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INTRODUCTION
Over the past few years, technical improvements in the acquisition and
processing of structural neuroimaging data, particularly with magnetic
resonance imaging (MRI), have provided vivid visual representations of
the human brain, both as two-dimensional (2D) slices through the brain,
and as three-dimensional (3D) views of the external surface and internal
structures of the brain. Computerized tomography (CT) was the first
imaging modality to provide in vivo evidence of gross brain morphological
abnormalities in schizophrenia (39), with many CT reports of increase in
cerebrospinal fluid (CSF)-filled spaces, both centrally (ventricles), and
peripherally (sulci) in a variety of psychiatric patients (80). MRI, with its
superior tissue contrast for differentiation of white matter from gray
matter, and greater flexibility in acquiring, or re-slicing images in
orientations best suited for viewing and measuring specific structures,
has provided additional capabilities for uncovering both generalized and
regionally specific morphometric brain abnormalities associated with
schizophrenia, and other mental disorders (46, 88). Patients with
psychiatric disorders generally manifest brain abnormalities of a subtle
and/or diffuse nature, best characterized by systematic and reliable
quantification techniques rather than qualitative assessments.
Sources of contrast other than that based on manipulation of T1, T2, and
proton density have been exploited to extend the information available
through MRI. One of these is based on magnetization transfer, which
exploits the difference between free and restricted (typically in myelin)
hydrogen molecules. Off-resonance RF pulses are used to selectively
saturate the restricted pool, inducing an exchange of magnetization
between free and restricted hydrogen protons and promoting T1
relaxation. The resulting contrast is believed to reflect the structural
integrity of the tissue being imaged (27, 58) particularly white matter.
Figure 1.
MRI scans acquired in axial (A), coronal (B) and sagittal (C) planes. All
images were acquired with a field of view of 24 cm, NEX = 1, and 256 x
256 matrix. Left: Axial image, 5-mm thick, passing through the lateral
ventricles and basal ganglia. Image was acquired in an oblique plane
parallel to the AC-PC line. Image was acquired using a spin-echo
sequence, gated to achieve an effective TR of >2400 ms with one
excitation for each of 256 phase encodes and TE of 20 ms. Center: Mid-
sagittal image, 3 mm thick, acquired using a single-echo pulse sequence
(TR=600 msec; TE=20 msec), collected without using internal
anatomical landmarks. Image highlights the corpus callosum, brain stem
and cerebellum. Right: Coronal image, 3 mm thick, passing through
laeral ventricles and temporal lobes. Image was acquired in a plane
perpendicular to the AC-PC line using a multiecho, flow compensated,
cardiac gated pulse sequence (TE=40 msec; effective TR2800 msec).
Artifact
Tradeoffs
A recurring theme in any discussion of MRI data acquisition for clinical
studies is the constant tradeoff an investigator must make between
resolution of the image, its SNR, and time of the subject in the scanner.
Even with cooperative and relaxed subjects, involuntary head movements
during a lengthy scan session can be a problem. Optimal image
acquisition parameters for specific studies need to be determined
empirically and will vary depending on the structure being imaged,
scanner hardware, and the clinical characteristics of the subjects being
studied. The high cost of MRI scanning time, along with limitations in
patient tolerance, combine to favor short acquisition sessions. However,
reductions in scanning time may be at the cost of poorer image resolution
and contrast, or sampling less of the brain. A more detailed technical
treatment of pulse design issues and their relative strengths and
weaknesses is available elsewhere (e.g., 85).
Resolution Issues
Resolution is limited by parameters of the data collection protocol,
including in-plane resolution and slice thickness. Generally 2D data are
analyzed as acquired, with a known in-plane resolution and slice
thickness. In contrast, 3D data sets offer the opportunity for
reformatting images in user-defined planes in any orientation and slice
thickness. This provides greater flexibility in optimizing the view of
specific structures. However, re-slicing is bound, not only by the
hardware and software constraints of the acquisition parameters, but also
by constraints of the object space ( i.e., the defined plane and thickness)
of the original images. The effective thickness of a user-defined slice will
depend on the orientation of the slice in the 3D volume. For example,
with an isotropic data set, (i.e., each voxel is a true cube with side length
= L) where resolution in the x, y, and z axes is equal, the maximum
distance between opposite corners of the cube will be sqrt(3)*L. Hence a
slice reconstructed normal to a line connecting these two corners would
have an effective slice sampling of sqrt(3)*L. This orientation-dependent
effective slice-thickness needs to be kept in mind when analyzing such
data. This problem is compounded further when the data set is
anisotropic, as are most.
Models for tissue segmentation which work well on healthy young brains
may fail when applied to aging subjects or populations with greater tissue
pathologies, particularly of the white matter (e.g., 73). Furthermore,
assessments of subcortical gray matter volume using thresholding
algorithms can be affected by variations in tissue iron content which
shortens T2, resulting in signal loss. Iron content-related changes in T2
occur with normal aging and in basal ganglia disorders, particularly in
the substantia nigra and globus pallidus (78). The misclassification of
WMHI as gray matter can be handled by visual checking and manual
correction (e.g. 75) in samples where this occurs infrequently. Clinical
populations where focal abnormalities such as gliosis, edema,
demyelination, and ischemia, processes that alter the properties of tissue
water and produce changes in white and gray matter signal intensity, are
common require new approaches to tissue segmentation. Magnetization
transfer ratio is one such approach, specifically designed to characterize
white matter pathology (96, 103).
While much can be inferred from global measures of overall brain volume
and volume of different tissue compartments, specific regions particularly
the frontal and temporal lobes as well as limbic and striatal structures
are believed to be of particular interest in characterizing the
pathophysiology of psychiatric disorders (12). New capabilities for 3D
display of brain images have greatly expanded options for delineating
brain regions according to sulcal and gyral landmarks, but also can
confound the investigator with the complexity and variability of the
human brain. For example, while the central sulcus provides the
boundary separating frontal lobes from parietal lobes, its configuration
varies between individuals and between each cerebral hemisphere. One
of the earliest MRI estimates of frontal lobe volume was based on manual
tracing of a single midsaggital slice (2), yielding a single measure
representing a fraction of the entire structure. Now investigators are
combining surface sulcal landmarks (79) with multiple, orthogonal views
of brain tissue to identify and trace boundaries of specific cortical gyri
(11, 108), although these are not the same as functionally homogenous
cytoarchitectonic brain regions. Among the subregions defined and
segmented into white and gray matter are superior, medial, inferior,
orbital, insular and cingulate regions. This painstaking approach
requires interactive neuroanatomic judgments, considerably speeded by
visual enhancement of sulcal boundaries, and simultaneous display of
internal images in different orthogonal planes. A recent application of
this technique to the prefrontal cortex in schizophrenia found a gray
matter deficit only in the inferior region (11).
Rules for defining boundaries for temporal lobe as a whole, and its
subsections such as the superior temporal gyrus (STG) and planum
temporale have been constrained in many cases by the resolution and
plane of view available to the investigator, and have not been comparable
across laboratories. Increasing availability of high resolution 3D
acquisition protocols, and interactive 3D image processing systems will
enable closer approximation to established anatomical criteria, and
hopefully the adoption of standardized criteria. Absence of standard
definitions for mesial temporal lobe structures, particularly hippocampus
and amygdala, has been particularly evident in MRI studies of these
regions in patients with schizophrenia (for review, see 35). Meta
analysis, which provides greater power to detect effects submerged in
varying sources of error in individual studies, indicates that mesial
temporal structures are reduced in volume in schizophrenia, whether or
not the amygdala is included in the measure (66). The intensely
demanding requirements for interactive delineation of hippocampal
structures, as well as the error inherent in subjective assessment of
structure boundaries motivated development of an automated approach,
that measures not only volume (31) but also characterizes shape (30).
Application of multi-dimensional transformations based on pattern
matching has identified specific shape deformations of the hippocampus
in patients with schizophrenia localized to regions of this structure that
send projections to the frontal cortex (19). Such analysis was not only
more sensitive in differentiating patients from controls than simple
volumetric measurements, but also identified an abnormality consistent
with the hypothesized disconnection of hippocampal-prefrontal circuitry.
go to Figure 2
Figure 2.
The simplest case of co-registration is when both data sets have been
collected on the same imaging hardware, without moving the subject, as
is typically the case with fMRI and MRSI scanning (Figure 3). For PET
scanning, differences in hardware and time of scan are unavoidable.
Several different approaches to image acquisition to facilitate subsequent
matching of acquired PET and MR images have been developed. These
include use of external landmarks, or fiducials, consistently placed and of
a size and property to be adequately imaged by both modalities (22), and
head holders to stabilize and standardize head position between scanners
(41). Varying levels of sophistication have been applied to compute a
transformation matrix between two sets of images, including iterative
matching of brain surfaces (48, 70) projections (93) or overall brain tissue
(25, 110). The automated image registration (AIR) (110) and statistical
parametric mapping (SPM) (25) systems are now the most commonly
used. They have recently been cross-validated and their reliability
established (43)
Figure 3.
Co-registration of structural MRI and proton MRS images,
acquired in the same scan session from a healthy young control.
Left column (upper) illustrates unprocessed axial water-based
structural image, and (lower) edge-detected version. Right
column (upper) illustrates proton inversion recovery MRS image
of n-acetylaspartic acid (NAA) distribution in the axial plane, and
(lower) a linear combination of NAA distribution and structural
edges providing neuroanatomic definition without obscuring
spectroscopic data. Figure provided courtesy of Daniel Spielman,
Department of Radiology, Stanford University.
go to Figure 4
Figure 4.
Reslicing and co-registration of structural MRI and FDG PET images
of glucose metabolism from a 39 year old healthy female control.
Original MRI was acquired in the sagittal plane, and original FDG
PET in the axial plane. Surface matching (Analyze) software enabled
images in each modality to be resliced to match the orientation of the
other modality, and then fused to provide anatomic definition for
functional image. The PET scan was obtained on a 7 slice
Scanditronix PC1024-7B dedicated head scanner with an in-plane
resolution of 5.2mm and an axial resolution of 11mm. The tracer was
5mCi of FDG. There were 4 transmission scans (one for each frame)
with a rotating Ge/Ga pin source. The subject had a hexalite head
holder and eyepatches on and performed an auditory continuous
performance task for 30 minutes and was then scanned for 30
minutes (4 frames of 7 slices to yield 28 interleaved slices). The
interslice distance is 13.75mm for the 7 original slices and hence
3.4375mm for the 28 slices resulting from the 4 interleaved frames.
The PET image resliced in the sagittal plane clearly shows the
brainstem, cerebellum and fourth ventricle. The sagittally acquired
MRI was obtained on a Picker 0.5T scanner. Slice thickness 2.5mm,
acquired with 2 repetitions. 256 x 256 pixels x 64 slices. It is a T1
weighted field echo scan with TR=36, TE=6, flip angle=30 degrees.
Figure provided courtesy of T. Ketter, NIH.
LONGITUDINAL STUDIES
As neuroimaging matures and becomes a standard element of psychiatric
clinical research, longitudinal studies of change over time will
increasingly replace the inferences made from cross-sectional studies.
Direct longitudinal comparisons over time are hampered by major
advances in technology (e.g. replacement of CT with MRI) as well as
system upgrades within a technology. However, the advantages of direct
longitudinal evaluation of the progression of a disease over inference
from cross sectional studies motivates the development and application of
procedures both to standardize collection parameters over time and to
estimate and correct for the error introduced by uncontrolled factors.
CONCLUSIONS
REFERENCES