A brief history of human brain mapping

Human functional brain mapping as we presently know it began when the

experimental strategies of cognitive psychology were combined with
modern brain-imaging techniques (first positron emission tomography and
then functional magnetic resonance imaging) to examine how brain
function supports mental activities. This marriage of disciplines and
techniques galvanized the field of cognitive neuroscience, which has rapidly
expanded to include a broad range of the social sciences in addition to basic
scientists interested in the neurophysiology, cell biology and genetics of the
imaging signals. Although much of this work has transpired over the past
couple of decades, its roots can be traced back more than a century.
Introduction
Over the past 30 years the field of cognitive neuroscience has emerged as
an important growth area in neuroscience. Cognitive neuroscience
combines the experimental strategies of cognitive psychology with various
techniques to actually examine how brain function supports mental
activities. Leading this research in normal humans are the techniques of
functional brain imaging: positron emission tomography (PET) and
functional magnetic resonance imaging (fMRI) along with
electroencephalography (EEG), electrocorticography (ECoG),
Magnetoencephalography (MEG) and, most recently, optical imaging with
nearinfrared spectroscopy (NIRS).
It is easy to conclude that much of the work leading to the emergence of
functional brain imaging in particular and cognitive neuroscience in general
has transpired over the past decade or so because of much recent
prominence at scientific meetings and in the scientific literature.
Additionally, it has received substantial media attention probably related to
the human fascination with brain-mind questions. In truth, crucial work has
been occurring for more than a century.
To place current work in perspective, I present a brief historical overview
(Figure 1) of some of the concepts, events and personalities that have shaped
functional brain imaging as we know it today. I call upon not only published
accounts of many events and discoveries but also recollections shared with
me by those who have lived through the remarkable events of the past
several decades. Such views serve to not only breathe life into the science
but also carry the caveat that they are necessarily colored by one’s own
involvement.
I focus on human brain imaging with PET and fMRI recognizing that other
techniques, particularly electrical (e.g. EEG, MEG and ECoG), also have
and will continue to have an important role. I begin with a discussion of the
physiology of brain imaging with PET and fMRI.
Physiology
The signals obtained with PET and fMRI are based on changes in blood
flow, oxygen consumption and glucose utilization that relate in a
surprisingly precise way to the cellular activity of the brain, including
astrocytes and neurons. The details of these relationships are presented,
discussed and debated elsewhere [1–6]. Here, some basic facts necessary to
understand the history of functional brain imaging are briefly presented.
Blood flow
The majority of functional brain imaging with PET and MRI, in addition to
earlier non-tomographic techniques, is made possible because blood flow
changes locally in the brain in relation to changes in cellular activity [1].
The idea that local blood flow within the brain is intimately related to brain
function is surprisingly old. Angelo Mosso, a prominent Italian physiologist
of the 19th century, had ingeniously monitored the pulsations of the brain
in adults through neurosurgically created bony defects in the skulls of
patients. He noted that when his subjects engaged tasks such as
mathematical calculations the pulsations of the brain increased locally. Such
observations led him to conclude, presciently, that blood flow to the brain
followed function [7]. The actual physiological relationship between brain
function and blood flow was first explored in 1890 by Charles Roy and
Charles Sherrington [8].
Despite this promising beginning, interest in the relationship between brain
function and brain blood flow almost ceased during the first quarter of the
20th century. Undoubtedly, this was owing, in part, to a lack of tools
sufficiently sophisticated to pursue this line of research. In addition, the
work of Leonard Hill, Hunterian Professor of the Royal College of Surgeons
in England, was probably influential [9]. His eminence as a physiologist
overshadowed the inadequacy of his own experiments that wrongly led him
to conclude no relationship existed between brain function and brain
circulation.
There was no serious challenge to Leonard Hill’s views until a remarkable
clinical study of a patient Walter K. was reported by John Fulton in the 1928
issue of the journal Brain [10]. During the course of his evaluation and
treatment for a vascular malformation lying over his visual cortex, Walter
K. remarked to his physicians that a noise (i.e. bruit) that he perceived in
the back of his head increased in intensity when he was using his eyes. He
said that he had often noticed this during the proceeding several years but
had ‘never thought much of it’. As Fulton commented, ‘It was not difficult
to convince ourselves that when the patient suddenly began to use his eyes
after a prolonged period of rest in a dark room, there was a prompt and
noticeable increase in the intensity of his bruit. Activity of his other sense
organs, moreover, had no effect upon his bruit.’ The conclusion drawn from
this remarkable case was that blood flow to visual cortices was sensitive to
the attention paid to objects in the environment.
It was not until the close of World War II that Seymour Kety and his
colleagues (University of Pennsylvania and National Institutes of Health)
opened the next chapter in studies of brain circulation and metabolism. Kety
developed the first quantitative method for measuring wholebrain blood
flow and metabolism in humans [11]. Because their measurements were
confined to the whole brain they were not suitable for ‘brain mapping’.
However, their introduction of an in vivo tissue autoradiographic
measurement of regional blood flow in laboratory animals [12,13] provided
the first glimpse of quantitative regional changes in blood flow in the brain
related directly to brain function. Derivatives of this technique many years
later became important for the measurement of blood flow in humans when
PET provided a means of quantifying the spatial distribution of radiotracers
in tissue without the need for invasive autoradiography (see later).
Following on the heels of the work by Kety and colleagues, David Ingvar
(University of Lund, Sweden), Neils Lassen (University of Copenhagen,
Denmark) and their Scandinavian colleagues introduced methods
applicable to humans that permitted regional blood-flow measurements to
be made using scintillation detectors arrayed like a helmet over the head.
They demonstrated conclusively that brain blood flow changed regionally
in normal human subjects during task performance (for a summary of their
early work see Ref.
Metabolism
Until 1986 it was thought that behaviorally induced increases in local blood
flow were the direct consequence of an increase in the brain’s need for
oxygen to metabolize glucose to carbon dioxide and water for the
production of energy [15]. Based on this hypothesis, functionally induced
increases in blood flow should be accompanied by quantitatively similar
changes in oxygen consumption with no change in the ratio of oxy- to
deoxyhemoglobin. Although widely held, this hypothesis was based on
rather scanty data [16]. Furthermore, it ignored much earlier work by Ray
Cooper and colleagues (Burden Neurological Institute, Stapelton, Bristol,
UK) [17]. Cooper recorded oxygen availability in the human cortex in
patients undergoing evaluation for epilepsy while their subjects performed
various cognitive and motor tasks. They clearly showed taskinduced focal
increases in oxygen availability signifying that blood flow had increased
more than oxygen consumption (recordings by Cooper are hard to
distinguish from today’s task-induced fMRI blood oxygen-level-dependent
[BOLD] time–activity curves [17]).
Conventional wisdom was seriously challenged by much more substantial
quantitative data from PET [18,19]. These data (Figure 2a), derided at the
time by the established figures in the field as untrue because they violated
conventional wisdom, demonstrated conclusively that functionally induced
increases in blood flow in normal humans were not accompanied by
changes of similar magnitude in oxygen consumption. The increase in
glucose utilization also increased significantly more than would have been
predicted by the increase in oxygen consumption. Although the degree to
which oxygen consumption increases has varied across experiments [18–
22], it has always been significantly less than that predicted by the increase
in either the blood flow or the glucose utilization when these variables are
measured reliably by validated methods. The resulting fall in
deoxyhemoglobin, which was known from much earlier work to be
paramagnetic [23] (Box 1), was to have clear implications for the
interpretation of fMRI based on deoxyhemoglobin as an in vivo MRI
contrast agent (see later).
Functional brain imaging with PET or fMRI is based on changes in brain
circulation and metabolism that are associated with activity changes in both
neurons and astrocytes. The profile of these changes was first detailed by
PET (a), which showed that activity increases, in this case evoked by
stimulation of the visual cortex by a reversing annular checkerboard, consist
of increases in blood flow (49%) and glucose utilization (21%) that far
exceed that of oxygen utilization (5%) (images adapted from Ref. [19]). As
a result, the amount of oxygen available in the brain increases (supply
increases relative to demand) causing the relative percentage of
deoxyhemoglobin (a paramagnetic substance; Box 1) to decrease. The fMRI
signal arises because of this change in the relative amount of
deoxyhemoglobin (Hb). As shown in part (b), veins containing Hb (dark
areas on the upper image) disappear when the animal is breathed on 100%
oxygen (lower image) (original experimental data from Ogawa and
colleagues [43]). In the human fMRI experiment (c), Hb is decreased
because blood flow increases more than oxygen consumption as in part (a)
leading to an enhanced signal portrayed here as a localized increase in the
fMRI BOLD signal.
X-ray computed tomography
In 1971 Godfrey Hounsfield introduced X-ray computed tomography (or
CT as it is now called) at Atkinson Morley’s Hospital in London. In creating
CT, Hounsfield had arrived at a practical solution to the problem of creating
three-dimensional trans axial tomographic images of an intact object from
data obtained by passing highly focused X-ray beams through the object
and recording their attenuation. Hounsfield’s invention received enormous
attention and quite literally changed the way in which we looked at the
human brain. Gone, also, were difficult to interpret, unpleasant and
sometimes dangerous clinical techniques such as pneumoencephalography
(Box 2). CT was, however, an anatomical tool. Function was to be the
province of PET and MRI.
Deoxygenated hemoglobin
Deoxygenated hemoglobin as found in veins disrupts a magnetic field
whereas oxygenated hemoglobin as found in arteries does not. This results
from the fact that deoxygenated hemoglobin behaves like a little magnet
when in a magnet field owing to the presence of exposed iron in the
hemoglobin molecule. The presence of oxygen ‘neutralizes’ the effect of
the iron such that oxygenated blood can be present in a magnetic field
without disrupting it. Because of this property, deoxyhemoglobin is referred
to as paramagnetic. Its presence in larges veins in the resting state make the
veins stand out as dark lines (i.e. signal dropout; Figure 2b).
Pneumoencephalography
A technique used by neurologists and neurosurgeons until the advent of X-
ray CT to localize mass lesions such as tumors and blood clots in an around
the brain. The technique consisted of removing spinal fluid and replacing it
with air, which would rise in the remaining spinal fluid like air bubbles in
water into the brain ventricles and over its surface when the patient was in
an upright position. The patient was then manipulated in space while
strapped into a specially mounted chair facilitating the movement of the air
bubbles. X-rays were taken in various positions enabling clinicians to
‘outline’ the contours of the brain. Great skill was required to interpret these
X-rays and, for the patient, this was most unpleasant because of the
attendant severe headaches.
Positron emission tomography
PET derives its name and its fundamental properties from a group of
radionuclides (15O, 11C, 18F and 13N), whose properties include short
half-lives (15O = 2 min, 13N = 10 min, 11C = 20 min and 18F = 110 min),
a unique decay scheme involving the emission of positrons and chemical
properties whose relevance to studies in biology and medicine arises from
the fact that carbon, nitrogen and oxygen are the building blocks of most
biological molecules and fluorine can be substituted for hydrogen in some
molecules (for a review of PET fundamentals see Ref. [24]).
The use of radiopharmaceuticals labeled with positronemitting
radionuclides for biomedical research and clinical application had been the
objective of several research groups. The first medical cyclotron was
installed in the Hammersmith Hospital in London in 1955 and was followed
by installations at the Massachusetts General Hospital and Washington
University’s Mallinckrodt Institute of Radiology in 1965. By 1974 there
were 15 such installations worldwide [25]. Work among these groups
provided much important background knowledge for the introduction of
PET (for reviews, see Refs [26–28]).
A group of investigators at Washington University’s Mallinckrodt Institute
of Radiology were inspired by the introduction of X-ray CT. They were
working with radiopharmaceuticals labeled with positron-emitting
radionuclides with a focus on studies of the brain. They realized that if an
image of the density of a transverse section of the body could be
reconstructed from the measured attenuation of highly-focused X-ray
beams projected through the section (i.e. the basis of X-ray CT), then the
distribution of a radionuclide within the section (especially ones that
decayed by positron emission) could be accurately and quantitatively
reconstructed from its emissions (interestingly, this idea was first suggested,
but not implemented, in 1951 [29]). A flurry of activity ensued resulting in
the design and construction of a positron emission tomograph christened
PETT (positron emission transaxial tomography) [30,31]. The term
‘transaxial’ was later dropped to make it simply PET as we know it today.
Metabolism versus blood flow
Work on the neural correlates of human behaviors with PET began with
studies of brain glucose metabolism and the tracer 18F-2-fluoro-2-deoxy-
D-glucose (FDG). This was an extension of the autoradiographic
deoxyglucose technique (Box 3) developed by Sokoloff and his colleagues
(National Institutes of Health) for studies in laboratory animals [32].
Sokoloff had demonstrated the sensitivity of this technique to functional
changes in neuronal activity in a wide-ranging group of animal experiments
(for an excellent early summary see Ref. [33]).
With FDG PET, 30–40 min was used typically for image acquisition.
Because of this long data-acquisition time, functional brain mapping as we
know it today would not have developed. Needed were speed of data
acquisition and measurement repeatability to assess brain function. Because
of this, blood flow became the technique of choice with PET because it
could be measured quickly (<1 min) using an easily produced
radiopharmaceutical (H215O) whose short half life (123 s) enabled repeat
(up to 12) measurements in the same subject.
Magnet resonance imaging
Finally, another technology emerged contemporaneously with PET and CT.
This was MRI. MRI is based upon yet another set of physical principles
associated with the behavior of atoms in water (often described by their
nuclei or protons) in a magnetic field. When placed in a strong magnet field,
these protons behave like tiny bar magnets by lining up in parallel with the
magnet field. When these protons are disturbed from their equilibrium state
by radio frequency pulses, a voltage is induced in a receiver coil that can be
characterized by its change in magnitude over time. Because these time-
dependent changes in voltage are a function of the local environment of the
protons, many important deductions can be made about the tissue being
examined.
The physical principles associated with MRI were discovered
independently by Felix Bloch (Harvard University) and Edward Purcell
(Stanford University) and his colleagues in 1946 (for detailed early reviews
of this work see Refs [34,35]). Many years of research followed, in which
the technique was used for basic research in chemistry. During this time it
was known as nuclear magnetic resonance (NMR).
In 1973, Paul Lauterbur [36] came up with a strategy in which the NMR
signals could be used to create cross sectional images in much the same
manner as CT (for a review, see Ref. [37]). Interest was immediate not only
because the technique was free of any ionizing radiation but also because it
produced superb images of the human body with much greater detail and
variety than CT because of its sensitivity to soft tissues. Although imaging
with this technique initially retained the name nuclear magnetic resonance
or NMR, it was changed after a short time to magnetic resonance imaging
or MRI to eliminate the term ‘nuclear’, which some thought might detract
from its clinical acceptance.
Although clinical imaging with MRI flourished after its introduction, there
also existed in the scientific community the knowledge that MRI could also
tell us much about tissue chemistry, perfusion and metabolism. This view
was the result of many years of basic NMR research indicating that intrinsic
signals from tissue in addition to signals from exogenously administered
MRI contrast agents could be used to extract such information. Functional
brain imaging with MRI was able to tap this knowledge base with
remarkable results. It was an interesting convergence of research in MRI
techniques, studies of the magnetic properties of deoxyhemoglobin and
research on circulatory and metabolic correlates of changes in brain activity
(see earlier) that led to the development of this approach.
The emergence of functional MRI
A important first step in the development of fMRI was the work of group
of researchers at the Massachusetts General Hospital working on the use of
exogenously administered MRI contrast agents designed to produce
transient changes in the MRI image as the agent passed through the brain
after its intravenous administration. Work in rodents [38] and dogs [39]
using contrast agents confined to the vascular compartment and novel rapid
data acquisition strategies demonstrated for the first time with MRI that it
was possible to measure changes in brain blood volume produced by
physiological manipulations of brain blood flow. This approach was
extended to normal human volunteers for task activation brain mapping by
the same group in 1991 [40] in a much heralded study demonstrating for the
first time that MRI was to be a serious player in the functional mapping of
the human brain.
This study caused much excitement, especially in the MRI community,
which was anxious to join the rapidly expanding cognitive neuroscience
revolution. What this study demonstrated clearly was that, within one
imaging modality, superb anatomical images and physiology relevant to
brain function could be combined. The primary limitation of the approach
was the need to administer a contrast agent, which is something that could
only be done a limited number of times. However, physiology (Figure 2a)
and the ingenuity of the MRI researchers came to the rescue. The answer
came from the property of deoxyhemoglobin in a magnetic field.
It was Michael Faraday who first studied the magnetic properties of
hemoglobin. In experiments on the 8 November 1845 he noted (to his
surprise because hemoglobin contains iron) that dried blood was not
magnetic, writing ‘Must try fluid blood’ [41]. Remarkably, 91 years later
his obscure laboratory note somehow caught the attention of Linus Pauling
and Charles Coryell [23] who found that the magnetic susceptibilities (i.e.
the ability to interact with a magnetic field) of oxygenated and
deoxygenated hemoglobin differed significantly. Deoxyhemoglobin was
paramagnetic and, hence, equivalent to an MRI contrast agent, whereas
oxyhemoglobin was not (Box 1). Of course, the role of this observation in
the development of fMRI did not occur to Pauling and Coryell.
In 1982, Keith Thulborn took the story one step further while seeking to
exploit the difference in magnetic susceptibility of oxy- and
deoxyhemoglobin for the measurement of brain oxygen consumption with
MRI [42]. In this often overlooked work he clearly demonstrated the
feasibility of measuring the state of oxygenation of blood in vivo with MRI,
another crucial step on the road to fMRI BOLD imaging as we know it.
Experiments performed by Sieji Ogawa and colleagues (AT&T Bell
Laboratories) were a crucial next step in establishing the basis of fMRI
BOLD imaging. In their experiments, the concentration of deoxygenated
blood in the brains of living rodents was manipulated by alternately
breathing his animals on room air and 100% oxygen. On room air, detailed
anatomy of venules and veins were easily visible throughout the rat brain as
dark structures (Figure 2b). This was owing to the loss of MRI signal in the
presence of deoxyhemoglobin (Box 1). On 100% oxygen, the venous
structures disappeared. Ogawa labeled his finding ‘blood oxygen level
dependent contrast’ or BOLD contrast [43] and noted that ‘BOLD contrast
adds an additional feature to magnetic resonance imaging and complements
other techniques that are attempting to provide positron emission
tomography-like measurements related to regional neural activity’ [43].
The potential of BOLD fMRI was soon realized (Figure 2c) with
publications from three groups in 1992 [44–46]. The events leading up to
these publications (particularly from the group at the Massachusetts General
Hospital led by Ken Kwong [44] and the group that represented the
combined resources Sieji Ogawa and David Tank from the AT&T Bell
Laboratories and Kamil Ugirbil, Ravi Menon and their colleagues at the
University of Minnesota [46]) provide insight into how the research actually
unfolded. Space here does not permit a detailed recounting of these
fascinating events. Interested readers might wish to read a more detailed
account, based on my interviews with the key participants [47].
Since the introduction of fMRI BOLD imaging, the growth of functional
brain imaging has been nothing short of spectacular. Although MRI also
offers additional approaches to the measurement of brain function [44,48],
it is BOLD imaging that has dominated the research agenda thus far.
However, the success of the human brain imaging was the product not only
of relevant physiology that could be imaged and the scanning devices that
could accomplish this but also of the behavioral paradigms that approached
human behavior in a principled and quantitative manner while
accommodating the constraints of the imaging environment and strategies
to process the resulting data. I turn to these important issues next.
Stereotaxy
As PET images of task-induced changes in regional blood flow started to
accumulate, an old problem resurfaced. How do you objectively relate
functional imaging data to brain anatomy? This problem was neither new to
functional brain imaging with PET nor previously unexplored.
The solution came in the form of a technique called ‘stereotaxy’, which was
first developed by Horsley and Clarke for animal research in 1908 and much
later applied by to humans by neurosurgeons (for additional details see Ref.
[47]). Stereotaxy in humans is usually based on the assumption that all
points in the cerebral hemispheres of an individual have a predictable
relationship to a horizontal plane running through the anterior and posterior
commissures. Acquiring specific measurements of an individual brain,
obtained from a skull X-ray [49], CT, MRI or even a PET blood-flow image
[50], permits an exact relationship to be established with a ‘standard’ brain
in one of the stereotaxic brain atlases.
Although continuing to be modified and refined, this strategy has remained
a central feature of all functional brain imaging in humans. Interesting
recent advances have included the development of a probabilistic brain atlas
by an international consortium of researchers [51] and surface-based
coordinate systems of the human cerebral cortex [52].
Image averaging
The initial use of stereotaxy in PET functional brain imaging was to
determine the location of activity changes. This approach worked nicely for
robust responses that could be appreciated in individual difference images
(Figure 2a). However, other early experiments yielded data in which the
responses were not robust, were varied from subject to subject in location
and were easily confused by what was being termed image ‘noise’. These
data were proving to be problematic and generated much concern. Most
worrisome was the observation that, after conversion of a response focus
from an individual difference image into stereotaxic space, there remained
considerable variability in the location of the responses across individuals.
In response to these problems and concerns, an effort was mounted at
Washington University to obtain averages of difference images across
subjects in a standard stereotaxic space. The wisdom of this effort was not
universally embraced by members of the laboratory. The skeptics
maintained that individual variability was simply too great to accommodate
averaging. The skeptics predicted that averaged images would be just
‘mush’.
When the first set of averaged blood-flow images from a group of five
subjects receiving somatosensory stimulation of one hand came up on the
monitor, it was obvious to everyone present that they were neither
unrecognizable nor ‘mush’. Noise was dramatically reduced and responses
were crisp and clear [53]. Skepticism vanished instantly. The processing of
functional brain images had taken an important step forward. From PET on
to fMRI, averaging in one form or another both across and within
individuals, is a key element in the processing of functional image data.
Statistical analysis
With the aforementioned strategies in hand (i.e. stereotaxic normalization,
image averaging), investigators using PET were suddenly confronted with
yet another challenge: images containing enormous amounts of data. The
specter of unacceptably high false discovery rates loomed large without an
obvious remedy. One obvious approach would have been to place
independently determined regions of interest within difference images to
test specific hypotheses about how the task under investigation was
instantiated in the brain (i.e. traditional hypothesis testing). One important
drawback to this approach was that it assumed the very knowledge that was
being sought, namely, how the brain is organized. What was needed was a
hypothesis generating approach.
Many of the details of how these uniquely challenging statistical questions
were addressed are now of historical interest only (for more details see Ref.
[47]). Statisticians, statistically minded neuroscientists and others quickly
found the problems inherent in the analysis of functional brain images from
PET and MRI stimulating and challenging (for a review, see Ref. [47]).
From these important beginnings the approaches have become increasingly
sophisticated, varied and powerful.
The behavioral agenda
The study of human cognition with PET was aided greatly by the
involvement of cognitive psychologists in the 1980s whose experimental
designs for dissecting human behaviors using information-processing
theories fit extremely well with emerging functional brain-imaging
strategies [54]. It might have been the combination of cognitive psychology
and systems neuroscience with brain imaging that lifted this work from a
state of indifference and obscurity in the neuroscience community in the
1970s to its current role of prominence.
This strategy was based on a concept introduced by the Dutch physiologist
Franciscus C. Donders in 1868 (reprinted in Ref. [55]). Donders proposed
a general method to measure thought processes based on a simple logic. He
subtracted the time needed to respond to a light (say, by pressing a key)
from the time needed to respond to a particular color of light. He found that
discriminating color required 50 ms. In this way, Donders isolated and
measured a mental process for the first time by subtracting a control state
(i.e. responding to a light) from a task state (i.e. discriminating the color of
the light). This strategy was first fully implemented in an early series of
papers on single-word processing [56,57] (Figure 3). Since then, it has been
exploited with exponentially increasing sophistication in the functional
imaging world.
Although much that is currently being done with fMRI can be viewed as a
logical extension of work with PET, one addition to the fMRI
armamentarium represented a truly unique and important advance in the
way in which functional brain imaging was done. This was the introduction
of single-trial or event-related fMRI [58–61]. When the cognitive
subtraction strategy was implemented, cognitive psychologists had to
abandon their traditional mixed-trial design in which the properties of
stimuli were varied within a single trial. PET imaging even with blood flow
was too slow to measure responses to individual stimuli with any accuracy.
fMRI, however, was quite capable of doing so. As with other aspects of
imaging, single-trial fMRI has advanced rapidly in terms of sophistication.

Iconic PET blood-flow-difference images obtained from an early study of

the processing of single words [57], in this case common English nouns.
This was one of the first studies to combine a hierarchical task design (visual
fixation – hearing or seeing nouns – speaking nouns – generating verbs)
with image subtraction, cross-subject image registration and averaging. It
established a basic paradigm for this type of work that has persisted to the
present.
The present
It is easy to be optimistic about the human brain-mapping agenda. Its
growth, particularly since the advent of fMRI BOLD imaging, has been
dramatic. However, challenges do arise because of the immense diversity
of this agenda. Neuroscientists interested in brain function from a cellular
and molecular perspective now are obliged to understand not only the
concepts and strategies of cognitive psychology but also a wide array of
behavioral disciplines covered under the rubric of social neuroscience
[62,63]. At the same time, behavioral scientists interested in relating their
work to the brain are confronted by a rapidly increasing body of knowledge
concerning the biological correlates of functional neuroimaging signals.
Understanding this work depends on complex concepts not only from
neurophysiology [2,6] but also from theoretical neuroscience [64,65], cell
biology [1] and even genetics [66]. The complexity of all of this increases
when issues related to disease are introduced as they are with increasing
frequency. It is easy to understand, then, how researchers at all levels
occasionally feel a sense of unease in dealing comprehensively with this
agenda. Under such circumstances, it is tempting to retreat into the narrow
confines of one’s own area of expertise; a pathway, however, that will
ultimately limit the potential of one’s work.
The future
As we look to the future, changes clearly appear on the horizon. It might be
too strong to suggest that we are facing a paradigm shift [67], but certainly
some reorientation is taking place in terms of how we understand brain
function. Although this reorientation has received substantial stimulation
from imaging work with PET and fMRI, it has its roots in more than a
century of discussions on the nature of brain functions.
A comparison of activity decreases during the performance of goal directed
tasks (a) in the default network [77] and coherent activity within the same
network in the resting state derived from spontaneous fluctuations in the
fMRI BOLD signal (see Ref. [73] for further details). Performance of a wide
variety of tasks has called attention to a group of brain areas (a) that
decrease their activity during task performance (data adapted from Ref.
[78]). This particular group of brain areas has come to be known as the
‘default network’ and serves as an exemplar of all areas of the cerebral
cortex that exhibit a systems level organization in the resting (default) state
[73]. If the spontaneous fMRI BOLD signal activity in these areas is
recorded [arrows in part (a)] in the resting state, what emerges is a
remarkable correlation in the spontaneous fluctuations of the fMRI BOLD
signals obtained from the two areas (b). Using these fluctuations to analyze
the network as a whole [73] reveals a level of functional organization (c)
that parallels that seen in the task-related activity decreases (a). These data
provide a dramatic demonstration of the intrinsic organization of the human
brain, which is likely to provide a crucial context for all human behavior in
health and disease. These data were adapted from our earlier published work
[79].
Since the 19th century, and possibly longer, two perspectives on brain
functions have existed (an excellent introduction is to be found in chapter 1
of Ref. [68]). One view posits that the brain is primarily driven by external
inputs; the other holds that the brain operates on its own, intrinsically, with
sensory information interacting with rather than determining its operation.
Although neither view is today dominant, the former clearly has motivated
the majority of research at all levels of neuroscience including that in
cognitive neuroscience. This is not entirely surprising given the enormous
success of experiments measuring brain responses to controlled stimuli.
From a cost-based perspective, however, intrinsic activity seems to be far
more important than evoked activity in terms of overall brain function.
Studies of the actual changes in energy consumption associated with evoked
changes in brain activity have revealed that the additional energy required
for such brain responses represents an extremely small percent (1.0%) of
the ongoing energy consumption (for a review, see Ref. [1]). Furthermore,
converging data indicate that 60–80% of the ongoing energy consumption
reflects work associated with the input and output of neurons (for a review,
see Ref. [1]). From this perspective it seems fair to conclude that a large
fraction of the functional activity of the brain is unaccounted for [69]. What
do we know about the organization of this activity from an imaging
perspective?
PET provided an initial clue in the form of highly organized activity
decreases during the performance of most goal-directed behaviors. This led
to the concept of an organized default mode of intrinsic brain function [70]
and the identification of a unique network of brain areas that typified this
organization (i.e. the default mode network of the brain; Figure 4a; for a
recent review of its functional importance see Ref. [71]). More recently, it
was discovered by Biswal and colleagues [72] that the ‘noise’ in the fMRI
BOLD signal in the frequency range below 0.1 Hz reflects spontaneous
fluctuating neuronal activity (for a recent review, see Ref. [73]). This
activity exhibits striking patterns of coherence within known brain networks
in the absence of observable behaviors (Figure 4c). Future work in
functional brain imaging using this approach is most exciting to anticipate.
Finally, a too often overlooked feature of brain-imaging signals is the
presence of aerobic glycolysis (Figure 2a). Aerobic glycolysis is present in
the resting state [74,75] and, when looked for, is observed to increase locally
with increases in activity [19,22,76] (Figure 2a). The many unique
contributions of glycolysis to such things as protein phosphorylation;
membrane, DNA and RNA synthesis; and the brain’s redox state are
routinely overlooked when its importance is assessed solely on the basis of
the amount of energy it provides (only 2 ATP versus 30 ATP for oxidative
phosphorylation). As we seek to enrich our understanding of brain-imaging
signals in the context of such important processes as learning, memory and
development, understanding the role of glycolysis independent of its role in
oxidative phosphorylation probably will be most informative.
Functional neuroimaging: a brief overview and
feasibility for use in chiropractic research
There is a need to further our understanding of the neurophysiological
effects of chiropractic spinal manipulation on brain activity as it pertains to
both musculoskeletal and non-musculoskeletal complaints. This paper aims
to provide a basic overview of the most commonly utilised techniques in
the neurosciences for functional imaging the brain (positron emission
tomography, single-photon emission computerized tomography, functional
magnetic resonance imaging, electroencephalography, and
Magnetoencephalography), and discuss their applicability in future
chiropractic research. Functional neuroimaging modalities are used in a
wide range of different research and clinical settings, and are powerful tools
in the investigation of neuronal activity in the human brain. There are many
potential applications for functional neuroimaging in future chiropractic
research, but there are some feasibility issues, mainly pertaining to access
and funding. We strongly encourage the use of functional neuroimaging in
future investigations of the effects of chiropractic spinal manipulation on
brain function.
Introduction
Chiropractic research to date has mostly been concerned with various
aspects of low back pain, neck pain, and headaches.1 However, a number
of chiropractic patients are receiving chiropractic care and reporting
improvements for other non-musculoskeletal complaints.2,3 Indeed, some
of the complaints are conditions and disorders that are closely associated
with the function of the brain, including such as autistic spectrum disorder
(ASD), depression and attention deficit hyperactivity disorder (ADHD).
Although there is anecdotal evidence that suggest chiropractic spinal
manipulation (SM) can be beneficial for some of these patients, the nature
of SM effects on these conditions and complaints are by and large poorly
investigated.4 Unfortunately, undisciplined rhetoric from some
practitioners promulgating unsupported claims of benefit from SM has
occurred based on these preliminary and limited studies. Such speculation
is unwarranted and casts chiropractic in a poor light with other disciplines.
Chiropractic SM has been shown to induce a barrage of mechanoreceptive
afferent input, originating mainly from paraspinal muscle spindle receptors
and Golgi tendon organs.5 Such afferent input has been shown to modulate
local spinal cord neurophysiology affecting both pain processing and the
motor control system. In a study by Terrett and Vernon6 it was
demonstrated that SM caused a reduction in pain sensitivity. An increase in
paraspinal electromyography (EMG) activity was found in asymptomatic
subjects following cervical, thoracic, lumbar and sacroiliac SM.7 Murphy,
Dawson and Slack8 demonstrated a decrease in the H-reflex from the tibial
nerve following sacroiliac SM in asymptomatic subjects. Attenuation of
motor neuron activity following both cervical and lumbar spine SM has also
been demonstrated.9,10 Furthermore, modulation of local spinal cord
neurophysiology can cause a change to the afferent arm of the
somatovisceral reflex, however it is likely that supraspinal influences play
a major role in this effect.
Limited evidence suggests chiropractic SM can induce changes in the
central nervous system (CNS) above the level of the spinal cord.12,13
Indeed, a few case studies have used objective neurophysiological
measurement tools, such as electroencephalography (EEG), to evaluate
changes in CNS neural activity following SM.14–16 In a recent pseudo-
randomised study using EEG technology (somatosensory evoked
potentials[SEP]), Haavik-Taylor and Murphy17 demonstrated that
chiropractic SM can indeed modulate sensorimotor integration in the CNS.
However, little other objective neurophysiological evidence is available.4
This manuscript aims to: (i) provide a basic overview of the most commonly
utilised techniques used for imaging in neurosciences, namely functional
magnetic resonance imaging (fMRI), positron emission tomography (PET),
single-photon emission computerised tomography (SPECT),
electroencephalography (EEG), and magnetoencephalography (MEG); (ii)
discussing how functional neuroimaging might serve the profession in
investigations of the supraspinal effects of chiropractic SM; and (iii)
discussing the feasibility of utilising functional neuroimaging in future
chiropractic research. The different modalities will be presented in terms of
necessary equipment and facilities, the degree of invasiveness, spatial
resolution, and temporal resolution.
The electronic database MEDLINE was searched from 1997 to present for
literature concerning functional neuroimaging techniques. Although many
different technologies are available, some of which with several
applications, this paper is limited to the neuroimaging techniques mentioned
above and their utilization in investigating brain activity.
Discussion
In the human brain, elevated neural activity increases the local neuronal
metabolic demand, and regional synaptic activity correlates with neuronal
glucose utilisation and subsequent changes in cerebral blood perfusion.18
However, the traditional view that glucose consumption directly reflects
neural activity has recently changed.19 Kasischke et al20 have shown that
neurons preferentially metabolise lactate rather than glucose, and that
astrocytes, a type of glial cell in the brain, respond to neuronal activity by
consuming more glucose as well as producing more lactate. Consequently,
imaging based on glucose consumption primarily reflects astrocytic activity
rather than neuronal activity. However, the activation of both cell types is
correlated in the majority of cases.21 Hence, an indirect measure of the
underlying neural activity can be obtained by measuring the haemodynamic
response.
Positron emission tomography (PET)
PET typically measure regional cerebral blood flow (rCBF) or regional
cerebral metabolic rate of glucose (rCMTG), using radioactively labelled
molecules (tracer molecules), which are usually injected intravenously or
continuously inhaled by the patient or research participant. 19,22,23 See
Figure 2 for a schematic diagram of a PET scanner. Positron-emitting
radioisotopes of carbon, nitrogen, oxygen, and fluorine are commonly used
in these tracer molecules, and a variety of data may be obtained with these
different tracer molecules.24 A particle accelerator (cyclotron) is required
to produce the radioisotopes used in PET imaging, and it has to be in close
proximity to the PET scanner due to the short radioactive half-life of the
radioisotopes.24 The cyclotron contributes significantly towards the higher
acquisition cost of a PET system compared to the other modalities.
Furthermore, the comparatively high operating cost of PET can be
attributed to the production of expensive tracers.
Temporal resolution refers to how closely the measured activity
corresponds to the timing of the actual neuronal activity.22 The temporal
resolution with PET is poor compared to both fMRI, EEG and MEG, and is
limited by both the technique and the metabolism of the tracer molecule.22
Spatial resolution refers to how accurately the measured activity is localised
within the brain.22 The spatial resolution of PET is good, but it depends on
several different factors pertaining to the characteristics of various
components of the PET camera, in particular the size and material of the
scintillating crystal used in the coincidence detectors, and the number of
detector rings.25 Figure 3a depicts a modern PET system.
An individual typically absorbs 0.5 to 2 mSv (milli- Sieverts) of radiation
per PET study.23 This is comparable to diagnostic imaging, for example an
anterior to posterior (AP) lumbar spine x-ray or a whole head CT scan,
which have effective doses of typically 0.7 mSV and 2 mSv, respectively.26
The reader is referred to Wintermark et al23 for a more thorough discussion
of PET.
Comparison of spatial and temporal resolutions. The area occupied by the
boxes represents the spatial and temporal resolutions of the respective
functional neuroimaging technique. The shading of the boxes represents the
degree of invasiveness of each modality, darker shading indicates higher
invasiveness.

Schematic diagram of a single ring detector of a PET camera. When an

emitted positron comes in contact with an electron, they annihilate each
other and produce two photons (-rays) travelling in opposite directions. The
PET camera employs paired gamma detectors linked in a coincidence
circuit that only records decay events when photons trigger both detectors
“simultaneously.” Coincidence detection can be localized to the line
connecting a pair of isolated detectors.
Single-photon emission computerised tomography (SPECT)
SPECT detects neuronal activity indirectly by measuring changes in
rCBF.19 Similar to PET, SPECT generates tomographic images of the three
dimensional distribution of a radioisotope.23 However, the radioisotopes
utilised in SPECT have more advantageous radioactive half-lives and decay
to directly emit gamma rays.18 Nevertheless, the typical effective radiation
dose in SPECT is considerably higher compared to PET.23 Repeated
scanning with both PET and SPECT is usually restricted because the
participants are exposed to radiation, thus limiting task repetitions or
multiple tasks in the same session.
SPECT cameras are either rotating cameras, comparable to x-ray computed
tomography (CT) systems (except that the emitting source is within the
patient and the type of radiation is gamma rays), or detector rings similar to
those in PET. Figure 3b depicts a modern SPECT system. SPECT systems
using multiple detector-rings are designed to maximise the number of
detectors recording activity from the brain, and can achieve a reasonably
good spatial resolution.23 Less expensive detector cameras and no need for
a cyclotron are responsible for making the acquisition of a SPECT system
more affordable than a PET system. SPECT is dependent on the
haemodynamic response and sufficient detection of photon emissions, and
has therefore relatively poor temporal resolution. The spatial resolution of
SPECT is fairly good, albeit not quite that of PET. The reader is referred to
Wintermark et al23 for a more in-depth presentation of SPECT.
Functional magnetic resonance imaging (fMRI)
Functional MRI relies on detecting small changes in the signals used to
produce magnetic resonance images.27 There is no need to introduce
radioisotopes in fMRI as the iron in the blood haemoglobin serves as an
inherent intravascular contrast agent.18 This is possible due to the fact that
deoxygenated haemoglobin has greater magnetic susceptibility as compared
with tissue and oxygenated haemoglobin. The balance of oxygenated and
deoxygenated haemoglobin in the blood is blood oxygenation level
dependent (BOLD), and changes in blood oxygenation occur as a
consequence of neuronal activity.28 The main limitation of fMRI arise from
the vascular origin of the signal changes, hence, a temporal resolution of no
better than 2 to 5 seconds can be expected with BOLD-fMRI.24
Conventional MRI scanners utilise a large superconductive magnet capable
of generating the strong magnetic field (1.5 T or above) necessary in MRI
procedures.24 Figure 3c depicts a modern MRI system. As the signal
intensity increases with the magnetic field strength, many fMRI researchers
are turning to scanners of 3 T or greater to improve spatial resolution.24
Newer techniques and stronger magnets are expected to enable researchers
to identify structures in the submillimeter range.29 Thus, fMRI is
considered to have the best spatial resolution among the functional
neuroimaging techniques.18,22 The operating costs of fMRI are more
reasonable than the nuclear imaging techniques (PET and SPECT). The
reader is referred to a review by Hennig et al30 for more information
regarding methodological aspects and clinical applications of fMRI.
In regards to the exposure to strong magnetic fields in fMRI, a few things
are worth noting. Although no known health risks are associated with MRI
scanning, induction of flow potentials around the heart, induction of ectopic
heart beats and an increased likelihood of re-entrant arrhythmia, have been
observed.33 Furthermore, induction of vertigo and nausea have been
observed during movement in static fields greater than 2 T.33 However,
movement is detrimental to the image quality in MRI, and every effort is
made to prevent movement to occur during MRI procedures. The main
concern with MRI scanning is the potential for movement or heating of
ferromagnetic objects in the body. This issue is resolved by excluding
participants with inserted pacemakers, surgical clips, or any other
ferromagnetic objects.22 Subjects are exposed to loud acoustic noise (100–
130 decibel, 1–4 kHz) with mechanical vibration during the typically 2 to
30 minutes it takes to acquire the necessary data.24,28,31 Earplugs that can
provide about 20–30 dB noise attenuation at these frequencies are therefore
commonly used in both functional and conventional MRI procedures.32
Electroencephalography (EEG)
EEG records changes in the electrical potentials generated by large
populations of synchronously active neurons. 34 Although electrical
activity can be measured directly from the cortical surface
(electrocortiography) or by using depth probes (electrography), this paper
will only refer to EEG recorded from the scalp surface. From its neuronal
source, current has to penetrate through skull, skin, and other layers, before
being detected by electrodes on the scalp.35,36 The spatial orientation of
neuronal populations, relative to the scalp surface, varies from radial in the
gyri to tangential in the sulci. EEG is sensitive to both tangential and radial
components of a current source, but seems to be dominated by radial
sources.34 See Figure 4 for an illustration of radial and tangential current
sources in the cerebral cortex.
EEG systems are relatively novel and consist of electrodes with conductive
media, amplifiers with filters, analogue to digital (A/D) converters, and
computer equipment for recording and signal processing.36 Thus, EEG
equipment can be acquired for only a fraction of the cost of the other
technologies. Figure 3d depicts the components of a modern EEG system.
Skin preparation of the scalp and the use of a conductive medium are usually
required to obtain appropriate conductance and lowering of contact
impedance at the electrode-skin interface.36 This is generally well
tolerated, but it may cause irritation, pain, bleeding, and infection,
especially when repeated EEG measurements are made from the same
electrode points.
EEG has an excellent temporal resolution of only a fraction of a millisecond
enabling brain activity to be recorded in real-time.37 Furthermore, with the
use of modern signal analysis methods the spatial resolution of EEG, which
often is considered as its biggest limitation, might in fact approach that of
conventional fMRI.39 The reader is referred to a recent review by Michel
et al39 for a discussion on various methods of signal analysis in EEG source
imaging.

Radial and tangential sources and their associated magnetic fields. The
electrical current source is indicated by an arrow, and its associated
magnetic field is indicated by a dashed line. (A) A radial current source
located in the gyrus of the cerebral cortex (radial source) has its associated
magnetic field oriented tangential to the scalp surface. (B) The magnetic
field associated with a current source located in the sulcus (tangential
source) is perpendicular to the scalp surface. Only tangential current sources
generate neuromagnetic fields detectable by MEG.
Magnetoencephalography (MEG)
MEG is a sophisticated non-invasive functional neuroimaging technique
that measures the external magnetic field generated by the neural activity of
the brain. Changes in the neuromagnetic field are a direct and instantaneous
reflection of neural events in the brain. In order to generate a neuromagnetic
field detectable by MEG sensors, large neuronal populations have to be
aligned tangentially to the scalp surface and be synchronously active.40 See
Figure 4 for an illustration of radial and tangential current sources and their
associated neuromagnetic fields. Thus, EEG and MEG provide a
complimentary detection of the electromagnetic activity of neuronal
networks in the brain.
The neuromagnetic field (approximately 10 to 103 fT) is several orders of
magnitude weaker than the ambient magnetic noise (approximately 108 fT
), which includes the earth magnetic field.34 Hence, both sufficient
magnetic shielding against external magnetic fields and exquisitely
sensitive equipment are required to measure the neuromagnetic field.
Enclosing the MEG system within a magnetically shielded room is the most
straightforward method for reduction of environmental noise.41 Different
enclosure approaches are available, including; shielding by eddy currents
using high-conductivity metal, shielded mu-metal rooms, and
superconducting shields.41 The equipment sensitivity is provided by a
device known as SQUID (Superconductiong QUantum Interference
Device), which is immersed in liquid helium, along with other components
and contained within a vacuum-insulated container (dewar).40 See Figure
5 for a schematic of an MEG dewar. Figure 3e depicts a modern MEG
system.
One of the most important features of MEG is that the technology provides
measurements with an excellent temporal resolution, allowing the recording
of neuronal activity in real-time.37 The spatial resolution of MEG is
reasonably good.34 Source localisation is less complicated with MEG than
with EEG because the tissues are transparent to the neuromagnetic field,
whereas knowledge of the tissue conductivity distribution is usually
required in EEG.41 Thus, MEG has traditionally been able to offer better
source localisation than EEG. Although the operational costs of MEG are
typically less expensive than fMRI, they are both significantly more
expensive than EEG. The reader is referred to Ioannides37 for a more
thorough discussion of MEG as a research tool.
Schematic diagram of a MEG dewar with SQUIDs. Detection coils are
placed tangential to the scalp surface. The detection coil “senses” the
neuromagnetic field and produce currents that are “transmitted” to the
SQUID by signal coils. The SQUID then “converts” the currents in the
signal coils to voltages that can be amplified and recorded by conventional
electronic devices.

Current use of neuroimaging techniques

Functional neuroimaging has many applications in the clinical setting, in
particular investigating cerebrovascular disorders (PET and SPECT),23
pre-surgical localization of cortical areas (PET, SPECT, MEG, EEG and
fMRI),23,30,42–43 and detecting the location of epileptic discharges
(MEG, EEG, PET and SPECT).23,35,44 To a lesser degree, PET is also
used in the localisation of brain tumours, and the investigation of dementia
and movement disorders.23 SPECT is used to confirm brain death by
assessing cerebral perfusion, and is also used for investigations in a variety
of psychiatric disorders such as, depression, post-traumatic stress disorder,
schizophrenia, and dementia.23 Indeed, an expanding body of clinical
evidence supports the value of using non-invasive functional neuroimaging
(MEG and EEG) with cases of attention deficit hyperactivity disorder,
autism, dyslexia, and epilepsy.4
In the research setting, functional neuroimaging has traditionally been used
in studies of brain activation, and for this purpose fMRI has to a large extent
replaced PET.23,30 The main reasons being fMRI: (i) does not involve
exposing participants to ionising radiation; (ii) offers superior spatial
resolution; (iii) has faster data acquisition time; and (iv) has a lower
operating cost per investigation. Nevertheless, PET (and SPECT) may still
be particularly helpful in the study of specific neurotransmitter- receptor
interactions due to the many tracers that can be utilised with these
technologies.
EEG, MEG and fMRI are used extensively by clinical researchers in both
basic and cognitive neuroscience, as well as in contemporary
psychophysiology.27,47–49 Theneural correlates of several psychological
and psychiatric disorders have been investigated, including, but not limited
to; ADHD,50 ASD,51 and depression.52 In addition to basic brain
activation studies, functional neuroimaging has a history of investigating
the effects of pharmaceuticals on psychiatric disorders.53 However, more
recently there have also been investigations into the effects of
psychotherapies in these disorders.53 An increasing number of
neuroimaging investigations involve topics important to rehabilitation, such
as investigations of the neural correlates of recovery after stroke and
determining the effects of treatment interventions.22,54 Similar
investigations have been conducted in patients with Parkinson’s disease,
multiple sclerosis and Alzheimer’s disease.54 Furthermore, the effects of
acupuncture on brain activity have also recently been investigated with
neuroimaging techniques.38 Neuroimaging research in fibromyalgia and
other chronic pain conditions without a known nociceptive source have
provided objective evidence of abnormal central regulation of pain.55
Nakabeppu et al56 observed decreased rCBFm in the thalamus in patients
with chronic pain using SPECT. Flor et al57 found extensive reorganisation
of the primary somatosensory cortex in patients with chronic low back pain,
using MEG. Further investigations are warranted to elucidate the
mechanism(s) by which SM benefit patients with these conditions.
Potential applications in chiropractic research
There is a need to investigate the effects of SM on brain activity and further
our understanding of the neurophysiological effects of chiropractic SM as
it pertains to both musculoskeletal and non-musculoskeletal complaints.
Increased knowledge of how the brain responds to SM will also further the
understanding and the development of chiropractic, and will therefore have
an impact on both chiropractors and their patients. Expanding evidence of
central neural changes with SM from basic science research may also
eventually extend the scope of practice as an increasing number of health
professionals may encourage and refer patients to chiropractors. Functional
neuroimaging modalities appear to be appropriate tools to obtain the
valuable information about how brain function is altered with chiropractic
care.
Investigating the effects of dysfunctional spinal motion segments on brain
function may seem like a natural place to start. However, the design of
appropriate experiments may be ethically challenging with human subjects,
and perhaps animal studies may be more appropriate initially. Bakkum et
al58 demonstrated in a study on cats that chronic vertebral hypomobility of
lumbar segments (surgically induced) resulted in plastic changes in the
spinal cord. This is for obvious reasons not feasible with healthy human
subjects. However, it may be possible to evaluate a cohort of patients
scheduled for spinal fusion before and after surgery using functional
neuroimaging. Alternatively, possible changes in brain activity may be
detected in animal studies using a similar experimental set-up used by the
beforehand mentioned study by Bakkum et al
In humans, documenting normative data from basic science studies whether
SM can change brain function would be a priority before investigations on
various clinical entities are undertaken. Different parameters of brain
function are of interest and should be investigated with regards to
magnitude, time-scale, distribution, and location of altered brain activity.
Various aspects of sensorimotor integration are of particular interest in
relation to musculoskeletal conditions. Indeed, recent studies by Haavik-
Taylor and Murphy17,59 using EEG have shown changes in sensorimotor
integration following cervical SM. Whereas these initial studies have used
electrical nerve stimulation to evoke electrical potentials detectable with
EEG, future investigations could perhaps use passive or active movement
to evoke electrical potentials and magnetic fields, which could be recorded
by EEG and MEG, respectively. Future studies should look beyond cervical
SM and include investigations of changes in sensorimotor integration in
relation to lumbopelvic SM. Furthermore, potential differences across
various types of SM could also be investigated. In addition, improvements
in reaction times following SM has previously been identified,12–13 and
further elucidation of changes in sensorimotor integration may be of interest
from both a sports chiropractic and athlete performance enhancement point
of view, as well as in the context of chiropractic care and fall prevention
strategies for the geriatric population. Furthermore, the effect of SM on
sensorimotor integration may also be investigated in relation to
neurodevelopmental disorders (e.g. ADHD, ASD and cerebral palsy),
which commonly display motor impairments. Functional neuroimaging
may help explain some of the improvements in patients with these
conditions receiving chiropractic care.
Another parameter worth investigating is central pain processing, and in
particular the potential modulation of central pain processing in patients
with chronic pain syndromes. Functional neuroimaging modalities could be
utilised to provide objective neurophysiological evidence of the efficacy of
chiropractic SM by measuring potential changes in the abnormal brain
function already identified in these patients. These outcomes could then be
coupled with validated paper based disability and pain inventories
Furthermore, functional neuroimaging may be used to identify the best
treatment approaches, which patients respond to SM, and which
combinations of treatment have synergistic therapeutic effects.
Another parameter worth investigating is central pain processing, and in
particular the potential modulation of central pain processing in patients
with chronic pain syndromes. Functional neuroimaging modalities could be
utilised to provide objective neurophysiological evidence of the efficacy of
chiropractic SM by measuring potential changes in the abnormal brain
function already identified in these patients. These outcomes could then be
coupled with validated paper based disability and pain inventories.
Furthermore, functional neuroimaging may be used to identify the best
treatment approaches, which patients respond to SM, and which
combinations of treatment have synergistic therapeutic effects. research in
psychiatry has implicated hypoactivation of the left prefrontal cortex in
depression.60 Thus, the effect of chiropractic intervention for patients with
depression could potentially be evaluated by functional neuroimaging of
left prefrontal cortex activation. A similar approach is possible with ADHD
which is associated with prefrontal brain dysfunction related to processes of
response inhibition.61 In the advent of positive findings it would be
appropriate to set up clinical trials where objective neurophysiological
evidence of efficacy could be correlated with validated paper based clinical
assessment tools. Depression, ADHD, and ASD are just a few disorders that
may be candidates for investigating chiropractic interventions using
functional neuroimaging.
Determining which technology is better is complicated as all functional
neuroimaging techniques have advantages and disadvantages, but some
modalities are generally better suited to answer certain types of research
questions. Generally, the functional neuroimaging techniques relying on the
haemodynamic response (PET, SPECT and fMRI) would to be better suited
for answering questions concerning where, and neuroelectrical techniques
(EEG and MEG) are preferred to answer questions concerning when.
However, technological advances continue to improve the functional
neuroimaging techniques. fMRI appears to have replaced PET (and SPECT)
to a large extent with its superior spatial and temporal resolutions and
simpler operating (no use for radiopharmceuticals). MEG and EEG, in
addition to providing superior temporal resolution, are becoming
increasingly better suited for source localisation. Whilst EEG and MEG are
complimentary techniques, MEG appears to be superior in some aspects,
including spatial resolution if cost is not a factor.
Cost and access
Cost and accessibility appear to be major obstacles for utilisation of
functional neuroimaging in chiropractic research. The cost of acquiring
most functional neuroimaging equipment is very high, which may explain
the relatively limited number of these systems in existence. In addition,
these modalities typically require specialized staff to operate the
sophisticated equipment. The limited number of functional neuroimaging
systems are therefore typically located in either medical institutions (e.g.
hospitals) or research facilities dedicated to particular research interests in
specific fields (e.g. cognitive neuroscience, psychiatry and linguistics).
Thus, chiropractic researchers are likely to compete for laboratory time at
facilities which typically have other research priorities. It would therefore
be pertinent for chiropractic researchers to establish research partnerships
with these institutions in order to gain access to functional neuroimaging
equipment and conduct their experiments. Furthermore, it is generally
expensive to conduct research using most functional neuroimaging
modalities. Unfortunately there is very limited funding available for
chiropractic research, thus making it difficult for chiropractic researchers to
conduct experiments using functional neuroimaging.
In comparison to the other neuroimaging modalities, EEG equipment is
relatively inexpensive to acquire and operate. Chiropractic researches could
potentially set up their own dedicated EEG research facilities and avoid
competing for laboratory time to conduct their experiments. With
appropriate training it would be possible for the chiropractic researcher to
both operate the equipment and analyse the recorded data. Thus, the
operating costs would be limited to relatively inexpensive basic
consumables (conductive gel and electrodes), which would amount to far
less then the operating costs of the other modalities.
Technical considerations
It is important to avoid any head movement whenever investigating brain
activity using functional neuroimaging. In addition, many of the functional
neuroimaging systems feature confined spaces in order to obtain the data or
protect the investigators, or both. For these reasons, it is not feasible to
measure brain activity concurrent with chiropractic SM. Admittedly, it
would be interesting to demonstrate the neural pathways and circuitries that
are activated during SM. However, the elicited activity of certain
somatosensory neural circuitries during SM is arguably of less importance
than the sustained changes in brain function that might occur in response to
SM. These changes are best investigated by comparing brain activity before
and after SM using various stimulus presentations depending on which
aspect of brain function is of interest. A pre-post SM intervention design is
readily achievable and comparable to functional neuroimaging studies in
other fields. Depending on the brain region or function of interest, an array
of different stimuli may be presented during data acquisition, including, but
not limited to: somatosensory, auditory, visual, motor, or cognitive tasks
(e.g. solving mathematical problems).
Most MEG and EEG somatosensory studies utilize evoked response
paradigms, which looks at the transient response to brief sensory stimuli.38
Responses that occur at the same time after each stimulus (time-locked)
become visible against background noise after averaging trials. These time-
locked, averaged responses are called somatosensory evoked fields (SEFs)
when recorded with MEG and somatosensory evoked potentials (SEPs) for
EEG studies. Quantitative spectral analysis is another analysis method that
is often used to quantify EEG and MEG signals on the basis of the amount
of oscillations present (oscillatory power).38 Cortical oscillations are a
widespread feature of normal brain activity and occur at a variety of
different frequencies.62 Interestingly, the evoked response paradigm is
increasingly being substituted by event-related changes in cortical
oscillatory power.37,63 In the evoked response paradigm, a stimulus
initiates a sequence of activations that tends to propagate from one area to
the next. Any background rhythms are just uninteresting noise that must be
eliminated. However, because the cortex is always active, any stimulus
evoked effect must be seen as a perturbation of ongoing activity in several
areas. In order to understand the influence of the stimulus on the activity of
one area, the interaction between the effect of the stimulus and the local
background activity must be taken into account. In addition, other indirect
stimulus-evoked effects mediated by other areas should also be taken into
account. Oscillatory power changes do not just occur in response to a brief
event, but can exist over quite long periods of time during a ”state
change”.64
Conclusions
Functional neuroimaging techniques are powerful tools in the investigation
of neuronal activity in the human brain. The chiropractic research
community is encouraged to utilise the potential of functional neuroimaging
to discern how chiropractic SM may best stimulate positive neuroplastic
change in combination with clinical recovery. The use of functional
neuroimaging techniques, in particular fMRI, MEG and EEG, in future
chiropractic research is strongly recommended.
Functional Imaging and Related Techniques: An Introduction
for Rehabilitation Researchers
Abstract
Functional neuroimaging and related neuroimaging techniques are
becoming important tools for rehabilitation research. Functional
neuroimaging techniques can be used to determine the effects of brain injury
or disease on brain systems related to cognition and behavior and to
determine how rehabilitation changes brain systems. These techniques
include: functional magnetic resonance imaging (fMRI), positron emission
tomography (PET), electroencephalography (EEG),
magnetoencephalography (MEG), near infrared spectroscopy (NIRS), and
transcranial magnetic stimulation (TMS). Related diffusion weighted
magnetic resonance imaging techniques (DWI), including diffusion tensor
imaging (DTI) and high angular resolution diffusion imaging (HARDI), can
quantify white matter integrity. With the proliferation of these imaging
techniques in rehabilitation research, it is critical that rehabilitation
researchers, as well as consumers of rehabilitation research, become
familiar with neuroimaging techniques, what they can offer, and their
strengths and weaknesses The purpose to this review is to provide such an
introduction to these neuroimaging techniques. Over the past 25 years,
techniques to image brain structure and function have offered investigators
in the cognitive neurosciences and related fields unprecedented
opportunities to study how human brain systems work and are connected.
Indeed, the number of peerreviewed research articles using these techniques
has grown at an exponential rate during this period. Inevitably, investigators
have become interested in mapping neuroplastic changes that support
learning and memory using functional neuroimaging, andconcomitantly,
rehabilitation researchers have become interested in mapping changes in
brain systems responsible for treatment effects during the rehabilitation of
patients with stroke, traumatic brain injury, and other brain injury or
disease. This new rehabilitation research and development arena is
important because a greater understanding of how and why brain systems
remap in the service of rehabilitation will lead to the development of better
treatments.
At the same time that functional neuroimaging methods have been
developed, new structural neuroimaging techniques also have been added
to the tool box of rehabilitation researchers. For example, diffusion tensor
imaging (DTI) and related magnetic resonance (MR) techniques offer the
ability to assess human white matter pathways in vivo. Not only can these
techniques be used to estimate the integrity of a given volume of white
matter, but they also can be used to trace fiber tracts within the brain. This
latter development is exciting because most of what we know (or at least
thought we knew) about the connections of the human cortex has actually
come from research on nonhuman primates, leaving questions especially
about the phylogenetically newer portions of the cortex. In the rehabilitation
arena, a better understanding of how the brain’s connections are damaged
could help us to predict what treatments are best for different research
subjects and, eventually, might be useful in selecting the best treatment
strategies for individual patients.
Because the newer functional and structural neuroimaging techniques have
enormous
implications for rehabilitation research and development, it is highly
desirable that
rehabilitation researchers be able to evaluate the usefulness of the
techniques for
rehabilitation research and that the consumers of rehabilitation research
(i.e., clinicians and
researchers) be able to evaluate research findings that have applied the
techniques. The
purpose of this article is to discuss functional and structural imaging
techniques used in
rehabilitation research. We will not cover routine clinical MR or x-ray
computerized tomography (CT) images. Rather, we will concentrate on a
variety of techniques used most frequently, though not necessarily
exclusively, in research settings. The article will consist of two main
sections: (1) Because of the extraordinary versatility or MR techniques, the
large number of MR techniques will be discussed first. (2) Subsequently,
other functional neuroimaging techniques will be discussed, including:
Positron Emission Tomography (PET),
Magnetoencephalography/Magnetic Source Imaging (MEG/MSI), Near
Infrared Spectroscopy (NIRS), Transcranial Magnetic Stimulation (TMS),
and Electroencephalography/Evoked Potentials (EEG/EPs). For each
imaging modality, we will give a brief explanation of the modality, its
uses/potential uses in rehabilitation research, its strengths and limitations,
and an example of research in the area.
FUNCTIONAL IMAGING
Functional MRI (fMRI) is but one form of functional imaging. Before we
discuss fMRI or the other forms of functional imaging covered after the
discussion of MRI techniques, we must make several introductory
comments about functional imaging. The working knowledge of functional
imaging necessary to peruse the growing literature using functional imaging
in rehabilitation requires familiarity (1) with the measures on which
different kinds of functional imaging rely, (2) with the goals of functional
imaging, and (3) with common methodological issues.
To begin, functional imaging attempts to measure neuronal activity. Some
techniques measure neuronal activity relatively directly by measuring
changes in electrical activity as clusters of neurons become active
(electroencephalography: EEG) or by measuring the changes in magnetic
fields related to electrical activity changes (magnetoencephalography:
MEG). While these techniques measure activity of neuronal clusters in real
time, they do have limitations. One such limitation is the difficulty
measuring changes in electrical activity/magnetic fields in deep brain
structures.
When neurons become active, their need for energy drives changes in
metabolism. Hence, another form of functional imaging measures these
metabolic changes as a proxy for neuronal activity. Regional metabolic
changes have been measured with positron emission tomography (PET) by
tagging fluorodeoxyglucose (FDG) with a positron emitting isotope (18F)
or by using a positron emitting isotope of oxygen (15O). In practice, it takes
a relatively long time (several minutes) to absorb enough labeled glucose to
measure metabolic activity, and measuring oxygen metabolism has proven
to be elusive.
Thus, many functional imaging techniques today do not rely on direct
measures of metabolism. Rather, they rely on measuring hemodynamic
responses. The increase in metabolic activity that supports regional
increases in neuronal activity drives increases in blood flow to deliver the
fuel for metabolic activity and carry away unneeded byproducts of
metabolism. One PET method frequently used to measure changes in blood
flow is to tag water with a positron emitting oxygen isotope (H2 15O) and
inject it intravenously. It takes at least 40 seconds to accumulate enough
positron emitting events and at least two scans under different conditions to
measure changes in cerebral blood flow between the conditions. There are
other ways to capture regional hemodynamic responses. For example, it has
long been known that oxygenating blood changes its visible and infrared
absorption spectrum. These changes can be measured near the surface of
the brain with near infrared spectroscopy (NIRS). When a brain region
becomes active, the increase in blood flow overshoots the metabolic need
of the tissue for oxygen, and even though oxygen consumption increases,
there is a higher level of blood oxygenation in blood leaving an active region
than when it leaves that same region at rest. fMRI also relies on these
changes in blood oxygenation to measure hemodynamic responses related
to neuronal activity. For a relatively brief event of a second or two, the
hemodynamic response takes about 12 to 15 seconds to resolve. While this
is better temporal resolution than H2 15O, it is still relatively far from an
instantaneous measure of neuronal activity.
Each of the functional imaging techniques mentioned above will be covered
in greater detail below, with examples. The reader wishing to read further
about the history of functional brain imaging is referred to achapter by
(Raichle, 2000a).
In general, functional imaging can be used in two ways. The first is to look
at baseline levels of brain activity. In the early days of PET, 18F-FDG
frequently was used to measure baseline regional cerebral metabolism. For
example, Metter and his colleagues (Metter, Kempler, Jackson, Mazziotta,
& Phelps, 1989) measured cerebral metabolism in stroke patients with
aphasia, and they defined regions outside the area of infarcts that showed
decreased metabolism, which helped explain behavioral deficits. More
recently, MRI has been used to measure baseline cerebral perfusion. For
example, Love and her colleagues (T.Love, D. Swinney, E. Wong, & R.
Buxton, 2002) found they could explain the neural basis of reading deficits
in a patient with left hemisphere lesion when in addition to structural MRI,
they used arterial spin labeling (ASL), an MRI technique that allowed them
to image hypoperfusion in the left inferior parietal lobule. This region did
not show a lesion on standard structural images. While useful, such
measures of baseline brain function do not define what brain areas are
actually responsible for cognitive and behavioral activities. Over the past
twenty years, functional imaging has been more commonly used to image
regional changes in brain function that occur as a result of engaging in
specific activities. Thus, the second way in which functional imaging has
been used is to define regions that become active during specific behaviors
and cognitive activities. At its simplest level, this form of imaging compares
brain activity during contrasting states to define brain systems responsible
for behavior. As examples, this form of functional imaging has been used
to determine changes in motor cortex maps during rehabilitation (Dobkin,
Firestine, West, Saremi, & Woods, 2004) or to map changes in brain
systems responsible for language during rehabilitation (Breier et al., 2004;
Meinzer et al., 2008). Most of our discussion on functional neuroimaging
will cover this latter type of functional imaging, where brain regions
responsible for specific behaviors are mapped.
As mentioned above, mapping brain regions responsible for cognitive or
behavioral functions involves comparing images from two or more states.
There is always a baseline or control image or state from which changes can
be defined. For example, in order to map areas of cortex responsible for
moving a limb, images acquired during movement are compared to images
during which no movement is made. On the surface, the idea of comparing
two or more images to derive a map of regions responsible for a specific
kind of behavior seems relatively simple. In practice, it can be quite
complex. One strategy for doing so involves taking a complex cognitive
task with several components and comparing it to a baseline/control task
with all of the same elements except the one of interest. Peck and his
colleagues (Peck et al., 2004) showed one of the potential problems in using
this strategy. In an fMRI experiment with neurologically normal subjects,
they wished to isolate processes related to ordering the words in a sentence
(i.e., syntax). Subjects were shown a picture depicting a subject, an action
performed by the subject, and a recipient of the action. The process of
generating a sentence involved not only ordering the words in the sentence
correctly but also retrieving the proper words for the items pictured. Picture
naming could be used as the control task for sentence generation since it
included all of the elements of the sentence generation task except for
ordering of words. However, when this was tried, Broca’s area, which has
been shown to be involved in syntax in both lesion and functional imaging
studies, did not show any activity. This is probably because Broca’s area is
involved in word-finding processes as well as in syntax, although it could
also be because these types of subtle difference comparisons result in
changes in the BOLD fMRI signal below the detection or noise threshold.
Hence, when two cognitive tasks use the same neural component for
different kinds of processing, it is not a good idea to use one as a baseline
or control task for the other. When these investigators used passive viewing
of nonsense object pictures as a baseline task, activity in Broca’s area was
visible. In another study with neurologically normal subjects, Newman and
her colleagues (Newman, Twieg, & Carpenter,2001) demonstrated greater
extent of activity in language eloquent cortex when phoneme discrimination
was compared to a resting baseline than when the baseline task was either
tone discrimination or passive listening to the same stimuli as used in
phoneme discrimination. Damage to the neural components of systems
responsible for behavior, and especially cognitive functions like language,
may produce unpredictable recruitment of undamaged structures to
accomplish relevant tasks, even though such areas are not normally
recruited. Hence, cognitively similar tasks are more likely to recruit
overlapping areas in brain damaged subjects than in neurologically normal
subjects. This reasoning suggests that caution should be used regarding the
use of cognitively similar processes as baseline and experimental tasks in
individuals with brain damage. Hence, selection of simpler baseline tasks
may useful in functional imaging studies of rehabilitation. For readers
wishing to explore the issue of baseline tasks more completely, Petersen
and his colleagues (Petersen, van Mier, Fiez, & Raichle, 1998) have
provided an excellent discussion of the matter.
Another important issue in studies of rehabilitation with brain damaged
populations is mapping activity around lesions. An important issue in
studies of aphasia is whether perilesional structures in the left hemisphere
or structures in the previously nondominant right hemisphere are
responsible for recovery of function or the effects of rehabilitation. This
issue also has been addressed in studies of the motor system. In studies of
subjects without well-demarcated areas of brain damage, the most
frequently used analytic techniques involve deforming images of individual
subjects into a common atlas space and averaging images across subjects to
determine where significant activity differences between tasks or groups
exist. A key assumption in this type of analysis is that tissue examined in
any particular voxel for one subject corresponds to the tissue for that voxel
in atlas space for any other subject in the sample. (Voxels are the basic 3-
dimensional volume units containing the quantitative data from which
functional images are made). The problem with this assumption for patients
with strokes (ischemic or hemorrhagic) is that the lesions vary considerably
in shape, size, and location. The same voxel that is occupied by perilesional
activity in one subject may be occupied by lesion in other subjects, and
combining images across subjects may average away important perilesional
activity. Thus, when examining activity in the lesioned hemisphere is
important, another data analysis approach must be used.
These are but a few examples of the complexities in functional
neuroimaging research. In addition to these more general challenges, each
functional imaging technique has its limitations and problems, some of
which will be discussed in the following sections. However, it is difficult in
this survey of functional neuroimaging to cover all of the difficulties that
arise in research, or indeed in clinical applications. Instead, we will
endeavor to cover the most commonly encountered problems with each
technique.
MAGNETIC RESONANCE IMAGING AND SPECTROSCOPY
Basic Principles of Magnetic Resonance Imaging and Spectroscopy
Since a number of the techniques for brain imaging discussed in this review
rely on magnetic resonance technology, it is worth some space to describe
a few basic principles of magnetic resonance imaging and spectroscopy.
Nuclei of atoms are comprised of protons and neutrons. Isotopes which have
an odd number of either protons or neutrons have a nonzero spin and an
associated nuclear magnetic moment (i.e., nuclear magnetism of specific
strength and direction); those with an even number of both protons and
neutrons have no magnetic moment and are not observable with nuclear
magnetic resonance (NMR, often shortened to MR).
Nuclear magnets can align parallel or anti-parallel to the applied magnetic
field, called B0. Since slightly more align with the field than against, a net
macroscopic nuclear magnetization M exists. As a result of the property of
spin, nuclear magnets have angular momentum causing them to precess
around an applied magnet field (B0). Precession can be thought of as a
wobbling of the magnetic moment around the magnetic field (B0), similar
to the way a toy top both spins and precesses about its gravitational vector.
The frequency of precession in a magnetic field of a specific strength is
called the Larmor frequency. The direction of precession is dependent upon
the parallel or anti-parallel orientation of the magnetic moment about the
B0 axis, with precession occurring in opposite directions for the parallel vs
anti-parallel orientations.
If a radiofrequency (rf) field with the Larmor frequency (rf pulse) is briefly
applied to the sample, the spins can absorb energy and flip between the
energy state levels. This moves the vector M out of alignment with B0, and
it precesses around B0 and creates an oscillating magnetic field which can
be detected with a coil in which a sinusoidal voltage is induced. The degree
to which the vector M tips out of alignment with B0 (i.e., the flip angle) is
dependent on the strength and duration of the rf pulse. The signal induced
in the rf coil decays with a time constant referred to as T2. T1 is a time
constant which describes the time it takes M to return, or relax, to its original
state of alignment with B0. In biological samples, T2 is shorter than T1. By
varying image acquisition parameters, one can produce T1- weighted
images (where cerebrospinal fluid has low signal relative to grey and white
matter) or T2-weighted images (where cerebrospinal fluid has high signal
relative to grey and white matter). Other types of weighting are possible.
In general, many rf excitation pulses must be used in data acquisitions, and
the time between excitation pulses for a given slice of tissue is referred to
as the repetition time, or simply TR. In functional MRI, the TR determines
how quickly a single brain image is acquired. To analyze how signal
changes in concert with experimental manipulations, it is necessary to
acquire many brain images during a functional MRI experiment. The time
from application of the rf excitation pulse to the signal acquisition is
referred to as the echo time or TE. In blood oxygenation level dependent
(BOLD) functional MRI (see below for explanation), the most common
form of functional MRI, a relatively long TE will yield greater changes in
functional signal between activation and baseline states, but also will also
cause greater artifacts near air-tissue interfaces and lessened overall signal
intensity. Hence, the choice of a TE in BOLD functional MRI often will be
a trade-off between the need to produce a relatively strong signal and the
desire to limit artifacts.
Water, the most ubiquitous hydrogen-containing molecule in the body,
offers a medium for magnetic resonance imaging and resonates at a single
frequency in a uniform magnetic field. However, the Larmor frequency and
phase of precession can be manipulated by creating slight gradients within
the main magnetic field (B0), such that the strength of the field varies with
a linear relationship to distance. Within an acquisition plane (image slice),
the location of a signal in one direction is determined by slight changes in
frequency and in the orthogonal direction by changes in phase of the
induced signal. The third spatial dimension of the image is addressed by
acquiring multiple relatively thin slices. Slice selection is also accomplished
by creating a gradient in the magnetic field. All of these gradients in the
magnetic field are created with gradient coils separate from the
superconducting coil used to generate the B0 field.
Magnetic resonance spectroscopy can be used to detect some molecules in
the brain other than water. Atomic nuclei in molecules have electrons
associated with them in certain specific geometric spatial locations dictated
by bonding forces to neighboring atoms. These orbitals constitute effective
circuits through which the electrons circulate. In an applied magnetic field,
these circulating currents induce a field in opposition to B0, which shields
the nucleus from the applied B0 field. This means that, for example,
hydrogen atoms in different parts of a molecule have different frequencies,
or chemical shifts. Signals can be localized to voxels using selective
excitation for single voxel spectroscopy or chemical shift imaging (CSI).
The physics of magnetic resonance imaging and spectroscopy is much more
complex than can be described in the available space. We have endeavored
to provide the reader with a brief description of some of the more common
concepts. The reader wishing greater detail is referred to the excellent text
by (Buxton, 2001).
BOLD contrast fMRI
At the time of this review, BOLD contrast is the most common method for
obtaining functional magnetic resonance images (fMRI). As noted above,
BOLD is the acronym for blood oxygenation level dependent contrast.
BOLD contrast is derived primarily from the paramagnetic properties of
deoxygenated hemoglobin (deoxyhemoglobin). Paramagnetic materials
tend to concentrate magnetic flux, decreasing the MR signal when a pulse
sequence sensitive to magnetic susceptibility differences is used. Hence,
regional cerebral increases in deoxyhemoglobin will cause decreases in the
MR signal for the region. However, the underlying phenomena generating
BOLD contrast are not as straightforward as it might seem at first glance.
When an area of the brain becomes active, metabolism increases to support
the activity. Aerobic metabolism increases oxygen extraction, and
concentrations of deoxyhemoglobin transiently increase in active areas,
thereby decreasing MR signal. However, rCBF then increases to deliver
more oxygenated hemoglobin for the increased local metabolism. The
increase in regional cerebral blood flow is in excess of what is needed to
supply the active tissue with oxygen; therefore, the relative concentration
of deoxyhemoglobin per unit volume in the active region decreases peaking
roughly 6 seconds later due to this overcompensation in perfusion and the
MR signal increases as a result. Thus, the BOLD signal is the result of a
complex interplay between changes in regional cerebral oxygen extraction,
blood flow, and blood volume. A hemodynamic response triggered by an
event taking less than a second to occur generates a hemodynamic response
that typically shows an increase in signal lasting 10-12 sec to rise to peak
and return to baseline. This positive change in signal may be followed by a
negative phase of several seconds, but this phase is often considered of no
interest. Figure 1 shows an example of a hemodynamic response derived
from our research. The x-axis represents time, and the y-axis represents
percent of change in MR signal. Other types of fMRI are covered below.
The reader is referred to (Buxton, 2001) for a more detailed explanation of
BOLD contrast.
fMRI has specific advantages and disadvantages relative to other functional
neuroimaging techniques. One advantage of BOLD-contrast fMRI over
positron emission tomography, another form of functional imaging, is that
BOLD contrast fMRI is noninvasive and does not expose the subject to
radiation. The contrast in this form of fMRI is endogenous; i.e., BOLD-
contrast takes advantage of existing substances in the body to produce
images. PET images require the injection of a radioactive, positron-emitting
contrast agent. Another advantage of fMRI over other imaging techniques
is its spatial resolution. Spatial resolution refers to the degree of accuracy
with which brain activity (i.e., hemodynamic responses) can be located in
space. The spatial resolution of fMRI is limited by the voxel size in which
images are acquired. The voxel size in fMRI images in human studies is
most often driven by practical as opposed to physical considerations.
Specifically, there is a trade off between spatial and temporal resolution.
Acquiring data in smaller voxels takes more time than acquiring data in
larger voxels because it takes more small than large voxels to cover the
brain. Practically speaking, 2 mm cubed voxels are the lower limit of what
it is practical to acquire in whole brain functional MR images on a
conventional 1.5-3 Tesla scanner. However, it is possible to acquire smaller
voxels than that, especially if whole-brain images are not needed or stronger
magnets are available. Temporal resolution refers to the degree of accuracy
on a temporal scale with which a functional imaging technique can describe
when a neural event occurred. Temporal resolution is an advantage for
fMRI over PET, but fMRI is at a disadvantage in temporal resolution
compared to techniques using electroencephalography (EEG) or
magnetoencephalography (MEG). PET’s ability to resolve neural events is
on the order of tens of seconds, fMRI’s ability to do so is on the order of
seconds, and the ability of EEG- and MEG-based techniques to do so is on
the order of milliseconds. Since the cascade of events through neural
systems happens on the millisecond scale, EEG- and MEG-based
techniques are most likely to be useful when this kind of temporal
information is needed. PET and fMRI can both image activity in deep,
subcortical structures, whereas this is difficult if not impossible with EEG-
and MEG-based techniques. Another advantage of fMRI is the ubiquity of
MRI scanners, and most have the potential to be used for fMRI. By
comparison, PET scanners are not as common, and to use PET as a
functional imaging technique for cognitive processes, it is necessary to have
a cyclotron and a radiochemist nearby. Another advantage for fMRI is that
the same platform used to acquire functional images can be used to acquire
high resolution anatomic images in the same space as functional images, so
that functional images can be overlaid onto structural images to allow for
precise anatomic localization. PET, MEG, EEG, TMS, and NIRS all have
to rely on structural MR images and/or atlases to localize activity in the
brain. Cost can be a disadvantage for fMRI if there is not a readily available
instrument to acquire images. Relative to EEG-based techniques, fMRI is
expensive. MRI scanners cost millions of dollars, and their maintenance can
be expensive as well. However, PET and MEG-based techniques have
similar costs for implementation. Other disadvantages for fMRI include the
confined space in which participants must be placed, which can induce
claustrophobia in susceptible participants, and the acoustic noise required
to obtain scans, to which the brain inevitably reacts.
The use of fMRI in rehabilitation studies is just beginning. In locomotor
rehabilitation, early evidence suggests that the amount of cortex involved in
a related motor function (ankle dorsiflexion) expands as a 12-week
rehabilitation program approaches its mid-point and then contracts again
toward the end of treatment. It also appears that representations for the
lower extremity can expand into cortex adjacent to their normal location
(Dobkin et al., 2004). Findings in the aphasia rehabilitation literature are
less clear, and there is a controversy regarding whether the right or the left
hemisphere is the site of rehabilitation gain in premorbidly right-handed
patients. A review of the literature suggests that both the right and the left
hemisphere may make contributions under different circumstances, or
indeed, within a single patient. The contribution of the left hemisphere may
be greater in small lesions, while the contribution of the right hemisphere to
treatment gains may be greater in large lesions (Crosson, McGregor et al.,
2007). A number of technical obstacles must be overcome to use fMRI in
aphasia treatment studies, particularly if language production is the target
of treatment. The reader interested in more details is referred to the review
by Crosson et al. (Crosson, McGregor et al., 2007).
Eventually, it is possible that fMRI will be used to predict what treatment
will work with which patient, to determine what structures can be recruited
for rehabilitation, and/or to measure brain system changes that result from
rehabilitation. However, a good deal of research must be accomplished
before we reach that point.
The following is an example of using fMRI in rehabilitation research from
our own laboratory (Crosson et al., 2009). In 2007, we demonstrated that a
treatment designed to relateralize language production mechanisms from
the left to the right frontal lobe produced a faster rate of relearning of words
than a similar control treatment (Crosson, Fabrizio et al., 2007). The
treatment used an intention manipulation (complex movement of the left
hand to initiate naming trials) because we thought that this manipulation
would help to re-lateralize language production mechanisms. To assess
whether or not the treatment actually relateralized frontal activity to the
right hemisphere, we administered a category-member generation task to
five patients during fMRI before and after the intention treatment. Four of
the five patients improved during treatment. The four patients who
improved in treatment showed a significant rightward shift in lateral frontal
activity, which became more concentrated in the ventral portion of the right
motor/premotor cortex or in pars opercularis just anterior to motor/premotor
cortex. Although laterality of frontal activity for those four patients was not
different from controls prior to treatment, it was significantly more
lateralized to the right hemisphere than in controls after treatment. With the
exception of the right hemisphere in one patient, activity in both frontal
lobes decreased from pre- to post treatment fMRI, suggesting greater
efficiency of processing after treatment. The one patient who did not
improve in treatment showed a leftward as opposed to a rightward shift in
lateral frontal activity, and an increase in left frontal activity. Figure 2 shows
the pre- and post-treatment activity most typical of those patients who
improved in treatment. The images have been equated for sensitivity to
BOLD responses between the two sessions. Note the total lack of right
frontal activity in post- compared to pre-treatment images, indicating a
rightward shift in lateral frontal laterality, and the reduction in activity in
the right as well as the left frontal lobe, suggesting greater efficiency of
processing post- compared to pretreatment processing. This study is of
interest because it indicates that it may be possible to target specific brain
structures for rehabilitation and use functional imaging to confirm the
success of the strategy. The ability to perform this kind of study eventually
should lead to development of better treatments for aphasia.
Other forms of fMRI
While BOLD contrast is by far the most common form of fMRI, it is
important to note that there are other kinds of fMRI. The reasons that these
forms of imaging have not gained the wide-spread usage and acceptance as
that of BOLD contrast fMRI are variable. We briefly discuss these reasons
and describe the following three techniques: arterial spin labeling, blood
oxygenation sensitive steady-state, and dynamic susceptibility contrast. In
addition, resting state or functional connectivity MRI (fcMRI) is described,
which is fMRI without a specific task, and provides a passive means of
interrogating functional brain networks and their connectivity.
Arterial spin labeling (ASL)
provides a measure of cerebral blood flow, using anvendogenous tracer,
blood water, to noninvasively measure tissue perfusion to evaluate
thevtissue viability or functionality (Golay, Hendrikse, & Lim, 2004; Liu &
Brown, 2007). InvASL, two sets of images are alternately acquired, a set of
labeling images and a set ofvcontrol images. In the labeling experiment,
arterial blood spins on the proximal side of thevimaging slab are inverted.
After a short delay of a second or so, to allow arterial blood that isvtagged
in this fashion to perfuse throughout the brain, images are acquired from the
imagingvslab. In the control imaging experiment, no arterial blood is
inverted, and after the samevshort delay, images are acquired from the
imaging slab. After pair-wise subtraction ofvcontrol from labeling images,
MRI signals from static brain tissue can be cancelled, leavingvsignal only
from the labeled inflowing blood water perfusing brain tissue. The
differencevimage from pair-wise subtraction of control images from
labeling images is referred to as avperfusion-weighted image, or PWI
(Figure 3). By using an appropriate perfusion modelv(Parkes, 2005),
cerebral blood flow (CBF) maps can be reconstructed. There are
severalvvariants of ASL techniques (Liu & Brown, 2007).
The application of inversion RF pulses can generate magnetization transfer
(MT) effects (Wolff & Balaban, 1989) on tissue. In MT, irradiation of broad
signals from macromolecules to which water is transiently binding changes
the water signal intensity. If the MT effects are not the same between the
labeling and control experiments, these MT effects can confound ASL
perfusion signals. Using either an asymmetric control RF pulse in the same
proximal site or a symmetric control RF pulse in the mirrored distal site can
control MT effects by using the same RF pulses as in the labeling
experiment, with adjusted radiation frequency.
ASL has become particularly useful in circumstances where baseline
cerebral blood flow measures are useful. For example, ASL showed a
hypoperfused area in the left parietal cortex of a stroke patient, consistent
with the patient’s reading deficit, which appeared normal on conventional
anatomic images (T. Love, D. Swinney, E. Wong, & R. B. Buxton, 2002).
An example of this type of application of ASL from one of our own
laboratories is shown in Figure 4. Measuring quantitative CBF changes
induced by pharmaceutical agent challenge is also a promising for clinical
application of ASL. For example, the specificity of cerebral perfusion
changes under hypercapnia or hypocapnia states has been evaluated
(Pollock et al., 2009). The effects on CBF of other drugs that can alter the
physiological or neurophysiologic states of the brain have also been studied
by ASL. For example, the global increase of brain perfusion with
remifentanil challenge is mainly due to remifentanil’s depression of
breathing and the consequent increase of blood PaCO2 (MacIntosh et
al.,2008). In another ASL perfusion study, acetazolamide, a carbonic
anhydrase inhibitor, was administrated to evaluate the augmentation of
cerebral blood flow with patients with ischemic symptoms due to arterial
stenosis (Detre et al., 1999).
ASL also can be used for functional images, although fMRI has not become
a wide-spread use for ASL. One problem with most ASL techniques is that
it is hard to acquire wholebrain fMRI on a time scale that would allow for
visualization of the hemodynamic response. Hence, the investigator has to
be satisfied with a few image slices covering critical areas. However, in
ASL fMRI, a much shorter TE is usually used compared to BOLD fMRI,
which reduces the signal loss due to susceptibility effects and provides
better spatial specificity than BOLD fMRI, where large draining veins can
contribute artifactual signal. For example, (Kemeny, Ye, Birn, & Braun,
2005) demonstrated that ASL could be used to collect fMRI data during
sentence production in such a way as to eliminate artifacts present on BOLD
images when subjects speak.
Readers desiring more detail on ASL are referred to the article on
techniques (Liu & Brown, 2007) and the companion article on applications
(Brown, Clark, & Liu, 2007).
Blood oxygenation sensitive steady-state (BOSS)
relies on a change in the MR signal frequency for deoxyhemoglobin relative
to oxyhemoglobin. The BOSS acquisition capitalizes on this signal shift to
collect images in which the signal from oxyhemoglobin will be positive and
the signal from deoxyhemoglobin will be negative. BOLD and BOSS fMRI
both measure signal changes resulting from the deoxyhemoglobin
frequency shift. However, BOLD contrast fMRI measures that frequency
shift indirectly as signal dephasing, and BOSS measures the shift directly.
Because increased activity causes a drop in the proportion of negative,
deoxyhemoglobin-related signal and an increase in the proportion of
positive oxyhemoglobin-related signal, the net BOSS signal increases
during activity (Milleret al., 2004). BOSS has advantages over BOLD. For
example, BOSS has a higher signal-tonoise ratio than BOLD, with BOSS
signal changes being roughly 2-3 times larger than BOLD. Further, BOSS
is not subject to the signal drop out around air-tissue interfaces that plagues
BOLD imaging. Among the reasons that BOSS fMRI has not become more
popular are the facts that it has not found its way into the commercially
available sequences on MR instruments and its implementation can be
complex. Readers wishing more detailed treatment of BOSS are referred to
the work of Miller and colleagues (Miller et al., 2004; Miller et al., 2003;
Miller, Smith, Jezzard, & Pauly, 2006).
Dynamic susceptibility contrast (DSC)
uses the paramagnetic property of gadolinium ions as a magnetic tracer.
Gadolinium ions causes a transient disruption of the magnetic field around
the vessels through which it flows, resulting in a transient signal loss
proportional to the amount of gadolinium. The signal loss can be used to
determine changes in relative cerebral blood volume at the voxel level.
Advantages to this technique include its high contrast-to-noise ratio, which
can be used to overcome artifacts during patient speech. The major
drawback to DSC is its invasiveness, since intravenous injection of
gadolinium is necessary. (Naeser et al., 2004) used DSC to study brain
activity during narrative language in patients with chronic nonfluent
aphasia. These authors also give a brief description of the technique.
Functional connectivity MRI (fcMRI)
detects interconnected brain regions which activate together as a functional
network. It is most often performed as resting state fMRI without a specific
task, in which the brain pseudo-randomly activates under little or no guiding
external influence. Since no task performance is required on the part of the
subject, the resting state implementation has the advantage of being a
passive method of interrogating functional brain networks and their
functional connectivity. This is an obvious benefit for application to stroke
and other pathologies that can make task performance and monitoring
difficult.
The acquisitions for fcMRI should have about 300 volumes or serial time
points, to adequately sample the low-frequency signal fluctuations (< 0.1
Hz) representative of vascular fcMRI responses to baseline neuronal
activity “at rest”. Collecting cardiac and respiratory waveforms in
conjunction with the fcMRI time course data is useful for regressing out
signal fluctuations due to these non-neuronal sources of physiological
variability, leaving signal fluctuations more nearly caused by vascular
responses to neuronal activity (Glover et al. 2000). Calibration of the BOLD
effect using breath hold (Thomason et al. 2007) or amplitude of resting state
signal fluctuations (Biswal, Kannurpatti, & Rypma, 2007)reduces
variability of individual vascular reactivity and improves group averages
and comparisons.
Analyses of fcMRI data are typically done in one of two ways: unguided
exploratory analyses by Independent Components Analysis, or ICA (De
Luca et al. 2006), or seed-based analysis by which voxels whose signal time
course correlates highly with those of the seed ROI are detected (DiMartino
et al. 2008).
There are few examples in the literature of how fcMRI can be applied to
stroke and rehabilitation. A left hemorrhagic posterior cerebral artery stroke
produced increased functional connectivity between areas V4/V8 and V5 of
the left hemisphere in comparison with the same areas in the intact
hemisphere when the subject viewed changing colors, suggesting that visual
perception after the V1 lesion is mediated by subcortical pathways that
bypass V1 and project first to V5 and V4/V8 and subsequently to V2/V3
(Schoenfeld at al. 2002). Spatial neglect in stroke subjects was studied by
fcMRI in both acute and chronic recovery stages in dorsal and ventral
frontoparietal areas (He et al. 2007). Part of the lesioned ventral network
was diffusely disrupted and showed no recovery, whereas in the structurally
intact dorsal network, posterior parietal cortex connectivity was acutely
disrupted but fully recovered. Disrupted connectivity in the ventral network
correlated with impaired attentional processing, and disconnection of the
frontal and parietal cortices was associated with more severe spatial neglect.
A recent review (Damoiseaux and Greicius 2009) highlights studies which
have combined structural (DTI, see following section) and functional
(fcMRI) connectivity methods. Information about brain networks and
functional connectivity affected by stroke and rehabilitation can also be
obtained from EEG (Gerloff et al. 2006, Meister et al. 2006) and MEG
(Schoenfeld at al. 2002).
One weakness in fcMRI is the certainty with which inferences can be made
regarding functional networks for specific cognitive or behavioral functions
when acquisitions are made in the resting state. Recently, techniques to
address functional networks during performance of relevant tasks have been
developed. These include adaptation of structural equation modeling (SEM)
and dynamic causal modeling (DCM) to define relationships between
components of functional networks. A potential drawback is that these
techniques work best when investigators have a model to test. Abutalebi et
al. (Abutalebi, Rosa, Tettamanti, Green, & Cappa, 2009) used DCM and
fMRI to study recovery of functional connectivity in a bilingual patient who
received therapy in his second language (L2) but not in his first language
(L1). The functional connectivity of selected left-hemisphere language and
cognitive control mechanisms increased across the course of therapy for L1,
consistent with increasing activity and language skills in these areas for L1,
while the functional connectivity of these structures decreased for L2,
consistent with stable to decreasing performance in L1. Before therapy
functional connections generally were stronger for L1 than L2, but the
reverse was true after therapy. We expect that DCM and SEM will be
increasingly applied to rehabilitation.
Diffusion Imaging and Diffusion Tensor Imaging
Although functional MRI has become a valuable tool for imaging changes
in brain function as a result of rehabilitation, this versatile technology also
has provided us with new methods of imaging brain structures, in particular
the brain’s white matter. Diffusion-weighted magnetic resonance imaging
(DW-MRI) is a non-invasive imaging technique that allows one to assess
the structural integrity of tissues in-vivo. DW-MRI measures the diffusion
of water molecules, random motion present due to thermal energy. In
tissues, diffusion is restricted by cell membranes as well as tissue
boundaries, resulting in diffusion anisotropy, or diffusion along one
preferred direction. For example, in white matter fiber bundles, the myelin
sheath surrounding axons prevents diffusion across the axon, restricting
water diffusion only along the longitudinal axis of the axon. Therefore, the
directionality of diffusion provides us with information about local fiber
orientation.
Mathematically, diffusion in a given voxel can be characterized by an
ellipsoid, or tensor, oriented along the direction of the fiber (Basser et al.,
1994). The major axes of the ellipsoid, called eigenvectors, describe spatial
orientation of the fibers. The lengths of the axes, known as the eigenvalues,
describe the strength of diffusion along each of the three axes. The diffusion
of water in white matter fiber bundles would be described by an ellipsoid
elongated along the principle diffusion direction (PDD), or the longitudinal
direction of the fiber. A scalar describing the proportion of the diffusion
along a particular direction (relative to all other directions) is called
fractional anisotropy, or FA. Values of FA range from 0 to 1, where 0
describes diffusion which is completely isotropic, or equal in all directions.
For instance, isotropic diffusion is usually observed in the ventricles, as
water molecules in CSF are able to disperse freely in all directions,
described by FA values close to 0. White matter fiber bundles would exhibit
FA values close to 1 as almost all diffusion is directed along the length of
the axons. The average rate of diffusion, or mean diffusivity (MD) is
another important scalar describing the average speed with which the
molecules traveled during a given time interval. MD values are higher in
the ventricles, as molecules are unrestricted and can travel larger distances
than in gray or white matter. Together, FA and MD maps can be used in
clinical settings to acquire information about the structural organization of
tissues not present in conventional MRI. For example, the sensitivity of FA
and MD measures have been shown to reveal damage in white matter in
ischemic leukoariosis abnormalities not noticeable on T2-weighted MR
scans, and to reveal Wallerian degeneration post-stroke months before it
could be detected by T1-weighted MRI (O’Sullivan et al., 2001; Thomalla
et al., 2004). Group studies investigating white matter abnormalities have
used FA measures to localize differences in the white matter in patients with
primary lateral sclerosis (PLS), amyotrophic lateral sclerosis (ALS) and
multiple sclerosis (MS), as well as to correlate these differences with the
Expanded Disability Status Scale (EDSS) (Ciccarelli et al., 2009; Smith et
al., 2007). In healthy populations, FA measures were shown to reflect
effects of myelination correlated with hours of practice in professional
piano players (Bengtsson et al.,2005)
Generally, FA and MD values are negatively correlated with higher MD
values and lower FA values indicating underlying tissue degeneration.
However, an inverse relation between these measures is not always
observed. Lower FA values indicate a reduction in preferred directionality
of diffusion. However, decreased fiber integrity in secondary directions can
artificially drive the FA value closer to 1 (Douaud et al., 2009) while MD
is also increasing. In such cases, the FA value would not be a good
indication of white matter integrity. Thus, to better describe structural
changes in white matter in neurological disease, it is important to consider
whether multiple DW-MRI measures provide converging evidence. Figure
5 shows images based on MD (top left), FA top Right, color coded PDD
maps from FA (bottom left), and fiber tracts derived from DTI data (bottom
right, see below for explanation).
In addition to assessment of white matter integrity, DW-MRI also allows
for white matter visualization using tractography. Tractography approaches
that trace the fibers by following the PDD are called streamline. Although
streamline methods produce robust results for large white matter tracts, such
as the corticospinal tract (CST), they have difficulty accurately representing
branching or crossing fibers, since in this case no single principal direction
exists. In this case a second category, called probabilistic tractography,
should be used to properly represent fiber architecture. Probabilistic
tractography approaches trace the tracts in many possible directions,
recording probabilities associated with each direction. Thus, at the
intersection of two tracts, both fibers will have comparable probabilities
associated with each corresponding direction, each of which will be traced
by the algorithm. In stroke rehabilitation studies, ratios computed as the
ipsi- over contra-lesional hemisphere tract volumes (numbers of voxels)
were shown to correlate with recovery (Nelles et al., 2007). In patients with
ALS disease, progression rates have been correlated with DW-MRI
measures of structural integrity in the CST fibers, using connectivity
measures generated by a probabilistic tractography approach (Ciccarelli et
al., 2006).
In summary, DW-MRI provides clinicians with many useful tools sensitive
to changes in the white matter. Moreover, these tools provide researchers
with information, such as fiber tract visualization, that has previously been
available only in primate studies and cadaver dissections. DW-MRI allows
us to investigate not only changes in structural organization of known white
matter projections, but also to ascertain the presence of new pathways,
making it crucial to understanding mechanisms of neurological disease. For
example, Figure 5 (bottom right) shows the visualization of fibers between
medial frontal cortices and Broca’s area (Ford, unpublished data), both of
which are involved in word production. One potential use of DW-MRI in
rehabilitation involves the measurement of integrity of various tracts and
correlating these measures with behavioral and cognitive measures or with
measures of rehabilitation outcome.
MR Spectroscopy
Magnetic Resonance Spectroscopy (MRS) provides a non-invasive way of
investigating brain chemistry. Although MR spectroscopy can be performed
using a number of different nuclei, only the most clinically established
method, 1H spectroscopy, will be described. With it, important brain
metabolites such as N-acetylaspartate (NAA), creatine (Cr) and choline
(Cho) can be measured, as well as molecules with weaker signals such as
glutamate (Glu), glutamine (Gln), myo-inositol (mI), and lactate (Lac)
(Govindaraju, Young, & Maudsley, 2000). Resonances (peaks) are
identified by their position (chemical shift) in the spectra, expressed in parts
per million (ppm) relative to a standard frequency. Peak areas are related to
the metabolite concentrations. The dominant peaks are from the acetyl
group of Nacetylaspartate (NAA) at 2.0 ppm, total creatine (Cr) at 3.0 ppm,
and total choline (Cho) at 3.2 ppm (Figure 6).
NAA is an amino acid present mostly in neurons and is widely regarded as
a marker of neuronal structural and functional health and integrity. Decrease
of NAA is observed in various cerebral pathologies such as ischemia, brain
tumors, gliosis, dementia, trauma, and multiple sclerosis. It is rarely
increased, one exception being Canavan’s disease. Longitudinal MRS
studies in stroke have found acute decreases in NAA, and a continuing fall
during the first week after the onset (Gideon et al., 1992; Saunders, 2000).
Recovery of the NAA levels has been observed in certain cases of reversible
ischemia (Brulatout et al.,1996) and acute brain injury (De, Matthews, &
Arnold, 1995), making NAA an important clinical outcome marker, as
reviewed recently (Eliassen et al., 2008). Effects of rehabilitation and
interventions have also been studied (Mountz, 2007), indicating relations
between metabolite changes and brain reorganization and plasticity. N-
acetylaspartate significance and changes under various conditions has been
reviewed
The total creatine (creatine and phosphocreatine) peak is a marker of the
energetic status of cells, and is often used as a standard or reference for
relative quantification of other metabolites, due to its relative consistency
with location in the brain, age, and physiological conditions. However,
caution needs to be exercised, since Cr levels do change in certain
pathologies such as tumors and stroke.
The total choline peak (phosphocholine, free choline, and
glycerophosphocholine) is a marker of cell membrane integrity and
viability. It has been shown to be elevated in dementia, multiple sclerosis,
aging, and tumors (Rudkin and Arnold 1999).
Lactate is below the MRS detection threshold in healthy brain, but is
measurable in ischemia (Graham et al., 1992) and hypoxia since it is the end
product of anaerobic processes.
Both data acquisition and analysis in MRS usually require significant
technical expertise. In single voxel spectroscopy, a proper and reliable
localization of the volume of interest is important, and usually requires an
MR operator with a good knowledge of brain anatomy. The quality of the
acquired spectra (the line-width and spectral resolution) is highly dependent
on the homogeneity (shimming) of the of B0 magnetic field. Most of the
MR vendors provide autoshim utilities, but in some brain areas a manual
adjustment of the shim currents is often necessary. The water signal is
orders of magnitude higher than the metabolite signals, so efficient water
suppression is important as well. In CSI techniques extra effort needs to be
taken for lipid signal suppression.
Processing the MRS data is in general complicated because of overlapping
peaks and the limited signal to noise ratio of in vivo spectra; accurate
quantification requires close attention to a number of details (Gillard, 2005).
An automatic post-processing tool that has gained popularity in both clinical
and research settings is LCModel (Provencher, 1993), which utilizes prior
spectral knowledge by analyzing the in vivo spectrum as a linear
combination of in vitro acquired metabolite model spectra (vendor provided
or locally acquired). Simulated lipid and macromolecule signals are also
included in the modeling. Accurate accounting for these signals is crucial
for proper metabolite quantification especially at short echo times, which
provide inherently higher signal-to-noise ratio.
Absolute metabolite quantification (Ernst, Kreis, & Ross, 1993; Kreis,
Ernst, & Ross, 1993) requires internal (Barker et al., 1993) or external
(Ernst, Kreis, & Ross, 1993; Kreis, Ernst,& Ross, 1993) reference
standards. A number of instrument dependent factors as well as in vivo
relaxation corrections complicate the quantification procedure. Since
relaxation corrections (Traber, Block, Lamerichs, Gieseke, & Schild, 2004)
are usually difficult to measure in vivo due to time constraints, it is often
recommended to use sufficiently long repetition times (TR) and as short as
possible echo times (TE) in the data acquisition.
Despite technical challenges, MRS is a valuable tool for measuring
biochemical changes in the brain in various pathologies and in recovery and
rehabilitation.
Positron Emission Tomography
Although fMRI is today the dominant form of functional neuroimaging for
cognition, the field owes much to scientists who used positron emission
tomography (PET) as a tool for imaging cognitive systems before fMRI was
a wide-spread technology. The technique relies on unique properties of
short half-life, positron emitting radionuclides to map brain systems
responsible for cognition. Specifically, a positron is a particle with the same
mass as an electron, but differs from an electron in that its charge is positive,
not negative. When emitted from the radionuclide, a positron will travel a
very short distance before encountering an electron with which it undergoes
annihilation. As a result of this process, two 511-KeV photons leave the site
of annihilation traveling almost exactly 180 degrees from one another. PET
images rely on rings of coincidence detectors and the concept that if two
photons are detected coincidentally, it is highly likely that an annihilation
event occurred on a straight line between the two points of detection. If
enough of the events are detected, then a computer can be used to create
images of the distribution of the radionuclide within the sample. 18F-
labeled fluorodeoxyglucose (18FDG) was administered in many early PET
studies to map baseline levels of regional glucose metabolism in the brain.
18F has a half-life of 110 minutes. Typically, 30 minutes or more was
allowed for nonmetabolized 18FDG to clear the brain. With the remaining
portion trapped in brain tissue, its distribution could be used as a good
indicator regional glucose metabolism levels. However, the 30+ minutes
needed to get a single image was not well suited to measure changes in brain
activity related to changes in cognition. Fortunately, increases in
metabolism that occur with neuronal activity also drive increases in blood
flow. A technique of injecting 15O-labeled water (H2 15O) into the blood
stream allowed PET investigators to image changes in regional cerebral
blood flow due to cognitive activities performed during the roughly 40-
second image acquisition. The relatively short half-life of 15O (123
seconds) allowed for multiple administrations of the radionuclide, and
images of cognitive activity could be compiled by assessing differences in
regional cerebral blood flow between images collected during two different
cognitive states. For more information on PET technology and its history,
the interested reader may wish to consult the chapter by Raichle (Raichle,
2000b).
While H2 15O-PET was better suited to measuring brain activity due to
cognitive states than 18FDG-PET, there were still important limitations to
the former technique. One drawback to the technique is the exposure of
subjects to radiation and the limitation in the number of scans that this
implies. From a practical standpoint, the most commonly used PET
technique for exploring the brain’s cognitive systems, measurement of
regional cerebral blood flow changes using H2 15O, is performed with a
123-second half-life contrast agent, which requires co-location with a
cyclotron and a radiochemist. These requirements historically limited the
availability of PET, whereas MRI scanners are much more common.
Another drawback to PET, as noted above, is that subjects have to perform
a task for roughly 40 seconds, rendering a temporal resolution in the tens of
seconds. fMRI on the other hand has a resolution on the order of seconds
for whole brain imaging. This temporal resolution for fMRI makes it
possible to measure the effects of a series of single events with fMRI,
whereas one can only measure long blocks of events with PET. Hence,
many fMRI studies currently use event-related paradigms, which offer
greater flexibility in experimental inquiry. PET is also at a disadvantage
relative to fMRI in terms of spatial resolution. Nonetheless, one advantage
that PET offers over fMRI is that it is not prone to the loss of signal near
air-tissue interfaces as is the case with BOLD contrast fMRI. A second
advantage is that the PET scanning environment suffers from less acoustic
noise than the fMRI environment.
An interesting analogue study of aphasia rehabilitation with PET was done
by (Musso et al.,1999). The authors performed 12 scans on each of four
patients with Wernicke’s aphasia using a comprehension task. In between
those scans, subjects were given intensive training in language
comprehension that involved use of linguistic and non-linguistic cues in a
variety of comprehension tasks. In addition to training in language
comprehension, subjects received a language comprehension test (Token
Test) between the PET scans. Hence, performance on the Token Test could
be correlated with voxel-wise values for regional cerebral blood flow at 12
different time points to determine if changes in performance correlated with
changes in regional cerebral blood flow. Regions best correlated with
training-induced improvement in verbal comprehension included the
posterior right superior temporal gyrus and the left precuneus (Musso et al.,
1999). Findings were taken as an indication of participation of the right-
hemsiphere homologue of Wernicke’s area in language comprehension
gains.
Magnetoencephalography/Magnetic Source Imaging and
Electroencaphalography/Evoked Potentails
Electroencephalography (EEG) and magnetoencephalography (MEG)
represent two noninvasive functional brain imaging methods that work in a
completely different manner than the above described functional imaging
techniques (e.g., fMRI, PET). Both make use of the same neurophysiologic
events, i.e., ionic currents caused by information exchange of neurons.
Active neurons generate small, fluctuating electrical currents. During EEG,
synchronized electrical activity of thousands of active neurons is detected
by means of electrodes that are attached to the scalp. The electric currents
inside the head also produce small magnetic field oscillations that are the
sources of the MEG signal. The strength and orientation of these magnetic
fields can be detected above the scalp by magnetometers inside the MEG
system. As the magnetic fields measured during MEG are very weak (i.e.,
a fraction of the of the earth’s magnetic field) it needs to be assessed within
a magnetically shielded room by using specific recording devices that are
sensitive to extremely small magnetic fields (superconducting quantum
interference devices, SQUID). As a result, MEG devices are extremely
expensive (millions of dollars) while even advanced EEG systems are
relatively inexpensive (several thousand dollars). EEG and MEG signals are
mainly produced by postsynaptic ionic currents of synchronically active
pyramidal cortical neurons. But due to the properties of the neural sources
of the respective signals that are measured during EEG and MEG (electric
current flow vs. magnetic fields that are oriented perpendicular to each
other), EEG is most sensitive to activity generated on top of the cortical
sulci, whereas MEG is more sensitive to activity in the sulci. Thus, both
techniques can provide complimentary information about neural activity
(Babiloni, Pizzella, Gratta, Ferretti, & Romani, 2009).
Similar to other imaging techniques, spontaneous or evoked activity in
response to specific behavior can be monitored (event-related electric
potentials or magnetic fields; ERPs/ERFs). In combination with anatomical
information (e.g., structural MRI) both techniques allow one to estimate the
underlying neuronal generators of the recorded surface activity by using
complex mathematical procedures. The main advantage of
electrophysiological techniques is that they can detect changes in brain
activity with millisecond temporal resolution. Thus, EEG and MEG are the
most direct correlate of online brain processing that can be obtained non-
invasively. On the other hand, the spatial resolution is in the range of
centimeters and thus lower than that obtained during fMRI. MEG offers a
slightly better spatial resolution than EEG, as the magnetic fields measured
are not affected by the surrounding tissue (Johnsrude & Hauk, 2005)
Spontaneous neuroelectric or neuromagnetic activity in the healthy brain is
characterized by rhythmic oscillatory activity in the frequency range above
8 Hz. Focal oscillations in lower frequency ranges (e.g., slow wave activity
in the delta frequency range; 0.5-4 Hz) can be found in the vicinity of
structural lesions (e.g., stroke, tumors) and have been interpreted as
indicative of dysfunctional information processing capacity due to a loss of
afferent input or due to a primary metabolic effect (Kamada et al., 1997).
Mapping of slow-wave activity can be useful to identify dysfunctional
network characteristics in neuropsychiatric disorders (Weisz, Moratti,
Meinzer, Dohrmann, & Elbert, 2005)or to detect changes in brain activity
over the course of recovery and in response to treatment. For example,
(Lewine, Davis, Sloan, Kodituwakku, & Orrison, 1999) demonstrated that
improved neuropsychological functioning after traumatic brain injury was
associated with reduced MEG-slow wave activity. Hensel et al. (Hensel,
Rockstroh, Berg, Elbert, & Schonle, 2004) reported reduced slow-wave
activity to be associated with spontaneous recovery of language functions
after stroke. Moreover, improvement of language functions after speech and
language therapy has been shown to covary with changes in delta frequency
in stroke sufferers (Meinzer et al. 2004) and (de Jongh et al., 2003) found
reduced slow-wave activity after successful resection of brain tumors.
Due to the excellent temporal resolution EEG and MEG have widely been
used to detect spatio-temporal distribution in the brain of higher cognitive
processes, like language functions. For example, during picture naming,
visual and conceptual processes take place within the first 175 msecs after
stimulus presentation, followed by lexical retrieval (until~250 msecs) and
phonological encoding of the word form (250-450 msecs (Indefrey
&Levelt, 2004). After neurological damage different aspects of word-
retrieval can be impaired (e.g., post-stroke anomia). This has been shown
by (Laganaro et al., 2009), who used EEG to compare temporal
characteristics of evoked responses during picture naming in patients with
two different types of anomia. Compared to a group of healthy subjects, the
authors found early event-related potential abnormalities (100-250 msecs)
in patients with lexicalsemantic impairments. In contrast, a group of patients
with predominantly phonological impairments evidenced abnormalities in
later time windows associated with phonological processing (300-450
msecs). Electrophysiological techniques have also been used to track
activity changes in response to treatment. For example, Cornelissen et al.
(Cornelissen et al.,2003) assessed changes in brain activity after speech and
language therapy that was designed to facilitate phonological encoding in
patients with aphasia by means of MEG and magnetic source imaging
(MSI). In line with studies in healthy subjects on phonological encoding
(Indefrey & Levelt, 2004), treatment-induced activity changes were found
in the time window between 300-600 msecs after picture presentation and
were localized in the left inferior parietal cortex, an area associated with
phonological encoding and storage.
Near Infrared Spectroscopy
Near Infrared spectroscopy (NIRS), like the various MR techniques, is a
noninvasive method of looking at brain tissue function. Although visible
light is strongly absorbed by various components in body tissue, light in
the near infrared frequency range (650-900 nm) is less strongly absorbed
and thus can penetrate through the skin and skull and a centimeter or two
into the typical adult brain. In addition to being absorbed by tissue, light is
strongly scattered. This further reduces the light intensity and penetration
and hinders the ability to precisely localize absorbing species. However,
the scattered ligLight absorption at a given wavelength follows the Beer-
Lambert Law, Aλ = ελcl, where A
is the absorption, λ is the wavelength, ε is absorption or molar extinction
coefficient, c is the molar concentration of the absorbing species, and l is
the optical path length. Molecules have different absorption spectra, which
is the variability of the absorption coefficient with wavelength. The major
species in tissue that absorb in the near infrared band and are present in
significant quantities are cytochrome oxidase and hemoglobin, both of
which exist in oxidized and reduced forms with unique absorption spectra.ht
can be used to measure cerebral blood flow.
It is possible to separately quantify the relative amounts of the reduced and
oxidized forms of hemoglobin or cytochrome oxidase by using two
measurement wavelengths (typically 760-780 nm for deoxyhemoglobin and
825-850 nm for oxyhemoglobin) at which the two forms have different
absorption coefficients. A separate measurement at an isosbestic point (815
nm for hemoglobin), a wavelength at which the absorption coefficients of
the two species are equal, provides the total amount of reduced and oxidized
forms, which is proportional to blood volume. From absorptions measured
at these three wavelengths, the concentrations of both oxidized and reduced
species are calculated. Thus NIRS can measure amounts of hemoglobin and
deoxyhemoglobin in tissue, which BOLD fMRI cannot, because BOLD
fMRI signal changes arise from a complex mixture of CBF, CBV, and
oxygenation changes.
In practice, NIRS is applied in vivo by placing a light source and a light
detector adjacent to each other above the region to be measured. The light
path through the tissue between and below them, a convex banana-shaped
tissue region, is sampled.
A combined NIRS-fMRI study of MCA stroke patients in chronic recovery
compared to control subjects demonstrated ipsilateral motor cortex
compensation in the stroke patients (Kato et al. 2002). NIRS monitoring of
mechanically- or therapist-assisted hemiplegic treadmill walking three
months post-stroke showed stronger activation with therapist assistance and
enhanced activation in the unaffected hemisphere (Miyai et al. 2002). A
longitudinal study by the same group with NIRS monitoring at three and
five months poststroke showed decreased activation in the unaffected
hemisphere and increased activation in the affected hemisphere in the
second compared to the first session (Miyai et al. 2003); this shift towards
normal lateralization has also been noted in fMRI studies of hand motor
function. A similar trend towards increased, normal laterality was also noted
in a longitudinal case study of NIRS monitoring of motor cortex activity
during ten consecutive days of constraint-induced movement therapy (Park
et al. 2004). A Japanese group used NIRS to monitor brain effects of 13
rehabilitation tasks in post-stroke hemiplegic patients (Saitou et al. 2000).
NIRS and transcranial Doppler ultrasound have been employed to monitor
arterial blood flow and blood volume changes in response to hypercapnia in
patients with lateralized stroke compared to normal controls (Vernieri et al.
1999). In the patients, NIRS showed an increase of blood volume with
hypercapnia in the spared but not in the lesioned hemisphere. The two
methods were also combined to monitor the effects of vinpocetine on
cerebral blood flow and oxyhemoglobin, deoxyhemoglobin, and total
hemoglobin in the strokeaffected hemisphere (Bonoczk, Panczel, & Nagy,
2002)); vinpocetine increased both CBF and oxygen extraction.
Reviews of NIRS and BOLD fMRI studies of stroke and brain tumors
(Sakatani et el. 2007) and of NIRS studies of stroke rehabilitation
(Strangman et al. 2006) provide an assessment of the opportunities and
challenges. The Strangman (2006) paper also reports results of testretest
reliability for NIRS.
In summary, NIRS has spatial resolution of slightly less than a cm, temporal
resolution of ms to tens of ms, light penetration of only about 1 cm into the
superficial portions of the brain, and the ability to estimate amounts of
oxyhemoglobin, deoxyhemoglobin, and total hemoglobin. Thus, for
superficial brain regions, it is a useful complement to fMRI. Its portability,
relatively low cost compared to MR, ability to be used in a normal and
unconfined environment, and noninvasiveness make it potentially useful
clinically.
Transcranial Magnetic Stimulation
Transcranial magnetic stimulation (TMS) is a painless, non-invasive
neurophysiological technique during which a strong (typically 1 to 2 Tesla)
focal magnetic pulse is directed at cortical areas from a stimulation coil
placed directly above the scalp. The brief (measured in microseconds)
change in magnetic field induces a corresponding electrical potential
change in the affected cortex resulting in a rapid neuronal depolarization
and the generation of action potentials. In the evaluation of the human motor
system, typical output measures of TMS stimulation to the primary motor
cortex (M1) are changes in the electromyographs (EMG) of target muscles
including, if the stimulation is properly applied, the generation of EMG
activity spikes known as magnetic evoked potentials (MEP). For the
purposes of clinical research, TMS is typically delivered using one of three
pulse (coil excitation) protocols: a single pulse, two pulses separated by a
brief delay (paired pulse), or rapid repetitive pulses (rTMS). The utility of
each within the domain of rehabilitative research will briefly be explored.
The oldest and most reported TMS procedure, single pulse TMS refers to
the application of a single magnetic field change during stimulation trials.
The technique has great clinical utility as a diagnostic tool for the motor
system. A prevalent single pulse method in neurology is the assessment of
an individual’s central motor conduction time (CMCT). In this procedure,
a neurologist or technician uses single pulses to M1 representations of
different muscles throughout the arm and hand. Delays or alterations in the
onset and latency of MEP spikes (from coil stimulation events) can
determine if an individual with suspected pathology deviates from age-
matched normal values. Disorders such as multiple sclerosis, amyotrophic
lateral sclerosis (ALS), stroke, leukoariaoisis, and traumatic brain injury can
all affect neural conduction rates from pyramidal cell impetus to the
measured muscle actuation (see Chen et al., 2008 for review). Another
clinical use of single pulse TMS is for mapping of the motor cortex. This
approach is particularly useful in the assessment of cortical plasticity in both
healthy and pathological states. During the mapping procedure, the location
of greatest sensitivity (requiring least stimulator current to produce MEP)
to a target muscle is first identified using a thresholding procedure (see
Kleim et al., 2007). After the “hotspot” is localized, stimulation proceeds at
radially contiguous sites until the boundaries (areas that do not produce
MEP) of the motor map are obtained. Figure 4 shows data from our lab
combining both fMRI and TMS motor maps. Rehabilitation research has
made use of single pulse cortical mapping to monitor change of maps over
time in populations including stroke (Butler et al., 2005; Foltys et al., 2003),
multiple sclerosis (Thickbroom et al., 2005), Parkinson’s disease (PD)
(Fillippi et al., 2001), ALS (de Carvalho et al., 1999), and even those
afflicted with polio (Oliveri et al., 1999).
Paired-pulse TMS is another technique that has been used in rehabilitation
research. In a paired pulse TMS paradigm, two pulses are delivered to the
motor cortex offset by a brief interstimulus interval. The initial pulse is
called the conditioning pulse and is usually relative to the magnitude of
current delivered to the coil during the second stimulation, which is called
the test pulse. Researchers have discovered that variations in the temporal
offset between the two pulses will alter the dynamics of the EMG output,
as does variation of the relative magnetization strength between the
conditioning and test stimulations. These changes can either produce a
faciliatory or inhibitory effect deemed intracortical facilitation (ICF) or
intracortical inhibition (ICI), respectively. Individuals afflicted with stroke
(Manganotti et al., 2008; Swayne et al., 2008; Liepert, 2006) or Parkinson’s
disease (Daeuper et al., 2002) appear to exhibit deviations in levels of both
ICF and ICI as compared to healthy adults. Interestingly, however,
treatments such as constraint-induced movement therapy (CIMT) in stroke
(Liepert, 2006) or stimulation of the subthalamic nucleus after deep brain
stimulation (Daeuper et al., 2002) have shown positive effect in normalizing
ICI and ICF.
Repetitive TMS (rTMS) utilizes a train of TMS pulses delivered at either
slow (up to 1Hz) or rapid (>1Hz) frequencies to alter the firing patterns of
affected cortex. Slow frequency rTMS tends to depress the excitability of a
target region, whereas high frequency has the opposite effect and tends to
increase excitability in affected areas. As opposed to single or paired pulse
TMS techniques, which are applied to the primary motor cortex and whose
output measures are change in EMG signal, rTMS can be applied to any
accessible cortical region including prefrontal, parietal, temporal or
occipital areas. rTMS is being used with greater regularity as a treatment
protocol for an increasing number of disorders. For example, in stroke
recovery, Naeser et al. (2005) used low frequency rTMS with patients
afflicted with Broca’s aphasia to improve naming ability without
concomitant speech therapy. rTMS has also been used in the treatment
depression (Paus & Barrett, 2004), Parkinson’s disease (Lefaucheur, 2006),
chronic pain (Leo & Latif, 2007), dystonia (Lefaucheur et al., 2004),
schizophrenia (Fitzgerald and Daskalakis, 2008) among many others.
Compared with other modalities of neurological research, TMS, as a
technique, offers some significant advantages. First, single and paired-pulse
TMS allows for direct inquiry into th activation of corticospinal tract, and
its measure (EMG change) can increase or decrease in magnitude relative
to the amount of current applied through the magnetic coil. Conversely,
fMRI and PET are indirect measures of neural activity which rely on
correlates of blood flow to index activity relative to a comparison state.
Measured responses in these modalities are therefore dependent on and
limited by the dynamics of the human cerebrovascular system. The motor-
related TMS procedures also benefit from the TMS’ excellent temporal
resolution in that MEP responses to TMS stimulation in target muscle
typically occur from 18-30 milliseconds after stimulation. Responses in
imaging modalities are limited to seconds (fMRI) or tens of seconds (PET)
to derive their respective responses. Finally, TMS offers great practical
advantages over other modalities in that the typical TMS apparatus is both
inexpensive (tens of thousands as compared to millions for fMRI, MEG and
PET) and quite portable (a single pulse system easily fits on a small cart).
However, TMS is beset by some limitations, as well. Primary amongst these
is the fact that the magnetic field produced by TMS coils can only show
effects at a depth of less than two centimeters from the stimulation site.
TMS can therefore only be used with cortical areas, whereas fMRI and PET
can also be used to probe subcortical processes. A second limitation of TMS
is its spatial resolution, which due to size of the delivery coil and the
diffusion of the generated magnetic field, is limited to about 1 cm2. Finally,
great care has to be taken in the screening of participants and adherence to
safety procedures due to the potential of headache and seizure from the
stimulation, particularly for rTMS.
Given the strengths and limitations of TMS in comparisons with imaging
modalities, many researchers have begun to combine the
neurophysiological technique with fMRI, particularly when using single or
paired pulse designs. Our lab has made use of the combination of the two
techniques in the assessment of cortical maps of the FDI muscle (Figure 4).
It is now possible to perform TMS stimulation while in the MRI scanner
(Bohning et al., 1998), a procedure being employed with greater frequency
as the technology becomes more widely available.
CONCLUSIONS
The potential impact of functional neuroimaging for rehabilitation research,
and ultimately for rehabilitation care, can hardly be overestimated. If
functional neuroimaging can help define how brain systems reorganize
during rehabilitation, it may be possible to design treatments that enhance
reorganization and thereby optimize rehabilitation. Further, it also is
possible that functional imaging results will be found to predict
rehabilitation outcome, including which treatments are optimal for patients
with specific patterns of brain activity during tasks relevant to
rehabilitation. Although the collection of a knowledge base adequate to
impact clinical rehabilitation on a day-to-day basis may be years, or even
decades away, important discoveries starting us down this path have already
been made.
Advances in imaging over the past two or three decades have left
rehabilitation investigators with a variety of tools to assess functional brain
networks for behavior and cognition. These techniques include fMRI, PET,
MEG, EEG, NIRS, and TMS, all of which were discussed briefly above.
Each technique has strengths and weaknesses relating to cost, availability,
temporal resolution, spatial resolution, and risk. For example, fMRI has
become by far the most widely used technique for functional imaging
because of its widespread availability, ability to perform structural images
on the same acquisition platform as functional images, and excellent spatial
resolution. However, fMRI does not have a temporal resolution capable of
defining in real time the cascade of neuronal events in brain systems like
EEG or MEG can, and the widely used BOLD contrast technique is
vulnerable to signal loss near air-tissue interfaces. Although selection of an
imaging technique for research is often a matter of instrument availability
and convenience, the kind of information necessary to answer experimental
questions also should be given some consideration in designing
rehabilitation studies. In addition to functional neuroimaging techniques,
new developments in structural neuroimaging, i.e., the use of diffusion
imaging techniques to define degree of white matter loss/integrity, can also
enhance our understanding of substrates for rehabilitation.
Rehabilitation clinicians and rehabilitation researchers who do not
participate in imaging research are consumers of neuroimaging research in
rehabilitation. To be discerning consumers, it is necessary to have some
fundamental knowledge of functional neuroimaging techniques. We have
tried not only to provide such fundamental information but also to refer the
interested reader to additional sources of further information. The next
decade or two is likely to bring important advances in our knowledge about
brain systems, their plasticity, and their role in rehabilitation. Our ability to
digest this information and use it in our clinical endeavors will enhance the
lives of our patients.
Hemodynamic response expressed as a percent change of the total signal.
Note the positive phase of the response takes around 12 sec to resolve.

Pre- and post-treatment images for one subject who received the intention
treatment. Red represents R2 ≥ .20; orange represents R2 ≥ .25. Note the
lack of left frontal activity on postcompared to pre-treatment images, and
the general reduction in frontal activity from pre to post treatment. Lateral
frontal laterality indices are displayed at the bottom of the image, with 1.0
representing activity entirely lateralized to the left and -1.0 representing
activity entirely lateralized to the right.

Schematic diagram for ASL imaging. The labeling of arterial blood is

proximal to the tissue of interest, as shown by the blue plane at left. After a
delay to let labeled blood to arrive at the tissue sites, imaging acquisitions
will be performed. In some ASL techniques, control experiments will be
done using the symmetric labeling RF pulse at the distal site to minimize
the MT effects (light blue plane at right). Crosson et al. Page 29 J

CBF maps (left) and asymmetry analysis results (right) from ASL perfusion
study of a 76 year-old female stroke patient. Asymmetry index (%) =
(CBF(right) - CBF(left))/ (CBF(right)+CBF(left)) × 100. Specific perfusion
territories are designated by ACA (anterior cerebral arteries), MCA (middle
cerebral arteries), and PCA (posterior cerebral arteries). In the bar graph,
the negative index value for ACA is indicated with a different pattern. In
the CBF maps, brighter colors indicate greater CBF. Note the decreased
CBF in the posterior right side of the images, consistent with the greater
asymmetry in CBF for the posterior cerebral artery (PCA) distribution
compared to the anterior cerebral artery (ACA) and middle cerebral artery
(MCA).

DW-MRI measures from left to right, top row: mean diffusivity (MD) map,
fractional anisotropy (FA) map; bottom row: FA map overlaid with the
principle diffusion direction (PDD) in color (red left to right, blue inferior
to superior, green anterior to posterior). Bottom right: 3-dimensional
rendering of previously undocumented fiber paths connecting Broca’s area
(Brodmann’s areas 44/45) with Brodmann’s area 9 (light green).
An example 1H spectrum, acquired at 3T, of the left basal ganglia of a
normal control subject, post-processed in LCModel. Metabolites included
in the modeled basis spectra are shown in the table on the right. Those
detected with a reasonable confidence are in blue font. The %SD indicate
Cramer-Rao lower error bounds.

Cortical motor map of first dorsal interosseous (FDI) muscle using single
pulse TMS overlaid onto 3-Dimensional rendering of fMRI activation
during FDI exercise. Site 74 (blue circle) represents cortical site of maximal
sensitivity to FDI activation (aka the “hotspot”). Green circles are areas that
also generate MEP in the target muscle, while red circles are the map’s
boundary. Orange areas represents active areas during fMRI at F > 5.0
(p<.0001,uncorrected).