, J. (1993). Psychological Science (In press). House, W. V. (1983). Theoretical basis for NMR imaging. In L. C. Partain,
A. E. James, D. F. Rollo, & R. R. Price (Eds.), Nuclear Magnetic Resonance Imaging Philadelphia: W.B. Saunders.
Hu, X., Tan, K.K, Levin, D.N. et al (1990). Three-dimensional magnetic resonance inages of the brain: application to neurosurgical planning. Tournal of Neurosurgury. 72(March), 433-440.
Humphreys, P., Kaufmann, W. E., & Galaburda, A. M. (1990). Developmental dyslexia in women: Neuropathological findings in three patients. Ann Neurol. 28. 727-738. Hynd, G. W., & Semrud-Clikeman (1989). Dyslexia and brain
morphology. Psychological Bulletin. 106.447-482. Inglis, J., & Lawson, J. S. (1981). Sex differences in the effects of unilateral brain damage on intelligence. Science. 212. 693-696.
Inglis, J., Ruckman, M., Lawson, J. S., Maclen, A. W., & Monga, T. N. (1983). Sex differences in the cognitive effects of unilateral brain damage: a comparison of stroke patients and normal control
subjects. Cortex, 12, 551-555.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Jacob, H., & Beckman, H. (1986). Prenatal developmental disturbances in the limbic allocortex in schizophrenics. I. Neural Transmission. 65.
303-326. James, A. E., Pickens, D. R., Rollo, D. F., Stephans, W. H., Erickson, J., Patton, J. A., Mitchel, M., Price, R. R., & Partain, L. C. (1983). The chemical potential of NMR: An overview. In L. C. Partain, A. E. James, D. F. Rollo, & R. R. Price (Eds.), Nuclear Magnetic Resonance Imaging Jernigan, T.,Zatz, L.M. et al. (1982). Computed tomography in
schizophrenics and normal volunteers: II. Cranial asymmetry.
Arch Gen Psychiatry. 39. 771-773.Philadelphia: W.B. Saunders. Jernigan, T., Zisook, S., Heaton, R. K., Moranville, J. T., Hesselink, J. R., &
Braff, D. L. (1991a). Magnetic resonance imaging abnormalities in
lenticular nuclei and cerebral cortex in schizophrenia. Arch Gen
Psychiatry, 48.881-890. Jernigan, T. L., Archibald, S. L., Berhow, M. T., Sowell, E. R., Foster, D. S.,
& Hesselink, J. R. (1991b). Cerebral structure on MRI: Part 1. Localization of age-related changes. Biological Psychiatry. 22,68-81.
Jernigan, T. L., Salmon, D. P., Butters, N., & Hesselink, J. R. (1991c).
Cerebral structure on MRI, Part II: Specific changes in Alzheimer’s and Huntington's diseases. Biological Psychiatry. 29. 68-81.
Jeste, D.V., Kleinman, J.E., Potkin, S.G., Luchins, D.J., and Weinberger,
D.R. (1982) Ex uno multi: Subtyping the schizophrenic syndrome. Biological Psychiatry 17.179-222.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Johnstone, E. C., Owens, D. G. C , Crow, T. J., Frith, C. D., Alexandropolis, K., Bydder, G., & Colter, N. (1989). Temporal lobe structure as
determined by nuclear magnetic resonance in schizophrenia and bipolar affective disorder. T. Neurology. Neurosurgery and Psychiatry. 52.736-741.
Jones, D. W. (1992a). CBDB Macros for NIH Image. Unpublished manuscript. Jones, D. W. (1992b). Unpublished manuscript.. Kelly, W. M. (1987). Image artifacts and technical limitations. In M. Brant- Zawadzki & D. Norman (Eds.), Magnetic Resonance Imaging of the
Central Nervous System. New York: Raven Press. Kelsoe, J. R., Cadet, J. L., Pickar, D., & Weinberger, D. W. (1988).
Quantitative neuroanatomy in schizophrenia. Arch. Gen Psychiatry. 45.533-541.
Kertesz, A., Polk, M., Black, S. E., & Howell, J. (1990). Sex, handedness and
the morphometry of cerebral asymmetries on magnetic resonance imaging. Brain Research. 530. 40-48.
Kikinis, R., Shenton, M., Jolesz, F., Gerig, G., Martin, J., Anderson, M., Metcalf, D., Guttman, C., McCarley, R. W., Lorensen, B., & Cline, H.
(1992). Routine quantitative analysis of brain and cerebrospinal fluid spaces with MR imaging. TMRI. 2, 619-629.
Kimura, D. (1983). Sex differences in cerebral organization for speech and praxic function. Can. T. Psychol.. 37.19-35. Kimura, D. (1987). Are men’s and women's brains really different?
Canadian Psychology,133-147. 22,
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Kimura, D. E., & Harshman, R. A. (1984). Sex differences in brain organization for verbal and nonverbal functions. In G. J. DeVries & et al. (Eds.), Progress in Brain Research Amsterdam: Elsevier
Science Publishers. Koff, E., Naeser, M. A., Pieniadz, J. M., Foundas, A. L., & Levine, H. L.
(1986). Computed tomographic scan hemispheric asymmetries in right and left-handed male and female subjects. Arch Neurol. 43. 487-491. Kolb, B., & Whishaw, I. Q. (1990). Fundamentals of Human
Neuropsychology (Third ed.). New York: W.H. Freeman and Co. Kulynych, J. J., Vladar, K., Jones, D. W., & Weinberger, D. R. (1993). Application of three-dimensional surface renderings to MRI
morphometry: A study of the planum temporale in normal subjects. TCAT. In press.
Larsen, J. P., Hoien, T., Lundberg, I., & Odegaard, H. (1990). MRI
evaluation of the size and symmetry of the planum temporale in adolescents with developmental dyslexia. Brain and Language. 39. 289-301.
Larsen, J. P., Odegaard, H., Grude, T. H., & Hoien, T. (1989). Magnetic resonance imaging - a method of studying the size and asymmetry of the planum temporale. Acta Neurol. 80. 438-443.
Lauter, J. L., Herscovitch, P., Formsby, C., & Raichle, M. E. (1985).
Tonotopic organization of the human auditory cortex revealed by positron emission tomography. Hear. Research. 20. 199-205.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LeMay, M. (1976). Morphological cerebral asymmetries of m odern man, fossil man, and nonhuman primates. Annals of the New York Academy of Sciences. 280.349-366.
LeMay, M. (1992). Left-right dissymetry. Handedness. ATNR. 13. 493-504.
LeMay, M., & Geschwind, N. (1975). Hemispheric differences in the brains of great apes. Brain Beh. Evol.. 11. 48-52.
LeMay, M., & Kido, D. K. (1978). Asymmetries of the cerebral hemispheres on computed tomograms. TCAT. 2, 471-476. Levin, D. N., Hu,X., Tan, K.K., and Galhotra, S. (1989). Surface of the
brain: Three-dimensional MR images created with volume rendering. Radiology. 171. 277-280.
Lauterbur, P.C. (1973) Image formation by induced local interactions: Examples employing nuclear magnetic resonance. Nature. 242.190-
191. Liegeois-Chauvel, C., Musolino, A., & Chauvel, P. (1991). Localization of the primary auditory area in man. Brain. 1114.139-153.
Luchins, D.J., Morihisa, J.M. et al. (1981) Cerebral asymmetry and cerebellar atrophy in schizophrenia: A controlled postmortem
study. Am- J- Psychiatry, 13& 1501-1503. Luchins, D.J., Weinberger, D.R., et al. (1982) Schizophrenia and cerebral asymmetry detected by computed tomography. Am. T. Psychiatry.
139: 753-757. Luchins, D.J. and Meltzer, H.Y. (1983) A blind, controlled study of occipital asymmetry in schizophrenia. Psychiatry Res.. 10: 87-95.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Maccoby, E., & Jacklin, C. (1974). The Psychology of Sex Differences.
Stanford: Stanford University Press. Mallard, J. (1983). NMR imaging at Aberdeen: A historical perspective. In L. C. Partain, A. E. James, D. F. Rollo, & R. R. Price (Eds.), Nuclear
Magnetic Resonance Imaging Philadelphia: W.B. Saunders. Marneros, A., Deister, A., & Rohde, A. (1991) Validity of the
negative/positive dichotomy for schizophrenic disorders under long-term conditions. Schizophrenia Research. 7. 117-123. Maudsley, A. A. (1983). Multiple line scanning NMR imaging. In L. C. Partain, A. E. James, D. F. Rollo, & R. R. Price (Eds.), Nuclear
Magnetic Resonance Imaging Philadelphia: W.B. Saunders.
McGlone, J. (1977). Sex differences in the cerebral organization of verbal
functions in patients with unilateral brain lesions. Brain. 100. 775-
793. McGlone, J. (1978). Sex differences in functional brain asymmetry. Cortex. 14(122-128).
McGlone, J. (1980). Sex differences in human brain asymmetry: a critical survey. Behavioral and Brain Sciences. 2, 215-263.
Nauta, W. J., & Feirtag, M. (1986). Fundamental Neuroanatom v. New York: W.H. Freeman and Compay.
Oldendorf, W., & Oldendorf, W. (1988). Basics of Magnetic Resonance
Imaging. Boston: Martinums Nijhoff Publishing.
Oldfield, R. C. (1979). The assessment and analysis of handedness: The
Edinburgh Inventory. Neuropsvchologia. % 97-113.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Ong, W. Y., & Garey, L. (1990). Neuronal architecture of the human temporal cortex. Anat. Embryol.. 181. 351-364.
Partain, C. L., Price, R. R., Patton, J. A., Stephens, W. H., Stewart, R. G., &
James, A. E. (1983). The physical basis for NMR imaging. In L. C. Partain, A. E. James, D. F. Rollo, & R. R. Price (Eds.), Nuclear Magnetic Resonance Imaging Philadelphia: W.B. Saunders.
Penfield, W., & Perot, P. (1963). The brain's record of auditory and visual experience: a final summary and discussion. Brain. 86. 595-696. Penfield, W., & Roberts, L. (1959). Speech and Brain Mechanisms. Princeton: Princeton University Press. Pfefferbaum, A., Lim, K. O., Rosenbloom, M., & Zipursky, R. B. (1990).
Brain magnetic resonance imaging: Approaches for investigating schizophrenia. Schizophrenia Bulletin. 16. 435-476.
Pfefferbaum, A., & Zipursky, R. B. (1991). Neuroimaging studies of
schizophrenia. Schizophrenia Research. 4, 193-208.
Pfeifer, R. A. (1936). Pathologie der horstrahlung und der corticalen
horsphare. In O. Bumke & O. Foerster (Eds.), Handbuch der Neurologie. Vol. 6 (pp. 533-626). Berlin: Springer.
Prorok, R. J., & Sawyer, A. M. (1992). Signa Advantage Applications
Guide. Volume 1. The General Electric Company.
Purcell, E., Torrey, H., & Pound, R. (1946). Resonance absorption by nuclear magnetic moments in a solid. Phvs. Rev.. 69. 37-38.
Raine, A., Harrison, G. N., Reynolds, G. P., Sheard, C., Cooper, J. E., & Medley, I. (1990). Structural and functional characteristics of the
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 150
corpus callosum in schizophrenics, psychiatric controls and normal controls. Arch Gen Psychiatry. 4 7 .1060-1064.
Rasband, W. (1992). NIH Image, Version 1.45.
Ratcliff, G., Dila, C., Taylor, L., & Milner, B. (1990). The morphological asymmetry of the hemispheres and cerebral dominance for speech: A possible relationship. Brain and Language. 11. 87-98. Raz, S., Raz, N., Weinberger, D. R., Boronow, J., Pickar, D., Bigler, E., &
Turkenheimer, E. (1987). Morphological brain abnormalities in schizophrenia determined by computed tomography: A problem of measurement? Psychiatric Research. 22. 91-98.
Reite, M., Teale, P., Zimmerman, J., Davis, K., Whalen, J., & Edrich, J. (1988). Source origin of a 50-msec latency auditory evoked field component in young schizophrenic men. Biological Psychiatry. 24.
495-506.
Reubens, A. B., Mahovvald, M. W., & Hutton, J. T. (1976). Asymmetry of the lateral (Sylvian) fissures in man. Neurology. 26. 620-624.
Roberts, G. W. (1991). Schizophrenia: A neuropathological perspective. British Tournal of Psychiatry. I5S, 8-17. Rossi, A., Stratta, P., D’Albenzio, L., & al., e. (1990). Reduced temporal lobe
areas in schizophrenia: preliminary evidences from a controlled multiplanar magnetic resonance imaging study. Biological
Psychiatry. 27,61-68.
Rossi, A., Stratta, P., Di Michele, V., & al., e. (1991). Temporal lobe structure by magnetic resonance in bipolar affective disorders and
schizophrenia. Disorders, 12,19-22.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Rossi, A., Stratta, P., Mattei, P., Cupillari, M., Bozzao, A., Gallucci, M., &
Casacchia, M. (1992). Planum temporale in schizophrenia: A magnetic resonance study. Schizophrenia Res. 7,19-22. Saunders, R. F., & Orr, J. S. (1983). Biologic effects of NMR. In L. C. Partain, A. E. James, D. F. Rollo, & R. R. Price (Eds.), Nuclear
Magnetic Resonance Imaging Philadelphia: W.B. Saunders.
Sedat, J., & Duvernay, H. (1990). Anatomical study of the temporal lobe. JL Neuroradiologv. 17. 26-49. Seldon, H. L. (1981). Structure of human auditory cortex. I.
Cytoarchitectonic and dendritic distributions. Brain Research. 2298. 277-294. Shenton, M. E., Kikinis, R., Jolesz, F. A., Poliak, S. D., LeMay, M., Wible, C. G., Hokama, H., Martin, J., Metcalf, D., Coleman, M., &
McCarley, R. W. (1992). Abnormalities of the left temporal lobe and
though disorder in schizophrenia. The New Eng. T. Med.. 327. 604- 612.
Springer, S., & Searleman, A. (1978). The ontogeny of hemispheric specialization: evidence from dichotic listening in twins.
Neuropsvchologia. IfL 269-281. Steinmetz, H., Furst, G., & Freund, H.-J. (1989). Cerebral cortical
localization: Application and validation of the proportional grid system in MR imaging. TCAT. 12(1), 10-19. Steinmetz, H., & Huang, Y. (1991). Two-dimensional mapping of brain surface anatomy. AJNR. 12. 997-1000.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Steinmetz, H., Rademacher, J., Huang, Y., H., H., Zilles, K., Thron, A., &
Freund, H.-J. (1989). Cerebral asymmetry: MR planimetry of the
human planum temporale. TCAT. 12.(1), 996-1005. Steinmetz, H., Rademacher, J., Jancke, L., Huang, Y. X., Thron, A., &
Zilles, K. (1990). Total surface of tempoparietal intrasylvian cortex: diverging left and right asymmetries. Brain Lang. 22(3), 357-72. Steinmetz, H., Volkman, J., Jancke, L., & Freund, H. (1991). Anatomical left-right asymmetry of language-related temporal cortex is different in left-and right-handers. Ann Neurol. 29. 315-319. Straughan, K., Spencer, D. H., & Bydder, G. M. (1983). NMR clinical
results: Hammersmith. In L. C. Partain, A. E. James, D. F. Rollo, &
R. R. Price (Eds.), Nuclear Magnetic Resonance Imaging
Philadelphia: W.B. Saunders. Strauss, E., Wada, J., & Goldwater, B. (1992). Sex differences in interhemispheric reorganization of speech. Neuropsvchologia. 30. 353-359.
Suddath, R. L., Casanova, M. F., Goldberg, T. E., Daniel, D. G., Kelsoe, J. R., & Weinberger, D. R. (1989). Temporal lobe pathology in
schizophrenia: A quantitative magnetic resonance imaging study. Am T. Psychiatry. 146.464-472.
Suddath, R. L., Christison, G. W., Torrey, E. F., Casanova, M. F., &
Weinberger, D. R. (1990). Anatomical abnormalities in the brains of monozygotic twins discordant for schizophrenia. New Eng. T. Med.. 322.789-94.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Svvayze, V. W., Andreasen, N. C., Randall, J., Alliger, W., Yuh, W. T. C., & Ehrhardt, J. C. (1992). Subcortical and temporal structures in
affective disorder and schizophrenia: A magnetic resonance imaging study. Biological Psychiatry. 31.221-240.
Talairach, J., & Tournoux, P. (1988). Co-Planar Stereotaxic Atlas of the Human Brain. New York: Thieme Medical Publishers, Inc.
Taylor, M. J., Smith, M. L., & Iron, K. S. (1990). Event-related potential evidence for sex differences in verbal and nonverbal memory tasks. Neuropsvchologi a. 28. 691-705.
Vladar, K. (1992). Unpublished data.
Von Bonin, G. (1962). Anatomical asymmetries of the cerebral hemispheres. In V. B. Mountcastle (Eds.), Interhemispheric
Relations and Cerebral Dominance Baltimore: Johns Hopkins
University Press. von Economo, C , & Horn, L. (1930). Gyral relief, size and cortical
architectonics of the suproatemporal surface: Their individual and lateral differences. Z Ges Neurol Psvchiatr. 130. 687-757. Waber, D. P. (1976). Sex differences in cognition: a function of maturation rate. Science. 192.572-574.
Wada, J. A., Clarke, R., & Hamm, A. (1975). Cerebral hemisphere
asymmetry in humans: Cortical speech zones in 100 adult and 100 infant brains. Arch Neurol. 32. 239-246.
Webster, W. R., & Garey, L. J. (1990). Auditory System. In G. Paxino (Eds.), The Human Nervous System New York: Academic Press.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Weinberger, D. R., Luchins, D.J., et al. (1982).Asymmetrical volumes of
the right and left frontal and occipital regions of the human brain. Ann Neurol. 11. 97-100.
Weinberger, D. R. (1987). Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry. 44. 660- 669. Weinberger, D. R. (1992). A neural systems approach to the frontal lobes.
In Syllabus: Behavioral Neurology-Neural Systems_and Networks San Diego: American Academy of Neurology.
Weinberger, D. R., Suddath, R. L., Casanova, M. R., Torrey, E. F., &
Kleinman, J. E. (1991). Crow’s "Lateralization Hypothesis" for schizophrenia. Arch. Gen Psychiatry. 48.85.
Weinberger, W. R. (1991). Anteromedial temporal-prefrontal connectivity: A functional neuroanatomical system implicated in schizophrenia. In B. J. Carroll & J. E. Barrett (Eds.), Psychopathology
and the Brain New York: Raven Press. Wendt, R. E., Murphy, P. H., Ford, J. J., Bryan, R. N., & Burdne, J. A. (1984). Flow and motion in NMR imaging: a tutorial introduction. In P. D. Esser & R. E. Johnston (Eds.), Technology of Nuclear
Magnetic Resonance New York: The Society of Nuclear Medicine, Inc.
Witelson, S. F. (1983). Bumps on the brain: Right-left anatomic
asymmetry as a key to functional lateralization. In S. J. Segalowitz (Eds.), Language Functions and Brain Organization New York:
Academic Press.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Witelson, S. F. (1991). Sex differences in neuroanatomical changes with aging. New Eng. I. Med.. 325(31. 221-222.
Witelson, S. F., & Kigar, D. (1988). Asymmetry in brain function follows
asymmetry in anatomical form: Gross, microscopic, postmortem
and imaging studies. In F. Boiler & J. Grafman (Eds.), Handbook of Neuropsychology. Amsterdam: Elsevier Science Publishers.
Witelson, S. F., & Kigar, D. L. (1992). Sylvian fissure morphology and asymmetry in men and women: Bilateral differences in relation to handedness in men. T. Comp. Neurology. 323. 326-340.
Witelson, S. F., & Palie, W. (1973). Left hemisphere specialization for
language in the newborn: Neuroanatomical evidence of asymmetry. Brain. 96. 641-646. Yeni-Komshian, G. H., & Benson, D. A. (1976). Anatomical study of
cerebral asymmetry in the temporal lobe of humans, chimpanzees and rhesus monkeys. Science. 192. 387-389. Young, A. H., Blackwood, D. H. R., Roxborough, H., & al., e. (1991). A
magnetic resonance imaging study of schizophrenia: Brain structure and clinical symptoms. Br. T. Psychiatry. 45.158-164.
Zee, R. F., & Weinberger, D. R. (1986). Brain areas implicated in
schizophrenia: A selective overview. In H. A. Nasrallah & D. R. Weinberger (Eds.), Handbook of Schizophrenia. Vol 1: The
Neurology of Schizophrenia Amsterdam: Elsevier Science
Publishers.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Zigun, J. R., & Weinberger, D. W. (1992). In vivo studies of brain
morphology in schizophrenia. In J. P. Lindenmayer & S. R. Kay (Eds.), New Biological Vistas on Schizophrenia New York:
Brunner/Mazel. Zilles, K. (1990). Cortex. In G. Paxinos (Eds.), The Human Nervous System
New York: Academic Press. Zilles, K , Armstrong, E., Schleicher, A., & Kretschmann, H.-J. (1988). The
human pattern of gyrification in the cerebral cort ^A. Anat Embryol. 179.173-179.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.