In Vivo Structural Brain Assessment

Kelvin O. Lim, Margaret Rosenbloom, and Adolf Pfefferbaum

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.

In addition to characterizing ever more specific brain dysmorphology (the

size, tissue composition, and shape of different cortical or subcortical
neuroanatomic structures), new advances have also made it possible to
use MRI to visualize and quantify the directional coherence of white
matter fibers (diffusion tensor imaging, DTI) (9), an application of
potential relevance for investigating levels of connectivity and
dysconnectivity between different brain regions.

All measures derived from neuroimaging technologies need to be

carefully interpreted in the context of other brain and biological features,
as well as the clinical and demographic characteristics of the patient,
before they can provide insight into the possible etiology, pathophysiology
and course of different mental disorders. The goal of this updated
chapter is to briefly recapitulate prior information, describe some new
advances in neuroimaging and outline their capabilities and limitations
and reiterate some of the important technical and methodological issues
connected with acquiring, measuring and interpreting these types of
data.
ACQUISITION OF MAGNETIC RESONANCE IMAGES

Mechanisms Of Tissue Contrast: Pulse Sequences

One of the strengths of MRI is that investigators can manipulate the

amount of contrast between different biological tissues by varying
elements of the image acquisition sequence. A highly simplified outline of
the principle of MRI is provided here to orient the reader to how these
acquisition elements can be varied. More detailed descriptions can be
found elsewhere (68). Atomic nuclei with an odd number of nucleons
(protons plus neutrons) behave as spinning tops with an electric charge,
and thus they produce a magnetic field, oriented along the axis of
rotation of the nucleus. Under normal circumstances, the spin axes of
these nuclei are randomly oriented so that the sum of all magnetic fields
is zero. However, when these nuclei are exposed to a strong external
magnetic field, they align either parallel or anti-parallel with the field in
an equilibrium state, that is either in a high or low energy state, with a
slight preponderance of the high energy state. These aligned atomic
nuclei rotate around their axes at a characteristic frequency, also
dependent on the strength of the magnetic field. Electromagnetic
radiofrequency (RF) pulses, applied at the appropriate frequency
perpendicular to the main magnetic field, excite the spinning nuclei,
knocking them out of equilibrium. When the radio waves are turned off,
the nuclei return to equilibrium. MRI employs appropriately tuned
radiofrequency coils to detect the radio signals given off as the nuclei
return to equilibrium, and localize them using magnetic gradients in the
three orthogonal axes.

Hydrogen atoms (protons) are the most abundant element in biological

tissue, primarily in the form of water. Proton MRI thus records signals
arising predominantly from free water (i.e., water not biochemically
bound in complex molecules), but there is also a measurable but much
lesser contribution from protons in fat. Proton density (PD), based on
the number of nuclei stimulated, and the relaxation times, T1 and T2,
which reflect the chemical environment of the tissue stimulated, each
determine in different ways the intensity at which different tissues will
appear in an acquired image. T1 is an exponential time constant which
represents the time taken for excited nuclei to return to equilibrium after
the RF pulse has been turned off. T2 is an exponential time constant
describing the time it takes for the excited nuclei to lose signal, mainly
due to dephasing in the transverse plane. The time between
radiofrequency pulses (TR), and the amount of time after the pulse at
which the signal is acquired (echo time, or TE), determine the influence
each of these parameters (PD, T1 and T2) have on the acquired image.
For example a long TR (2-3 sec), spin echo sequence with a long TE (80
msec) provides a heavily "T2-weighted" image in which CSF remains
bright, because CSF has a long T2, while signal from brain
parenchyma,which has a shorter T2, has declined, rendering this tisue
darker and homogeneous. In contrast, a relatively short TR (200-400
msec) spin echo or inversion recovery sequence with a short TE (20
msec) provides a "T1-weighted" image which optimizes contrast between
gray matter and white matter. In T1-weighted images, tissue with shorter
T1s are brighter, whereas in T2 weighted images, tissues with longer T2s
are brighter. For brain imaging, the choice of T1 vs. T2 weighted images
presents a tradeoff between obtaining high contrast between gray matter
and white matter or obtaining high contrast between CSF and brain
parenchyma. While T1-weighted spin-echo and inversion recovery
sequences provide excellent white-gray contrast, and have been used
extensively for morphometric studies, they are limited by their poor
definition of CSF/skull margins for reliably measuring intracranial
volume. Thus, there is no single correct MR brain sequence, but rather a
range of options, with the optimal selection determined by the questions
being asked.

A major limitation in scanning patients has been the length of time

needed to obtain images, resulting in image degradation due to subject
motion. A major thrust for development of clinical imaging techniques
has been to reduce imaging time, either by reducing TR and TE while
incorporating additional pulses to provide contrast, or by acquiring more
data after each excitation pulse. Techniques that acquire the same
amount of data in less time produce image contrasts similar, but not
identical, to those of traditional spin-echo sequences. Sequences that
acquire all of the data needed for reconstructing an image after a single
excitation pulse (single shot techniques) include Echo Planar Imaging
(EPI) (53) and spiral imaging (61) techniques. While fast and convenient,
these images often suffer from lower signal-to-noise ratio (SNR) and
susceptibility induced distortions. Work is constantly under way by the
manufacturers and research groups to produce further enhancements
and overcome limitations. Approaches that minimize the influence of
susceptibility artifacts of EPI based systems by acquiring only part of the
data after each excitation include Rapid Acquisition with Relaxation
Enhancement (RARE) and Fast Spin Echo (FSE) sequences.

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.

Another source of contrast is based on the self-diffusion or the random

Brownian movement of water molecules. When diffusion is unrestricted,
e.g. as in a glass of water, the movement of water molecules has no
directional preference and is termed isotropic. However, when the
motion is restricted, e.g., by fibers such as constitute the white matter
tracts, diffusion is greater parallel to the fiber than perpendicular to it,
and is termed anisotropic. Anisotropic diffusion can be imaged, and by
sequentially applying magnetic gradients in six non-collinear directions,
its directionality and magnitude can be quantified. This form of imaging
has been called diffusion tensor imaging (DTI) (9). Subsequent analysis
applies a mathematical construct, a tensor, to describe the
multidimensional vector systems and quantify the diffusion. Vector
measures have been used to map white matter fiber tracts in the brain.
Scalar measures of the diffusion, such as fractional anisotropy and
relative anisotropy, provide an overall index of tissue anisotropy (52).
This approach has recently been used to reveal possibly compromised
white matter tracts in patients with schizophrenia (13, 50).

Two-dimensional Multi-slice and Three-dimensional Imaging

Two-dimensional (2D) images are acquired in a defined orthogonal plane,

typically in axial, sagittal and coronal orientations (Figure 1). Image
orientation is defined by use of selective RF pulse excitations and the
appropriate magnetic gradients in the three orthogonal axes. Each
orientation provides a different view of the brain with optimal
visualization of different structures. For example, mid-sagittal images
provide clear delineation of the prefrontal cortex and the corpus
callosum, coronal images provide views of the hippocampus and limbic
structures over several sections or slices and axial images provide a good
view of basal ganglia structures such as the putamen, globus pallidus,
caudate and substantia nigra, as well as the lateral ventricular system.
One limitation of 2D image acquisition is that only selected slices, of
specified thickness, are excited and imaged and, unless these slices have
been collected using standardized internal neuroanatomic landmarks,
they may not be directly comparable across subjects. Comparability is
enhanced by orienting each slice acquisition relative to a specific
anatomic plane such as that passing through the anterior and posterior
commissures, perpendicular to the sagittal plane (95).

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).

Three-dimensional (3D) volume acquisition protocols encompass the

entire brain and can be reformatted, post acquisition, into any plane
subject to the limitations imposed by the resolution of the original data.
This post-acquisition flexibility in defining 3D planes for analysis can
reduce measurement errors related to head misalignment between
subjects, or within a subject in a longitudinal study. 3D images are
acquired by exciting a broad volume of tissue with a non-slice selective
RF pulse (5). Additional magnetic gradients are then used to spatially
encode within the excited region. After the raw image data have been
collected, a Fourier transform decodes slice positions from the entire data
set. These slice data are further reconstructed with a 2D Fourier
transform into the final image. Limitations in post-scan analysis of 3D
data sets are discussed in more detail in the section on image analysis
below. Among the 3D acquisition protocols which are widely used in
psychiatric neuroimaging are spoiled gradient recall acquisition (SPGR)
and magnetization prepared rapid gradient echo (MPRAGE) (63) each of
which are T1-weighted, provide reasonable gray/white differentiation,
and can sample the entire brain with 1.5mm or thinner slices in 10
minutes or less.

Image Resolution, Signal-To-Noise-Ratio, and Slice Thickness

An image is composed of a grid (usually 256 x 256) of 2D picture

elements (pixels). The resolution of the image is affected both by in-
plane resolution and by slice thickness. An in-plane resolution of 1 mm
means that each pixel in the image matrix represents 1 mm2. However if
the slice is as thick as 5 mm, once standard for 2D MRI protocols, each
image pixel actually represent a voxel volume of 5 mm3. The larger the
voxel, the greater the likelihood it will be "partially volumed", i.e., contain
some combination of CSF, white matter or gray matter rather than being
homogenous for brain tissue type. To reduce partial voluming, high in-
plane resolution and thin slices are desired. However, technical factors
such as gradient strength and the amount of RF energy used to excite the
object, limit the minimum thickness effectively available to approximately
1-2 mm. In addition the SNR per voxel will be lower because there is less
material producing the signal in a thin slice. Thus, while the resolution
may be "finer" there will be more noise and less signal per pixel. Thinner
slices may also require an increased number of acquisitions and thus
longer scanning time to encompass an equivalent volume of the brain,
with the attendant disadvantages of requiring subjects to remain still in
the scanner.

Artifact

MR images are susceptible to various types of artifact, some of which can

be minimized during image acquisition and others which can only be
remedied during data analysis.

Hardware Induced Artifact

The RF coil's sensitivity is not homogeneous across all dimensions of the

imaging plane which often introduces a low frequency gradient of signal
intensity across a given image. While the human visual system can
maintain contrast detection in the face of this artifact, most automated
thresholding techniques assume a constant baseline level and require the
RF inhomogeneity to be corrected before the image can be processed. A
variety of solutions have been proposed to this problem, including
filtering (51) bi-feature thresholding (44), and line by line inversion of the
slope of the pixel values within each slice (17) and adaptive filtering
(107).

Effects Of CSF And Blood Pulsation, And Subject Movement

Physiological sources of artifact include pulsation of blood and CSF

through regions of the brain being imaged. The limbic system is
particularly vulnerable to this artifact because of its vascularization
pattern and relationship to the ventricular system. Cardiac-gating and
flow compensated pulse sequences help reduce these sources of
movement artifact, although not without cost. Because more gradients
are used with flow compensation, the minimum echo time is lengthened
and the maximum number of slices that can be acquired is reduced.
Voluntary or involuntary gross head movements are another source of
artifact to which 3D, functional MRI and DTI are particularly susceptible.
Head restraints or bitebars (41, 60) provide one solution A
complementary approach, adopted by some research groups for
structural imaging, involves administering a sedative hypnotic, adequate
to calm the subject or induce sleep.

Need For Phantoms

The accuracy and reproducibility of image data is directly related to the
stability of the imaging hardware, especially the magnetic field gradient
systems, the main magnetic field, and the RF pulse system. Routine
imaging of a quality assurance phantom permits monitoring of the
scanner's stability over time, stability between hardware upgrades, and
establishment of standardized techniques for multi-center studies (101).

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).

ANALYSIS OF MAGNETIC RESONANCE BRAIN IMAGES

Automated computerized analysis of many elements or characteristics of

an image is becoming increasingly feasible and accessible to
investigators. These approaches offer considerable advantages of
flexibility and efficiency, though even automated analysis approaches may
not overcome all limitations of image resolution, and distortions due to
artifact in data collection. Most analysis approaches combine both
automated and interactive elements (e.g., 24). Clinical reading or
qualitative scoring of MRI brain data, still widely used by
neuroradiologists, serves as a useful complement to quantification,
particularly for assessment of image features that until recently have
defied reliable quantification such as white matter lucencies or gross
"abnormalities" in brain morphology. However recent advances in
characterizing tissue quality (e.g., 96) and shape (e.g., 10, 19) of defined
structures are making even these abnormalities amenable to
quantification.

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.

Measurement Of Gross Morphology/Issues Of Reliability And

Validity
MRI provides great flexibility in acquiring a number of different visual
representations of the human brain, each designed to enhance contrast
between different tissue types, highlight abnormalities within a tissue
type, or provide an optimal view of a specific lobar region or subcortical
neuroanatomic structure. Techniques for morphometric analysis rely to
varying degrees on user interaction with a visual representation of the
brain image, displayed on film or a computer console, and automated
algorithms applied to the matrix of numerical values representing each
pixel in the image. Validity must be established for both interactive and
automated approaches, though in the absence of satisfactory in vivo
validation models, automated approaches are frequently validated against
the "gold standard" of a human expert, by establishing consistency with
known effects such as changes with age, by comparisons with
pathological samples, or by use of phantoms simulating different tissue
types (1). Given the complexity and individual variability of each brain,
issues of reliability acquire a particular salience when human input is
involved, but should also be documented for automated elements of any
analysis procedure (e.g., 8, 105)

Volumetric Vs. Area Measures

The size of structures of the brain can be estimated using linear, area, or
volumetric measurements. In the early CT literature, planimetric (area)
measures were most commonly used and applied to one or two "best
view" slices. This approach was accessible to investigators without
computerized image processing facilities, but was vulnerable to sampling
error, and sacrificed volumetric information. With the advent of MR, and
increasing availability of computerized analysis, volumetric analysis has
become the norm. A volumetric approach, ideally encompassing the
entire structure in each hemisphere, is particularly important for
studying left-right asymmetry of structures that are not evenly aligned
relative to the plane of view on a single slice of a given image (112). This
approach can compensate for any bias in selection of imaging plane, or
apparent asymmetries due to head placement.
Segmentation of CSF, Gray Matter and White Matter
Before brain tissue can be segmented, its extent must be defined. In vivo
estimates of brain size are usually based on estimates of the total volume
of brain tissue and CSF, including both ventricular and subarachnoid
fluid. Non-brain material must be identified or removed from the image
before the brain as a whole can be measured and its external features
identified. Correct identification of the outer brain/dural boundary
involves certain assumptions and estimations and is complicated by the
fact that bone can easily be confused with CSF and tissue in many MRI
acquisition sequences, especially T1 sequences designed to enhance
contrast between white matter and gray matter. Such ambiguities may
underlie the recently observed variation in estimated brain size between
a number of MRI studies (71). One solution to the problem is to use late
echo images in which CSF, with its long T2, can be sharply differentiated
from bone, for identifying subarachnoid fluid margins and then transfer
information about these boundary locations to images obtained with
sequence parameters on which CSF/tissue and white/gray matter
contrasts are optimized (51). Although brain tissue volume is the
principal object of study in the effort to identify neuronal substrates of
dysfunction, the size of CSF-filled spaces relative to the size of the
intracranial vault can also be instructive for interpretation regarding
degeneration of tissue and progression of disease.

Tissue segmentation routines to differentiate CSF from tissue, and

subdivide tissue into gray matter and white matter all have limitations
because there is no discrete image intensity signature, even across echo
times, for each tissue type. Segmentation is also complicated both by the
presence of areas of white matter hyperintensity (WMHI), and by the fact
that individual voxels may be partially volumed and thus contain mixtures
of CSF and gray matter or gray matter and white matter. Approaches to
this analysis include edge detection, application of various forms of
filters, and fuzzy clustering, each of which can be implemented with
varying degrees of operator interaction. Edge detection, for example, of
the outer margin of the brain, the ventricles, white matter tracts, or
specific subcortical structures such as the hippocampus or striatal
structures (89) can be done by a human tracing outlines on a computer
display or by using algorithms which identify pixels whose value differs
sufficiently from neighboring pixels to qualify them as a boundary pixels
(7). Such automated edge detection works well when contrast is high and
structures to be outlined are of a relatively simple shape. Operator input
frequently supplements automated outlining.

Thresholding involves classifying pixels according to image intensity as

representative of CSF or different tissue types. Some approaches take
advantage of the different contrasts obtained by different pulse
sequences or echo times, either combining data from T1, T2 and proton
density weighted images (e.g., 1) or subtracting one image from another
to enhance CSF-tissue contrast (32, 51). More recently, "fuzzy" cluster or
classifier approaches, which adopt a probabilistic model towards each
voxel and thus are better able to account for partial voluming effects have
been found to have high reliability, accuracy and validity (33, 82).
Automated assessments may employ discriminant functions based on
ranges of pixel values representing known tissue and fluid samples (e.g.,
14, 17).

One interactive approach requires an operator to adjust a 2-bit image

until a pixel value is identified which correctly differentiates CSF from
tissue (51). Another takes advantage of the fact that while losses in
signal differentiation, for whatever cause, make automated segmentation
more difficult, the human visual system, which is quite robust to local
intensity changes, can often compensate for thempeople can see the
gray-white tissue differences even when the segmentation routines fail.
In this situation, stereological point counting methods (11, 28, 42) might
be superior. This approach involves the random placement of a grid with
sufficient resolution (in two or three dimensions) over the structure of
interest and counting the points overlying the region or structure of
interest. The only requirements are that the grid completely encompass
the region or structure, that it be placed on the structure randomly, and
that an adequate number of points (150-200) be counted on an adequate
number of slices (~10). The approach can be very efficient and is
statistically sound. The stereological point counting approach has the
additional advantage of providing a coefficient of error of the
measurement of the volume of the structure of interest which estimates
the magnitude of difference that can be determined between subject
groups.

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).

Defining Anatomical Structures And Regions Of Interest For

Measurement
As in image acquisition, where tradeoffs need to be made between time in
scanner and optimizing image resolution, tissue contrast, and range of
structures visualized, so in image analysis there are tradeoffs to be made
between labor intensive, interactive delineation of boundaries, and
automated approaches, whether using geometrically based boundary
drawing algorithms (e.g., 111), parcellation against a standardized set of
coordinates (e.g., 4), or template matching (98). As research laboratories
collect ever increasing numbers of brains for analysis, automated
approaches which can be implemented quickly and with less ongoing
neuroanatomic expertise become very attractive. The jury is still out on
whether the advantages of speed and reliability of such systems offset
inaccuracies introduced by the deformations involved in a "one size fits
all" measurement approach. Approaches combining automation with
expert supervision attempt to get the best of both worlds.

One approach to automated measurement of major brain regions uses an

MRI-derived anatomic atlas, based on a stereotactic coordinate system
(95). Individual 3D brains are linearly transformed to fit neuroanatomic
anchor points from the atlas and volumes of ROIs are computed by
summing brain voxels coinciding with the atlas boxes assigned to each
ROI (e.g., 4). This approach has been extended by thresholding brains
into CSF, white, and gray matter to delineate subcortical gray matter
structures as well as overall cerebrum, cerebellum and ventricular
volumes (40) and validated against interactively defined gold standards
and by demonstrating predicted gender, age and group effects. For a
more comprehensive treatment the variety of brain atlases available, and
different approaches to deformations the reader is referred to a recent
specialized publication (102).

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.

The development and application of laboratory-specific boundaries,

criteria, and procedures for defining neuroanatomic regions will lead to
inconsistencies rather than convergence in the literature.

Assessment of Shape and Complex Morphological Features.

New analyses incorporating advances in physics and mathematics are
now enabling examination of both focal and global characteristics of a
structure that are independent of variations in size, and can be performed
with varying degrees of automaticity. Until recently, a 3D representation
of brain structures could only be visualized in the investigator's
imagination. Now 3D displays of the external surfaces, with ability to
slice through selected planes are routinely available in most brain
imaging laboratories. Creation of 3D images employs a range of rapidly
evolving computer graphics software and hardware methods (23),
surface and volume rendering techniques. While visually compelling,
rendered images may contain distortions introduced by the viewing
model and image preprocessing that must be taken into account before
quantitative analysis is made of the rendered image.

Neurosurgeons and neurologists have lead the way in applying these

techniques for localizing lesions and vasculature before neurosurgery
(e.g., 20), developing neuroanatomic teaching tools enabling students to
explore the structure and function of the brain in virtual reality (e.g., 99),
characterizing the normal surface anatomy of the brain (104), and
identifying specific neuroanatomic regions based on specific sulcal and
gyral landmarks (79). Fluid deformations of one exterior brain surface
against another (template) followed by encoding and mapping of
probability of displacement are being used to assess individual and group
differences in the immensely complex and variable gyral and sulcal
topography (98). These probability statistics expand on earlier concepts
of anatomic atlases by simultaneously characterizing both locational and
geometric variation and open up a new dimension in characterizing and
quantifying regional abnormality relative to age and gender norms.
Other structures for which shape analyses have uncovered specific
dysmorphologies in schizophrenia include the hippocampus (19) and the
corpus callosum (16, 97).

go to Figure 2

Figure 2.

Three-dimensional renderings of MRI dataset presenting images of the

brain as if viewed from above (top) left and right, and behind (bottom).
Figure provided courtesy of Patrick Barta, NIMH.
Co-Registration With Other In Vivo Neuroimages
The relatively poor in-plane resolution and wide slices of images from
functional imaging techniques such as positron emission tomography
(PET) and proton or phosphorus magnetic spectroscopic imaging (MRSI)
limits anatomic localization. Structural information from MR images is
now routinely used for localizing and displaying high intensity areas of
activation derived from functional imaging modalities including PET (67,
91) and functional MRI (fMRI) (15). Indeed, this localization of
functional data is important not only for more precisely characterizing
the structures involved, but also to take regional or group differences in
CSF, gray and white matter composition of the partially volumed
functional voxels into account in interpreting results. Since voxels
obtained in MRS or PET tend to be larger than those now available with
MRI, co-registration of MR and PET or MRS images allows voxel
composition information from structural images to be applied to
functional images. This approach has been used for PET (59, 64), and
recently also for MRSI (34, 49, 75). Such corrections are computationally
challenging, but eventually will allow much greater precision in assessing
functional activity.

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.

A particular application for merging of data sets within an imaging

modality is the generation of averaged brains (3, 109). This approach
involves aligning and matching successive images relative to stereotactic
coordinates (21) and provides a useful visual summary of group
differences. Regions of statistically significant differences can also be
identified, but should be verified by a separate case by case quantification
of the structure or region in question (72). Image averaging works
better for assessing subcortical and midline structures, less affected by
deformations necessary to standardize brains, than cortical structures.

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.

INTERPRETATION OF MAGNETIC RESONANCE BRAIN IMAGES

Neuroimaging findings in some mental disorders can be elusive. The true

effect is small, and brain morphology is strongly affected by several
variables which are relatively independent of disease, such as age, sex
and somatic size, as well as those which might be associated with mental
disorder, e.g., alcohol consumption, socio-economic status and
handedness. These variables must be taken into consideration and
appropriate controls implemented before inferences about the
pathophysiology of various mental disorders can be properly drawn.

Selection of Appropriate Controls

When CT was the prevailing technology, medical patients with "normal"
scans were frequently used as controls in imaging studies of psychiatric
patients - a practice motivated, to some extent, by reluctance to expose
healthy subjects to unnecessary radiation. Whether or not this practice
contributed to observed group differences was never fully resolved (81,
92). With MRI scanning, this radiation concern is not relevant. However,
the prospective recruitment of control samples for any neuroimaging
studies of psychiatric disorder requires attention not only to excluding
cases with psychiatric disorders (90), but also to including subjects who
match the parental socioeconomic status, educational and ethnic status of
the patients (84). In addition to comparisons with normative data,
comparisons between pathologic groups are also valuable, especially
between different diagnostic groups with documented abnormalities in
common anatomic region(s). For example, comparisons between
patients with temporal lobe epilepsy and schizophrenia are appropriate
for studies investigating the role of limbic structures in these disorders
(55).

Accounting for Normal Developmental and Aging Effects

Schizophrenia is typically a disease with onset in late adolescence or
early adulthood, a period during which cortical gray matter undergoes
significant reduction, but cortical white continues to increase in volume
(74). Its course coincides with a period of stability of white matter
volume, but gradual reduction in gray matter and increase in CSF (37,
65, 74, 83) (Figure 5). These normal developmental and aging effects
need to be taken into account when interpreting observed brain
dysmorphology in schizophrenia. Studies of Alzheimer's disease (AD),
Parkinson's disease (PD) and other diseases which typically make their
appearance after middle age, likewise need to take into account not only
normal age-related changes occurring at this point in the life span, but
also the greater variability in brain tissue volumes found among the
healthy elderly than the healthy young (37, 38).

Accounting For Normal Variations In Somatic Size

Given the existence of a wide range of body and head sizes among the
population, it is important to demonstrate that any size difference of a
specific brain structure is independent of such non-disease-relevant
differences. In general, large people will have larger heads and larger
brains than small people, although such relationships have been easier to
demonstrate across gender and between racial groups than within them
(71). In most research contexts, this variability constitutes a form of
noise which investigators need to minimize in order to compare the
volume of a particular brain region or structure between individuals and
groups. Thus head size correction seems particularly appropriate when
gender differences in brain morphology are under investigation (18, 45).
One approach for head-size correction has been use of a ratio, such as the
ventricle brain ratio (VBR), which was developed to provide an index of
ventricular enlargement relative to the size of the total brain. Other
correction approaches have included proportions, where the size of a
structure, or the amount of tissue or CSF in a ROI, is divided by an
estimate of the intracranial volume (e.g., 37); or regression analysis
which partials out the components of quantitative brain measures
attributable to headsize variation (e.g., 74).

Concern that the ratio or proportion approaches to head size correction

could introduce error or obscure the complexity of underlying
relationships has lead some investigators to warn against their use, and
advocate regression or multifactorial approaches, as necessary, to parse
out contribution of non-specific variables (6). Others (57) have
demonstrated that a regression approach to head-size correction removes
irrelevant true-score variance which reduces reliability and improves the
correlation with validity criteria such as age and diagnostic status.
Linear regression of specific ROIs against estimated head-size in a
sample of normal control subjects highlighted the fact that different parts
of the brain bear different relationships to overall brain size and suggests
that ROI-specific correction factors should be applied (57).

While head-size correction is appropriate in some contexts, in others,

such as developmental studies (74), it may not be. For such studies,
absolute volumes of particular brain regions rather than head-size
corrected values should be used. Because investigators have described
reduced intracranial volume in patients with schizophrenia (69), the issue
has become more complicated. If schizophrenia affects the brain before
it has completed its growth, leading to diminished brain size and as a
result diminished skull size, the correction of all structural brain
measures for intracranial volume could obscure pathologically relevant
information. Regardless of possible disease-related reduction in head
size, however, an investigator asking whether particular brain structures
are disproportionately reduced, must examine and take into account
differences in intracranial volume.

Accounting For Widespread Tissue Deficits

Generalized morphological differences in the brains of psychiatric
patients compared to controls should be taken into account before
assessing smaller structures. For instance, schizophrenia appears to be
characterized by generalized ventricular and cortical sulcal enlargement
as well as a widespread loss of cortical gray matter (88). Therefore, it is
necessary to consider whether loss of tissue from the target region
exceeds that found from adjacent or control regions before concluding
that a specific brain structure or region is uniquely affected by the
disease (e.g., 112). Using such an analysis, recent studies have indeed
identified certain regions of frontal and parieto-temporal cortices (86, 94)
as particularly affected in schizophrenia.

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.

Within psychiatry, longitudinal neuroimaging studies are beginning to

show promise for studying the progression of the disease (29, 56, 76),
ideally with a matched control group also followed for comparable
intervals. Neuroimaging studies of multiple sclerosis, where the waxing
and waning of white matter lesions are regularly monitored provide some
important pointers for longitudinal studies of psychiatric patients (62).
Studies of multiple sclerosis were among the first to alert investigators to
the influence of measurement error due to misalignment between scans
over time on measures of real change (26). Other subtle sources of error
between tests identified by MS researchers include variation in scanner
sensitivity (106) and voxel dimensions (47). The use of phantom
standards in all scans greatly facilitates application of post hoc
adjustments (101).

Standardizing Measures In Face Of Changing Technology

As neuroimaging methods advance and new imaging techniques are used,
it is necessary to understand how morphometric methods are affected by
differences in imaging methods. A major transition in the past 15 years
has been the replacement of CT scanning with MRI scanning. While MRI
adds much information, particularly from its enhanced soft-tissue
resolution, to that provided by CT, it also provides similar information on
CSF-filled spaces, particularly ventricular enlargement, which has been a
hallmark of CT studies. Thus MRI values can potentially offer continuity
for longitudinal studies in which a transition was made from CT to MRI.
A comparison of CT and MRI-derived estimates of ventricular and sulcal
CSF volume obtained within two weeks of each other in patients meeting
RDC criteria for alcohol dependence (77) found that while CT and MRI
estimates of absolute ventricular volume were equivalent, CT
considerably underestimated cortical sulcal volume relative to MRI. This
underestimation could be due to poorer resolution and spectral shift
artifact on CT. Thus longitudinal studies of subjects initially scanned with
CT and subsequently with MRI may, with suitable caution, assess changes
in ventricular volume, but should not compare sulcal volume.

The increasing replacement of conventional 2D image acquisition

sequences with fast 2D and 3D acquisition sequences makes issues of
comparability across acquisition sequence within MRI extremely
relevant. While comparisons between MRI sequences for sensitivity to
detecting various types of lesions are common (e.g., 100) few
comparisons between regional volumes of CSF, white and gray matter
obtained by different sequences have been published. One pilot study,
tested the comparability of CSF, GM, and WM measures made from 3D
SPGR images to those acquired using a T2-weighted axial spin-echo
protocol (54) and found that although there was a high degree of
correlation between the CSF, white and gray matter values from both sets
of images, there was relatively greater white matter and less CSF and
gray matter in SPGR compared to spin echo images, suggesting a
systematic difference between the methods. Thus longitudinal
comparisons of data collected using different acquisition methods should
be made with caution since the differences in tissue contrast, signal-to-
noise ratios, and slice profiles will affect the results of morphometric
measures.

Longitudinal Measurement Error

Even when software protocols are identical, differences in head
positioning between scans can contribute measurement error in studies
involving repeat scans (26), particularly when 2D, rather than 3D images
are being compared. A longitudinal CT study on patients with AD
identified apparent intra-individual change in total cranial volume
between first and second scans ranging from -60.5 to 89.5 cc, which
correlated significantly, but differentially with several of the ROI change
scores. Since total cranial volume (CSF plus tissue) should not change
between scans in adults, this apparent change was used to derive a
specific correction factor for each ROI change (87). This procedure has
since been applied to longitudinal studies of patients with alcoholism (76)
and schizophrenia (56). Other approaches to correcting for differences
in head positioning between scans include realignment of scans in three
axes and reslicing along the AC-PC line (29). These efforts to correct
measurement error due to differences in head placement have only
recently been applied in longitudinal studies, and the lack of such
corrections in earlier longitudinal studies of brain morphological change
in patients with schizophrenia may account for inconsistent results.

Other sources of error include unreliability in measurement techniques

(36) as well as changing approaches to measurement. Problems limiting
the value of earlier neuroimaging follow-up studies can now be
substantially reduced by applying the same measurement approach to
baseline as well as follow-up data sets, assessing inter and intra-rater
reliabilities, and retesting control groups along with patient groups.

CONCLUSIONS

The superior resolution and flexibility of MR imaging has enabled the

examination of more detailed and specific anatomical questions in
psychiatric disorders. New developments in acquisition and image
processing software continue to expand the possibilities available to
investigators, not only for visual presentation, but also for quantitative
analyses. While there continue to be important methodological and
technical issues to attend to, investigators are becoming increasingly
sophisticated in using appropriate techniques, and adopting strategies to
ensure the reliability and validity of the data being produced.
Standardization of techniques between laboratories is becoming
increasingly viable though the dissemination of image analysis software
and posting of brain atlases in web sites. It continues to be important
that data are collected and analyzed in such a way that specific
hypotheses about particular regions of the brain can be tested within the
context of the brain as a whole.

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