Brain morphometry
Encyclopedia
Brain morphometry is a subfield of both morphometry and the brain sciences, concerned with the measurement of brain
structures and changes thereof during development, aging, learning
, disease
and evolution. Since autopsy
-like dissection is generally impossible on living brain
s, brain morphometry starts with noninvasive neuroimaging
data, typically obtained from magnetic resonance imaging
(or MRI for short). These data are born digital
, which allows researchers to analyze the brain images further by using advanced mathematical and statistical methods such as shape quantification or multivariate analysis
. This allows researchers to quantify
anatomical features of the brain in terms of shape
, mass
, volume
(e.g. of the hippocampus
, or of the primary versus secondary visual cortex
), and to derive more specific information, such as the encephalization quotient
, grey matter density and white matter connectivity, gyrification, cortical thickness, or the amount of cerebrospinal fluid
. These variables can then be mapped
within the brain volume or on the brain surface, providing a convenient way to assess their pattern and extent over time, across individuals or even between different biological species. The field is rapidly evolving along with neuroimaging techniques — which deliver the underlying data — but also develops in part independently from them, as part of the emerging field of neuroinformatics
, which is concerned with developing and adapting algorithm
s to analyze those data.
is often used interchangeably with brain morphometry, although mapping in the narrower sense of projecting
properties of the brain onto a template brain is, strictly speaking, only a subfield of brain morphometry. On the other hand, though much more rarely, neuromorphometry is also sometimes used as a synonym for brain morphometry (particularly in the earlier literature, e.g. Haug 1986), though technically is only one of its subfields.
like the brain are the result of numerous biochemical and biophysical processes interacting in a highly complex manner across multiple scales in space and time (Vallender et al., 2008). Most of the genes known to control these processes during brain development, maturation
and aging are highly conserved (Holland, 2003), though some show polymorphism
s (cf. Meda et al., 2008), and pronounced differences at the cognitive level abound even amongst closely related species
, or between individuals within a species (Roth and Dicke, 2005).
In contrast, variations in macroscopic
brain anatomy (i.e. at a level of detail still discernable by the naked human eye
) are sufficiently conserved to allow for comparative analyses
, yet diverse enough to reflect variations within and between individuals and species: As morphological analyses that compare brains at different ontogenetic or pathogenetic stages can reveal important information about the progression of normal or abnormal development within a given species, cross-species comparative studies have a similar potential to reveal evolutionary trends and phylogenetic relationships.
Given that the imaging modalities commonly employed for brain morphometric investigations are essentially of a molecular or even sub-atomic nature, a number of factors may interfere with
derived quantification of brain structures. These include all of the parameters mentioned in "Applications" but also the state of hydration, hormonal status, medication and substance abuse.
or brain disorders, they still provide a wealth of information about the nature of the processes involved. Shape comparisons have long been constrained to simple and mainly volume- or slice-based measures but profited enormously from the digital revolution, as now all sorts of shapes in any number of dimensions can be handled numerically.
In addition, though the extraction of morphometric parameters like brain mass or liquor volume may be relatively straightforward in post mortem samples, most studies in living subjects will by necessity have to use an indirect approach: A spatial representation of the brain or its components is obtained by some appropriate neuroimaging
technique, and the parameters of interest can then be analysed on that basis. Such a structural representation of the brain is also a prerequisite for the interpretation of functional neuroimaging
data (e.g. Anticevic et al., 2008) .
The design of a brain morphometric study depends on multiple factors that can be roughly categorized as follows: First, depending on whether ontogenetic, pathological or phylogenetic issues are targeted, the study can be designed as longitudinal
(within the same brain, measured at different times), cross-sectional
(across brains). Second, brain image data can be acquired using different neuroimaging
modalities. Third, brain properties can be analyzed at different scales (e.g. in the whole brain, regions of interest
, cortical or subcortical structures). Fourth, the data can be subjected to different kinds of processing and analysis steps. Brain morphometry as a discipline is mainly concerned with the development of tools addressing this fourth point and integration with the previous ones.
of the brain, neuroimaging data are generally stored as matrices
of voxel
s. The most popular morphometric method, thus, is known as Voxel-based morphometry (VBM; cf. Wright et al., 1995; Ashburner and Friston, 2000; Good et al., 2001). Yet as an imaging voxel is not a biologically meaningful unit, other approaches have been developed that potentially bear a closer correspondence to biological structures: Deformation-based morphometry (DBM), surface-based morphometry (SBM) and fiber tracking based on diffusion-weighted imaging (DTI or DSI). All four are usually performed based on Magnetic Resonance (MR) imaging
data, with the former three commonly using T1-weighted (e.g. Magnetization Prepared Rapid Gradient Echo, MP-RAGE) and sometimes T2-weighted pulse sequences, while DTI/DSI use diffusion
-weighted ones.
In the following, the image is segmented into non-brain and brain tissue, with the latter usually being sub-segmented into at least gray matter (GM), white matter (WM) and cerebrospinal fluid. Since
image voxels near the class boundaries do not generally contain just one kind of tissue, partial volume effects ensue that can be corrected for.
For comparisons across different scans (within or across subjects), differences in brain size and shape are eliminated by spatially normalizing (i.e. registering) the individual images to a the stereotactic space of a template brain.
Registration can be performed using low-resolution (i.e. rigid-body or affine transformations) or high-resolution (i.e. highly non-linear) methods, and templates can be generated from the study's pool of brains, from a brain atlas or a derived template generator.
Both the registered images and the deformation fields generated upon registration can be used for morphometric analyses, thereby providing the basis for Voxel-Based Morphometry (VBM) and Deformation-Based Morphometry (DBM). Images segmented into tissue classes can also be used to convert segmentation boundaries into parametric surfaces, the analysis of which is the focus of Surface-Based Morphometry (SBM).
to the template. Each voxel then contains a measure of the probability, according to which it belongs to a specific segmentation class. For gray matter, this quantity is usually referred to as gray matter density (GMD) or gray matter concentration (GMC), or gray matter probability (GMP).
In order to correct for the volume changes due to the registration, the gray matter volume (GMV) in the original brain can be calculated by multiplying the GMD with the Jacobian determinants of the deformations used to register the brain to the template. Class-specific volumes for WM and CSF are defined analogously.
The local differences in the density or volume of the different segmentation classes can then be statistically analyzed across scans and interpreted in anatomical terms (e.g. as gray matter atrophy). Since VBM is available for many of the major neuroimaging software packages (e.g. FSL
and SPM
), it provides an efficient tool to test or generate specific hypotheses about brain changes over time.
Of course, multiple solutions exist for such non-linear warping procedures, and to balance appropriately between the potentially opposing requirements for global and local shape fit, ever more sophisticated registration algorithms are being developed. Most of these, however, are computationally expensive if applied with a high-resolution grid. The biggest advantage of DBM with respect to VBM is its ability to detect subtle changes in longitudinal studies. However, due to the vast variety of registration algorithms, no widely accepted standard for DBM exists, which also prevented its incorporation into major neuroimaging software packages.
on which morphometric analysis can proceed (e.g. towards gyrification), or onto which results of such analyses can be projected
.
s within the brain by means of diffusion tensor imaging or diffusion-spectrum imaging (e.g. Douaud et al., 2007 and O'Donnell et al., 2009).
Currently, however, most applications of MR-based brain morphometry have a clinical focus, i.e. they help to diagnose and monitor neuropsychiatric disorders, in particular neurodegenerative diseases (like Alzheimer) or psychotic disorders (like schizophrenia).
Using voxel-based and a number of complementary approaches, these studies revealed (or non-invasively confirmed, from the perspective of previous histological studies which cannot be longitudinal) that brain maturation involves differential growth of gray and white matter, that the time course of the maturation is not linear and that it differs markedly across brain regions. . In order to interpret these findings, cellular processes have to be taken into consideration, especially those governing the pruning of axons, dendrites and synapses until an adult pattern of whole-brain connectivity is achieved (which can best be monitored using diffusion-weighted techniques).
That the white matter loss is not nearly as clear as that for gray matter indicates that changes also occur in non-neural tissue, e.g. the vasculature or microglia.
drivers in London
were found to exhibit bilaterally increased gray matter volume in the posterior part of the hippocampus
, both relative to controls from the general population and to London bus
drivers matched for driving experience and stress
levels. Similarly, gray matter changes were also found to correlate with professional experience in musicians, mathematicians and meditators, and with second language proficiency.
What is more, bilateral gray matter changes in the posterior and lateral parietal cortex of medical students memorizing for an intermediate exam could be detected over a period of just three months.
These studies of professional training inspired questions about the limits of MR-based morphometry in terms of time periods over which structural brain changes can be detected. Important determinants of these limits are the speed and spatial extent of the changes themselves. Of course, some events like accidents, a stroke, a tumor metastasis or a surgical intervention can profoundly change brain structure during very short periods, and these changes can be visualized with MR and other neuroimaging techniques. Given the time constraints under such conditions, brain morphometry is rarely involved in diagnostics but rather used for progress monitoring over periods of weeks and months and longer.
One study found that juggling
novices showed a bilateral gray matter expansion in the medial temporal visual area (also known as V5) over a three-month period during which they had learned to sustain a three-ball cascade for at least a minute. No changes were observed in a control group that did not engage in juggling. The extent of these changes in the jugglers reduced during a subsequent three-month period in which they did not practice juggling. To further resolve the time course of these changes, the experiment was repeated with another young cohort scanned in shorter intervals, and the by then typical changes in V5 could already be found after just seven days of juggling practice. Interestingly, the observed changes were larger in the initial learning phase than during continued training.
Whereas the former two studies involved students in their early twenties, the experiments were recently repeated with an elderly cohort, revealing the same kind of structural changes, although attenuated by lower juggling performance of this group.
Using a completely different kind of intervention -- application of Transcranial Magnetic Stimulation
in daily sessions over five days -- changes were observedin and near the TMS target areas as well as in the basal ganglia of volunteers in their mid-twenties, compared to a control group that had received placeboic TMS treatment. It is possible, though, that these changes simply reflect vascularization effects.
Taken together, these morphometric studies strongly support the notion that brain plasticity -- changes of brain structure -- remains possible throughout life and may well be an adaptation to changes in brain function which has also been shown to change with experience. The title of this section was meant to emphasize this, namely that plasticity and learning provide two perspectives -- functional and structural -- at the same phenomenon, a brain that changes over time.
However, in the context of disorders with a known or suspected hereditary component, a number of studies have compared the brain morphometry of patients with both that of non-affected controls and that of subjects at high risk for developing the disorder. The latter group usually includes family members.
Even larger time gaps can be bridged by comparing human populations with a sufficiently long history of genetic separation, such as Central Europeans and Japanese. One surface-based study compared the brain shape between these two groups and found a difference in their gender-dependent brain asymmetries. Neuroimaging studies of this kind, combined with functional ones and behavioural data, provide promising and so far largely unexplored avenues to understand similarities and differences between different groups of people.
Like morphological analyses that compare brains at different ontogenetic or pathogenetic stages can reveal important information about normal or abnormal development within a given species, cross-species comparative studies have a similar potential to reveal evolutionary trends and phylogenetic relationships. Indeed, shape comparisons (though historically with an emphasis on qualitative criteria) formed the basis of biological taxonomy before the era of genetics.
Three principal sources exist for comparative evolutionary investigations: Fossils, fresh-preserved post-mortem or in vivo
studies.
The fossil record is dominated by structures that were already biomineralized during the lifetime of the respective organism (in the case of vertebrates, mainly teeth and bones).
Brains, like other soft tissues, rarely fossilize, but occasionally they do. The probably oldest vertebrate brain known today belonged to a ratfish that lived around 300 million years ago (Pradel et al., 2009). While the technique most widely used to image fossils is computed tomography
(CT), this particular specimen was imaged by synchrotron tomography, and recent MR imaging studies with fossils suggest that the method may be used to image at least a subset of fossilized brains.
MR images have also been obtained from the brain of a 3200-year-old Egyptian
mummy
. The perspectives are slim, however, that any three-dimensional imaging dataset of a fossil, semi-fossil or mummified brain will ever be of much use to morphometric analyses of the kind described here, since the processes of mummification and fossilization heavily alter the structure of soft tissues in a way specific to the individual specimen and subregions therein.
Postmortem samples of living or recently extinct species, on the other hand, generally allow to obtain MR image qualities sufficient for morphometric analyses, though preservation artifacts would have to be taken into account. Previous MR imaging studies include specimens
preserved in formalin,
by freezing
or in alcohol .
The third line of comparative evidence would be cross-species in vivo MR imaging studies like the one by Rilling & Insel (1998), who investigated brains from eleven primate species by VBM in order to shed new light on primate brain evolution.
Other studies have combined morphometric with behavioural measures, and brain evolution does not only concern primates: Gyrification occurs across mammalian brains if they reach a size of several centimeters—with cetaceans dominating the upper end of the spectrum—and generally increases slowly with overall brain size, following a power law.
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
structures and changes thereof during development, aging, learning
Learning
Learning is acquiring new or modifying existing knowledge, behaviors, skills, values, or preferences and may involve synthesizing different types of information. The ability to learn is possessed by humans, animals and some machines. Progress over time tends to follow learning curves.Human learning...
, disease
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
and evolution. Since autopsy
Autopsy
An autopsy—also known as a post-mortem examination, necropsy , autopsia cadaverum, or obduction—is a highly specialized surgical procedure that consists of a thorough examination of a corpse to determine the cause and manner of death and to evaluate any disease or injury that may be present...
-like dissection is generally impossible on living brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
s, brain morphometry starts with noninvasive neuroimaging
Neuroimaging
Neuroimaging includes the use of various techniques to either directly or indirectly image the structure, function/pharmacology of the brain...
data, typically obtained from magnetic resonance imaging
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
(or MRI for short). These data are born digital
Born Digital
Born Digital: Understanding the First Generation of Digital Natives is a book by John Palfrey and Urs Gasser exploring the consequences of the wide availability of internet connectivity to the first generation of people born to it, who Palfrey and Gasser refer to as "digital natives"...
, which allows researchers to analyze the brain images further by using advanced mathematical and statistical methods such as shape quantification or multivariate analysis
Multivariate analysis
Multivariate analysis is based on the statistical principle of multivariate statistics, which involves observation and analysis of more than one statistical variable at a time...
. This allows researchers to quantify
Quantification
Quantification has several distinct senses. In mathematics and empirical science, it is the act of counting and measuring that maps human sense observations and experiences into members of some set of numbers. Quantification in this sense is fundamental to the scientific method.In logic,...
anatomical features of the brain in terms of shape
Shape
The shape of an object located in some space is a geometrical description of the part of that space occupied by the object, as determined by its external boundary – abstracting from location and orientation in space, size, and other properties such as colour, content, and material...
, mass
Mass
Mass can be defined as a quantitive measure of the resistance an object has to change in its velocity.In physics, mass commonly refers to any of the following three properties of matter, which have been shown experimentally to be equivalent:...
, volume
Volume
Volume is the quantity of three-dimensional space enclosed by some closed boundary, for example, the space that a substance or shape occupies or contains....
(e.g. of the hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
, or of the primary versus secondary visual cortex
Visual cortex
The visual cortex of the brain is the part of the cerebral cortex responsible for processing visual information. It is located in the occipital lobe, in the back of the brain....
), and to derive more specific information, such as the encephalization quotient
Encephalization quotient
Encephalization Quotient , or encephalization level is a measure of relative brain size defined as the ratio between actual brain mass and predicted brain mass for an animal of a given size, which is hypothesized to be a rough estimate of the intelligence of the animal.This is a more refined...
, grey matter density and white matter connectivity, gyrification, cortical thickness, or the amount of cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
. These variables can then be mapped
Brain mapping
Brain mapping is a set of neuroscience techniques predicated on the mapping of quantities or properties onto spatial representations of the brain resulting in maps.- Overview :...
within the brain volume or on the brain surface, providing a convenient way to assess their pattern and extent over time, across individuals or even between different biological species. The field is rapidly evolving along with neuroimaging techniques — which deliver the underlying data — but also develops in part independently from them, as part of the emerging field of neuroinformatics
Neuroinformatics
Neuroinformatics is a research field concerned with the organization of neuroscience data by the application of computational models and analytical tools. These areas of research are important for the integration and analysis of increasingly large-volume, high-dimensional, and fine-grain...
, which is concerned with developing and adapting algorithm
Algorithm
In mathematics and computer science, an algorithm is an effective method expressed as a finite list of well-defined instructions for calculating a function. Algorithms are used for calculation, data processing, and automated reasoning...
s to analyze those data.
Terminology
The term brain mappingBrain mapping
Brain mapping is a set of neuroscience techniques predicated on the mapping of quantities or properties onto spatial representations of the brain resulting in maps.- Overview :...
is often used interchangeably with brain morphometry, although mapping in the narrower sense of projecting
Map projection
A map projection is any method of representing the surface of a sphere or other three-dimensional body on a plane. Map projections are necessary for creating maps. All map projections distort the surface in some fashion...
properties of the brain onto a template brain is, strictly speaking, only a subfield of brain morphometry. On the other hand, though much more rarely, neuromorphometry is also sometimes used as a synonym for brain morphometry (particularly in the earlier literature, e.g. Haug 1986), though technically is only one of its subfields.
Biology
The morphology and function of a complex organOrgan (anatomy)
In biology, an organ is a collection of tissues joined in structural unit to serve a common function. Usually there is a main tissue and sporadic tissues . The main tissue is the one that is unique for the specific organ. For example, main tissue in the heart is the myocardium, while sporadic are...
like the brain are the result of numerous biochemical and biophysical processes interacting in a highly complex manner across multiple scales in space and time (Vallender et al., 2008). Most of the genes known to control these processes during brain development, maturation
Maturation
Maturation could refer to any of the following:* Fetal development* Developmental biology* Emotional development* Or physical maturation of any biological life form - see individual articles for maturation of different life forms....
and aging are highly conserved (Holland, 2003), though some show polymorphism
Polymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
s (cf. Meda et al., 2008), and pronounced differences at the cognitive level abound even amongst closely related species
Species
In biology, a species is one of the basic units of biological classification and a taxonomic rank. A species is often defined as a group of organisms capable of interbreeding and producing fertile offspring. While in many cases this definition is adequate, more precise or differing measures are...
, or between individuals within a species (Roth and Dicke, 2005).
In contrast, variations in macroscopic
Macroscopic
The macroscopic scale is the length scale on which objects or processes are of a size which is measurable and observable by the naked eye.When applied to phenomena and abstract objects, the macroscopic scale describes existence in the world as we perceive it, often in contrast to experiences or...
brain anatomy (i.e. at a level of detail still discernable by the naked human eye
Human eye
The human eye is an organ which reacts to light for several purposes. As a conscious sense organ, the eye allows vision. Rod and cone cells in the retina allow conscious light perception and vision including color differentiation and the perception of depth...
) are sufficiently conserved to allow for comparative analyses
Comparative analysis
Comparative analysis is type of analysis used in various of sciences and in different modifications:Criminology and forensics:* Comparative contextual analysis - criminology* Comparative bullet-lead analysis - forensicsSociology:...
, yet diverse enough to reflect variations within and between individuals and species: As morphological analyses that compare brains at different ontogenetic or pathogenetic stages can reveal important information about the progression of normal or abnormal development within a given species, cross-species comparative studies have a similar potential to reveal evolutionary trends and phylogenetic relationships.
Given that the imaging modalities commonly employed for brain morphometric investigations are essentially of a molecular or even sub-atomic nature, a number of factors may interfere with
derived quantification of brain structures. These include all of the parameters mentioned in "Applications" but also the state of hydration, hormonal status, medication and substance abuse.
Technical requirements
There are two major prerequisites for brain morphometry: First, the brain features of interest must be measurable, and second, statistical methods have to be in place to compare the measurements quantitatively. Shape feature comparisons form the basis of Linnaean taxonomy, and even in cases of convergent evolutionConvergent evolution
Convergent evolution describes the acquisition of the same biological trait in unrelated lineages.The wing is a classic example of convergent evolution in action. Although their last common ancestor did not have wings, both birds and bats do, and are capable of powered flight. The wings are...
or brain disorders, they still provide a wealth of information about the nature of the processes involved. Shape comparisons have long been constrained to simple and mainly volume- or slice-based measures but profited enormously from the digital revolution, as now all sorts of shapes in any number of dimensions can be handled numerically.
In addition, though the extraction of morphometric parameters like brain mass or liquor volume may be relatively straightforward in post mortem samples, most studies in living subjects will by necessity have to use an indirect approach: A spatial representation of the brain or its components is obtained by some appropriate neuroimaging
Neuroimaging
Neuroimaging includes the use of various techniques to either directly or indirectly image the structure, function/pharmacology of the brain...
technique, and the parameters of interest can then be analysed on that basis. Such a structural representation of the brain is also a prerequisite for the interpretation of functional neuroimaging
Neuroimaging
Neuroimaging includes the use of various techniques to either directly or indirectly image the structure, function/pharmacology of the brain...
data
The design of a brain morphometric study depends on multiple factors that can be roughly categorized as follows: First, depending on whether ontogenetic, pathological or phylogenetic issues are targeted, the study can be designed as longitudinal
Longitudinal study
A longitudinal study is a correlational research study that involves repeated observations of the same variables over long periods of time — often many decades. It is a type of observational study. Longitudinal studies are often used in psychology to study developmental trends across the...
(within the same brain, measured at different times), cross-sectional
Cross-sectional study
Cross-sectional studies form a class of research methods that involve observation of all of a population, or a representative subset, at one specific point in time...
(across brains). Second, brain image data can be acquired using different neuroimaging
Neuroimaging
Neuroimaging includes the use of various techniques to either directly or indirectly image the structure, function/pharmacology of the brain...
modalities. Third, brain properties can be analyzed at different scales (e.g. in the whole brain, regions of interest
Region of interest
A Region of Interest, often abbreviated ROI, is a selected subset of samples within a dataset identified for a particular purpose.For example:* on a waveform , a time or frequency interval...
, cortical or subcortical structures). Fourth, the data can be subjected to different kinds of processing and analysis steps. Brain morphometry as a discipline is mainly concerned with the development of tools addressing this fourth point and integration with the previous ones.
Methodologies
With the exception of the usually slice-based histologyHistology
Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope...
of the brain, neuroimaging data are generally stored as matrices
Matrix (biology)
In biology, matrix is the material between animal or plant cells, in which more specialized structures are embedded, and a specific part of the mitochondrion that is the site of oxidation of organic molecules. The internal structure of connective tissues is an extracellular matrix...
of voxel
Voxel
A voxel is a volume element, representing a value on a regular grid in three dimensional space. This is analogous to a pixel, which represents 2D image data in a bitmap...
s. The most popular morphometric method, thus, is known as Voxel-based morphometry (VBM; cf. Wright et al., 1995; Ashburner and Friston, 2000; Good et al., 2001). Yet as an imaging voxel is not a biologically meaningful unit, other approaches have been developed that potentially bear a closer correspondence to biological structures: Deformation-based morphometry (DBM), surface-based morphometry (SBM) and fiber tracking based on diffusion-weighted imaging (DTI or DSI). All four are usually performed based on Magnetic Resonance (MR) imaging
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
data, with the former three commonly using T1-weighted (e.g. Magnetization Prepared Rapid Gradient Echo, MP-RAGE) and sometimes T2-weighted pulse sequences, while DTI/DSI use diffusion
Diffusion
Molecular diffusion, often called simply diffusion, is the thermal motion of all particles at temperatures above absolute zero. The rate of this movement is a function of temperature, viscosity of the fluid and the size of the particles...
-weighted ones.
Preprocessing
MR images are generated by a complex interaction between static and dynamic electromagnetic fields and the tissue of interest, namely the brain that is encapsulated in the head of the subject. Hence, the raw images contain noise from various sources -- namely head movements (a scan suitable for morphometry typically takes on the order of 10 min) that can hardly be corrected or modeled, and bias fields (neither of the electromagnetic fields involved is homogeneous across the whole head nor brain) which can be modeled.In the following, the image is segmented into non-brain and brain tissue, with the latter usually being sub-segmented into at least gray matter (GM), white matter (WM) and cerebrospinal fluid. Since
image voxels near the class boundaries do not generally contain just one kind of tissue, partial volume effects ensue that can be corrected for.
For comparisons across different scans (within or across subjects), differences in brain size and shape are eliminated by spatially normalizing (i.e. registering) the individual images to a the stereotactic space of a template brain.
Registration can be performed using low-resolution (i.e. rigid-body or affine transformations) or high-resolution (i.e. highly non-linear) methods, and templates can be generated from the study's pool of brains, from a brain atlas or a derived template generator.
Both the registered images and the deformation fields generated upon registration can be used for morphometric analyses, thereby providing the basis for Voxel-Based Morphometry (VBM) and Deformation-Based Morphometry (DBM). Images segmented into tissue classes can also be used to convert segmentation boundaries into parametric surfaces, the analysis of which is the focus of Surface-Based Morphometry (SBM).
Voxel-based morphometry
After the individual images were segmented, they are registeredImage registration
Image registration is the process of transforming different sets of data into one coordinate system. Data may be multiple photographs, data from different sensors, from different times, or from different viewpoints. It is used in computer vision, medical imaging, military automatic target...
to the template. Each voxel then contains a measure of the probability, according to which it belongs to a specific segmentation class. For gray matter, this quantity is usually referred to as gray matter density (GMD) or gray matter concentration (GMC), or gray matter probability (GMP).
In order to correct for the volume changes due to the registration, the gray matter volume (GMV) in the original brain can be calculated by multiplying the GMD with the Jacobian determinants of the deformations used to register the brain to the template. Class-specific volumes for WM and CSF are defined analogously.
The local differences in the density or volume of the different segmentation classes can then be statistically analyzed across scans and interpreted in anatomical terms (e.g. as gray matter atrophy). Since VBM is available for many of the major neuroimaging software packages (e.g. FSL
FMRIB Software Library
The FMRIB Software Library is a software library containing image analysis and statistical tools for functional, structural and diffusion MRI brain imaging data....
and SPM
Statistical parametric mapping
Statistical parametric mapping or SPM is a statistical technique created by Karl Friston for examining differences in brain activity recorded during functional neuroimaging experiments using neuroimaging technologies such as fMRI or PET...
), it provides an efficient tool to test or generate specific hypotheses about brain changes over time.
Deformation-based morphometry
In DBM, highly non-linear registration algorithms are used, and the statistical analyses are not performed on the registered voxels but on the deformation fields used to register them (which requires multivariate approaches) or derived scalar properties thereof, which allows for univariate approaches. One common variant -- sometimes referred to as Tensor-based morphometry (TBM) -- is based on the Jacobian determinant of the deformation matrix.Of course, multiple solutions exist for such non-linear warping procedures, and to balance appropriately between the potentially opposing requirements for global and local shape fit, ever more sophisticated registration algorithms are being developed. Most of these, however, are computationally expensive if applied with a high-resolution grid. The biggest advantage of DBM with respect to VBM is its ability to detect subtle changes in longitudinal studies. However, due to the vast variety of registration algorithms, no widely accepted standard for DBM exists, which also prevented its incorporation into major neuroimaging software packages.
Pattern based morphometry
Pattern based morphometry (PBM) is a method of brain morphometry first put forth in (PBM) It builds upon DBM and VBM. PBM is based on the application of sparse dictionary learning to morphometry. As opposed to typical voxel based approaches which depend on univariate statistical tests at specific voxel locations, PBM extracts multivariate patterns directly from the entire image. The advantage of this is that the inferences are not made locally as in VBM or DBM but globally. This allows the method to detect if combinations of voxels are better suited to separate the groups being studied rather than single voxels. Also the method is more robust to variations in the underlying registration algorithms as compared to typical DBM analysisSurface-based morphometry
Once the brain is segmented, the boundary between different classes of tissue can be reconstructed as a surfaceSurface reconstruction
Surface reconstruction refers to the process by which atoms at the surface of a crystal assume a different structure than that of the bulk. Surface reconstructions are important in that they help in the understanding of surface chemistry for various materials, especially in the case where another...
on which morphometric analysis can proceed (e.g. towards gyrification), or onto which results of such analyses can be projected
Brain mapping
Brain mapping is a set of neuroscience techniques predicated on the mapping of quantities or properties onto spatial representations of the brain resulting in maps.- Overview :...
.
Fiber-tracking techniques
Nerve fiber-tracking techniques are the latest offspring of this suite of MR-based morphological approaches. They determine the tract of nerve fiberNerve fiber
A nerve fiber is a threadlike extension of a nerve cell and consists of an axon and myelin sheath in the nervous system. There are nerve fibers in the central nervous system and peripheral nervous system. A nerve fiber may be myelinated and/or unmyelinated. In the central nervous system , myelin...
s within the brain by means of diffusion tensor imaging or diffusion-spectrum imaging (e.g. Douaud et al., 2007 and O'Donnell et al., 2009).
Applications
The qualitatively largest changes within an individual generally occur during early development and more subtle ones during aging and learning, while pathological changes can vary highly in their extent and interindividual differences increase both during and across lifetimes. The above-described morphometric methods provide the means to analyze such changes quantitatively, and MR imaging has been applied to ever more brain populations relevant to these time scales, both within humans and across species.Currently, however, most applications of MR-based brain morphometry have a clinical focus, i.e. they help to diagnose and monitor neuropsychiatric disorders, in particular neurodegenerative diseases (like Alzheimer) or psychotic disorders (like schizophrenia).
Brain development
MR imaging is rarely performed during pregnancy and the neonatal period, in order to avoid stress for mother and child. In the cases of birth complications and other clinical events, however, such data are being acquired. Dubois et al., 2008, for instance, analyzed gyrification in premature newborns at birth and found it to be predictive of a functional score at term-equivalent age. Beyond preterms, there have been a number of large-scale longitudinal MR-morphometric studies (often combined with cross-sectional approaches and other neuroimaging modalities) of normal brain development in humans.Using voxel-based and a number of complementary approaches, these studies revealed (or non-invasively confirmed, from the perspective of previous histological studies which cannot be longitudinal) that brain maturation involves differential growth of gray and white matter, that the time course of the maturation is not linear and that it differs markedly across brain regions. . In order to interpret these findings, cellular processes have to be taken into consideration, especially those governing the pruning of axons, dendrites and synapses until an adult pattern of whole-brain connectivity is achieved (which can best be monitored using diffusion-weighted techniques).
Aging
While white matter increases throughout early development and adolescence, and gray matter decreases in that period generally do not involve neuronal cell bodies, the situation is different beyond the age of about 50 years when atrophy affects gray and possibly also white matter. The most convincing explanation for this is that individual neurons die, leading to the loss of both their cell bodies (i.e. gray matter) and their myelinated axons (i.e. white matter). The gray matter changes can be observed via both gray matter density and gyrification.That the white matter loss is not nearly as clear as that for gray matter indicates that changes also occur in non-neural tissue, e.g. the vasculature or microglia.
Learning and plasticity
Perhaps the most profound impact to date of brain morphometry on our understanding of the relationships between brain structure and function has been provided by a series of VBM studies targeted at proficiency in various performances: Licensed taxicabTaxicab
A taxicab, also taxi or cab, is a type of vehicle for hire with a driver, used by a single passenger or small group of passengers, often for a non-shared ride. A taxicab conveys passengers between locations of their choice...
drivers in London
London
London is the capital city of :England and the :United Kingdom, the largest metropolitan area in the United Kingdom, and the largest urban zone in the European Union by most measures. Located on the River Thames, London has been a major settlement for two millennia, its history going back to its...
were found to exhibit bilaterally increased gray matter volume in the posterior part of the hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
, both relative to controls from the general population and to London bus
Bus
A bus is a road vehicle designed to carry passengers. Buses can have a capacity as high as 300 passengers. The most common type of bus is the single-decker bus, with larger loads carried by double-decker buses and articulated buses, and smaller loads carried by midibuses and minibuses; coaches are...
drivers matched for driving experience and stress
Workplace stress
Workplace stress is the harmful physical and emotional response that occurs when there is a poor match between job demands and the capabilities, resources, or needs of the worker....
levels. Similarly, gray matter changes were also found to correlate with professional experience in musicians, mathematicians and meditators, and with second language proficiency.
What is more, bilateral gray matter changes in the posterior and lateral parietal cortex of medical students memorizing for an intermediate exam could be detected over a period of just three months.
These studies of professional training inspired questions about the limits of MR-based morphometry in terms of time periods over which structural brain changes can be detected. Important determinants of these limits are the speed and spatial extent of the changes themselves. Of course, some events like accidents, a stroke, a tumor metastasis or a surgical intervention can profoundly change brain structure during very short periods, and these changes can be visualized with MR and other neuroimaging techniques. Given the time constraints under such conditions, brain morphometry is rarely involved in diagnostics but rather used for progress monitoring over periods of weeks and months and longer.
One study found that juggling
Juggling
Juggling is a skill involving moving objects for entertainment or sport. The most recognizable form of juggling is toss juggling, in which the juggler throws objects up to catch and toss up again. This may be one object or many objects, at the same time with one or many hands. Jugglers often refer...
novices showed a bilateral gray matter expansion in the medial temporal visual area (also known as V5) over a three-month period during which they had learned to sustain a three-ball cascade for at least a minute. No changes were observed in a control group that did not engage in juggling. The extent of these changes in the jugglers reduced during a subsequent three-month period in which they did not practice juggling. To further resolve the time course of these changes, the experiment was repeated with another young cohort scanned in shorter intervals, and the by then typical changes in V5 could already be found after just seven days of juggling practice. Interestingly, the observed changes were larger in the initial learning phase than during continued training.
Whereas the former two studies involved students in their early twenties, the experiments were recently repeated with an elderly cohort, revealing the same kind of structural changes, although attenuated by lower juggling performance of this group.
Using a completely different kind of intervention -- application of Transcranial Magnetic Stimulation
Transcranial magnetic stimulation
Transcranial magnetic stimulation is a noninvasive method to cause depolarization or hyperpolarization in the neurons of the brain...
in daily sessions over five days -- changes were observedin and near the TMS target areas as well as in the basal ganglia of volunteers in their mid-twenties, compared to a control group that had received placeboic TMS treatment. It is possible, though, that these changes simply reflect vascularization effects.
Taken together, these morphometric studies strongly support the notion that brain plasticity -- changes of brain structure -- remains possible throughout life and may well be an adaptation to changes in brain function which has also been shown to change with experience. The title of this section was meant to emphasize this, namely that plasticity and learning provide two perspectives -- functional and structural -- at the same phenomenon, a brain that changes over time.
Brain disease
Brain diseases are the field to which brain morphometry is most often applied, and the volume of the literature on this is vast.Brain evolution
Brain changes also accumulate over periods longer than an individual life but even though twin studies have established that human brain structure is highly heritable, brain morphometric studies with such a broadened scope are rare.However, in the context of disorders with a known or suspected hereditary component, a number of studies have compared the brain morphometry of patients with both that of non-affected controls and that of subjects at high risk for developing the disorder. The latter group usually includes family members.
Even larger time gaps can be bridged by comparing human populations with a sufficiently long history of genetic separation, such as Central Europeans and Japanese. One surface-based study compared the brain shape between these two groups and found a difference in their gender-dependent brain asymmetries. Neuroimaging studies of this kind, combined with functional ones and behavioural data, provide promising and so far largely unexplored avenues to understand similarities and differences between different groups of people.
Like morphological analyses that compare brains at different ontogenetic or pathogenetic stages can reveal important information about normal or abnormal development within a given species, cross-species comparative studies have a similar potential to reveal evolutionary trends and phylogenetic relationships. Indeed, shape comparisons (though historically with an emphasis on qualitative criteria) formed the basis of biological taxonomy before the era of genetics.
Three principal sources exist for comparative evolutionary investigations: Fossils, fresh-preserved post-mortem or in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
studies.
The fossil record is dominated by structures that were already biomineralized during the lifetime of the respective organism (in the case of vertebrates, mainly teeth and bones).
Brains, like other soft tissues, rarely fossilize, but occasionally they do. The probably oldest vertebrate brain known today belonged to a ratfish that lived around 300 million years ago (Pradel et al., 2009). While the technique most widely used to image fossils is computed tomography
Computed tomography
X-ray computed tomography or Computer tomography , is a medical imaging method employing tomography created by computer processing...
(CT), this particular specimen was imaged by synchrotron tomography, and recent MR imaging studies with fossils suggest that the method may be used to image at least a subset of fossilized brains.
MR images have also been obtained from the brain of a 3200-year-old Egyptian
Ancient Egypt
Ancient Egypt was an ancient civilization of Northeastern Africa, concentrated along the lower reaches of the Nile River in what is now the modern country of Egypt. Egyptian civilization coalesced around 3150 BC with the political unification of Upper and Lower Egypt under the first pharaoh...
mummy
Mummy
A mummy is a body, human or animal, whose skin and organs have been preserved by either intentional or incidental exposure to chemicals, extreme coldness , very low humidity, or lack of air when bodies are submerged in bogs, so that the recovered body will not decay further if kept in cool and dry...
. The perspectives are slim, however, that any three-dimensional imaging dataset of a fossil, semi-fossil or mummified brain will ever be of much use to morphometric analyses of the kind described here, since the processes of mummification and fossilization heavily alter the structure of soft tissues in a way specific to the individual specimen and subregions therein.
Postmortem samples of living or recently extinct species, on the other hand, generally allow to obtain MR image qualities sufficient for morphometric analyses, though preservation artifacts would have to be taken into account. Previous MR imaging studies include specimens
preserved in formalin,
by freezing
or in alcohol .
The third line of comparative evidence would be cross-species in vivo MR imaging studies like the one by Rilling & Insel (1998), who investigated brains from eleven primate species by VBM in order to shed new light on primate brain evolution.
Other studies have combined morphometric with behavioural measures, and brain evolution does not only concern primates: Gyrification occurs across mammalian brains if they reach a size of several centimeters—with cetaceans dominating the upper end of the spectrum—and generally increases slowly with overall brain size, following a power law.