Steven C. Cramer
Functional Imaging in Stroke Recovery
ISSN: 1524-4628
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doi: 10.1161/01.STR.0000143326.36847.b0
2004, 35:2695-2698: originally published online September 23, 2004Stroke
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Functional Imaging in Stroke Recovery
Steven C. Cramer, MD
Abstract—Assessing neurobiology of brain systems can provide information not available from anatomic or behavioral
assessment. Such information may be of value in understanding, defining, and prescribing potential therapeutic
interventions that target restorative brain events after stroke. A number of methods have been used to study stroke
recovery, each with its relative merits and limitations. Several studies suggest that greater injury is associated with
reduced laterality of brain activity. This might be in relation to changes in interhemispheric inhibition and is a
phenomenon that is likely useful for functional gains in some patients. Many other features of brain activity change in
the months after a stroke, including the site and size of activation in relevant brain network nodes. While there is
incomplete agreement regarding which features of altered brain activity predict and parallel better behavioral outcome,
studies converge on the conclusion that best outcome is achieved by activating the brain in a pattern that most resembles
the normal state. (Stroke. 2004;35[suppl I]:2695-2698.)
Key Words: human brain mapping Ⅲ plasticity Ⅲ recovery of function Ⅲ stroke
The changes that arise in the brain over the weeks after a stroke
have been described at multiple levels. Cellular and molecular
studies in animals undergoing an experimental unilateral infarct
have characterized numerous bilateral events, but molecular data are
often difficult to measure in human patients. At the other end of the
spectrum, numerous studies have characterized the behavioral
evolution after stroke. A wide range of brain events can produce the
same behavioral phenotype, however. The best approach to treatment
might arise from a more precise understanding of stroke
physiology than is available from behavioral assessment. Functional
imaging, between the molecular and behavioral levels, provides
insights into brain changes at the systems level.
In some cases, functional imaging data provide biological insights
when behavioral examination or anatomic brain imaging
does not. For example, when neurological examination is normal,
genetic risk for dementia is described by functional magnetic
resonance imaging (fMRI) results.1 The brain effects of HIV
infection can be measured with fMRI even when behavioral
examination is normal.2 In patients with neurological deficits after
traumatic brain injury and normal anatomic MRI scans, positron
emission tomography (PET) scanning measures related changes in
cortical function.3 When stroke renders a patient hemiplegic and
examination is thus silent, fMRI permits measurement of activity
across brain motor networks.4 Even in patients without a neurological
diagnosis, functional brain imaging studies can measure differences
in cognitive reserve.
Studies suggest that a number of therapeutic approaches to
improving recovery are on the horizon, including cells, small
molecules, growth factors, robotic interventions, and intensive
physiotherapy. The details of therapeutic administration (How will
therapy be administered? To which subgroups will therapy be
administered? When will therapy be started, and for how long?) will
come from understanding the biological targets. Functional brain
imaging after stroke has the potential to provide such data.
Key Questions Raised in Considering
Functional Imaging of Stroke Recovery
Imaging brain function in the setting of stroke recovery raises
certain questions: (1) Which features of brain function change
after a stroke? (2) What is the relationship between strokerelated
changes in brain function and behavioral outcome?
These 2 questions are considered below, although precise
answers require further study. (3) How might key functional
imaging information from stroke patients be used to improve
clinical outcome and reduce disability?
The third question seeks to extract key physiological data to
improve clinical decision making and has precedence in medical
practice. When a patient presents with a ventricular tachyarrhythmia
or a refractory epileptic disorder, current practice often incorporates
electrophysiological data to guide specific decisions in treatment.
PET scanning of the brain is used to guide decision making in
treatment of brain tumors and for surgical planning. Note that much
of the enthusiasm for this goal is predicated on the assumption that
interventions will be clearly identified that can improve patient
outcomes.
Multiple Methods Used to Study Brain
Function After Stroke
No single method is sufficient to measure all aspects of brain
function; each has its relative advantages and limitations.
Many studies use fMRI with blood oxygenation level–
dependent contrast. This method has good temporal and
excellent spatial resolution, and fMRI data can be acquired in
Received June 11, 2004; accepted August 5, 2004.
From the Department of Neurology and the Department of Anatomy and Neurobiology, University of California, Irvine.
Correspondence to Dr Steven C. Cramer, University of California Irvine Medical Center, 101 The City Dr S, Bldg 53, Room 203, Orange, CA
92868-4280. E-mail scramer@uci.edu
© 2004 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org DOI: 10.1161/01.STR.0000143326.36847.b0
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the same session as scans for brain anatomy, tractography,
perfusion, injury, and spectroscopy. However, this method
measures shifts in blood flow as they are linked to neuronal
activity. Vascular pathology and altered cerebral blood flow
might influence some findings, although we have found that
stroke hemisphere cerebral blood flow can be reduced an
average of 21% with no reduction in brain activation.5
PET scanning has limited temporal resolution, but spatial
resolution has improved to be comparable to fMRI. Signal
change with brain activation is typically 10-fold greater than
with fMRI. Some PET scans measure flow and thus may
share the perfusion-related concerns that are raised with fMRI
in the setting of stroke. An advantage of PET scanning is the
ability to measure tissue metabolism, viability of ischemic
tissue, neurochemistry, and receptor kinetics.
Transcranial magnetic stimulation (TMS) provides insights
into neurophysiology of the motor system, including conduction
velocity, motor-evoked potentials, cortical inhibition,
and cortical excitability. Although spatial resolution is limited,
temporal resolution is at the millisecond level. The cost
of setting up TMS and then studying patients is less expensive
than the costs associated with fMRI and PET. TMS is
also capable of producing a virtual lesion in nonmotor brain
areas. TMS is generally used to study a limited portion of the
brain, whereas fMRI and PET scanning generally study most
or all of the brain at once.
Brain mapping methods such as electroencephalography, magnetoencephalography,
near-infrared spectroscopy, and optical imaging
have been used less frequently to date in the study of stroke
recovery. These methods generally provide millisecond temporal
resolution with somewhat limited spatial resolution.
A few studies have used multiple brain mapping modalities
during patient examination. Such combinations can provide a
powerful approach, for example, constraining neurophysiological
measurements to specific brain areas that show task-related
activation.
Factors Limiting the Current Understanding
of Events Underlying Stroke Recovery
Many patterns of altered brain function have been described
during the study of patients with stroke. The present review is
not intended to be exhaustive. The reader is referred elsewhere
for such treatments in the literature.6–8
Initial functional imaging studies were small and crosssectional.
Subsequent studies have examined stroke patient
subpopulations, increased sample size, correlated features of
brain activation with clinical measures, and monitored patients
over time. These studies have provided insights into
changes in the brain after stroke and have generated hypotheses
for subsequent investigations. However, the overall
understanding of changes in brain function after stroke, as
well as the relationship between these changes and clinical
measures, remains limited, in part because of the relative
dearth of such investigations. However, 2 other factors limit
the pace with which the literature clarifies the current
understanding of poststroke restorative events in humans.
First, numerous covariates likely modify brain function after
stroke (Table). Some of these are also important to the study of brain
function in health, while others are important to the study of brain
function in the setting of acute stroke. Additional study is required
to understand the effects and interactions arising from variables such
as those listed in the Table.
A second issue complicating the field of functional imaging
in stroke recovery is the divergence of investigative
approaches and reporting. Small differences in attention or in
the method used to activate the brain can have a major effect
on findings. However, poststroke functional imaging studies
rarely use identical brain activation methods. This is further
complicated by variability in methods used to analyze, define
the significance of, and report functional imaging results.
A related issue is the variability in clinical reporting
methods for stroke recovery. This contrasts with research
reports in multiple sclerosis, in which the Multiple Sclerosis
Functional Composite is routinely included, and in spinal
cord injury, in which the American Spinal Injury Association
scores and Impairment Scale are routinely reported.
It is true that acute stroke studies have been somewhat
consistent in incorporation of certain global stroke outcome
scales, but stroke recovery studies will likely need systemspecific
scales for 2 reasons. First, for a compound to be
effective in improving stroke recovery, abundant data suggest
that it must be coupled with relevant experience. Restorative
interventions will therefore likely focus on one or a few brain
systems such as motor or language. Appropriate scales for each
system are needed to detect treatment effects because global scales
would not likely have adequate sensitivity. Second, functional
imaging studies generally use a specific behavior to activate the
brain and thus are also focused on specific brain systems. While
specific approaches are sometimes needed to answer hypothesisbased
research, it is also true that adoption of standardized approaches
to some aspects of clinical assessment and functional
Clinical Variables That Potentially Influence Stroke Recovery
and Its Measurement by Functional Imaging
Stroke topography
Time after stroke
Age
Hemispheric dominance
Side of brain affected
Depression
Injury to other brain network nodes
Infarct volume
Initial stroke deficits
Arterial patency
Medical comorbidities
Prestroke disability
Prestroke experience and education
Type of poststroke therapy
Amount of poststroke therapy
Acute stroke interventions
Medications during stroke recovery period
Medications at time of brain mapping
Final clinical status
Stroke mechanism
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imaging in stroke recovery might facilitate a broader understanding
of the issues.
Changes in Brain Function Described
After Stroke
Despite these factors, a number of findings emerge from an
overview of functional imaging studies after stroke. The
earliest finding, which has been replicated repeatedly, was a
change in multiple nodes within relevant distributed networks.
Clearly, ischemic injury to one area changes function
in numerous connected brain regions.
One finding that might be of particular importance to
understanding stroke recovery in humans is a reduction in the
laterality of brain activity. Figure 1 presents a model that
compiles some results from animal and human studies. This
issue has also received considerable attention in the study of
normal aging. Early reports emphasized a less lateralized
pattern of activation after stroke than normal, ie, the effect of
stroke is to increase the extent to which both hemispheres are
recruited rather than just the contralateral hemisphere. Increasing
evidence emphasizes the importance of measuring
laterality across specific homologous brain areas, eg, changes
in laterality of primary motor cortex may be most informative
when measurements are restricted to this brain region rather
than combined with premotor cortex.
A number of factors modify the extent to which stroke is
associated with reduced laterality. Examples include time
after stroke, injury to dominant versus nondominant hemisphere,
and depth of injury. Other factors relevant to laterality
in normal subjects are also likely important after stroke, such
as task complexity, age, task familiarity, proximal versus
distal movement, and perhaps sex.
Several studies suggest that increased activity in the
nonstroke hemisphere after stroke, ie, reduced laterality,
reflects greater injury and/or deficits (Figure 2b). TMS
studies have further suggested possible mechanisms for this
finding. In primary motor cortex, stroke hemisphere inhibition
on the nonstroke hemisphere is reduced, and nonstroke
hemisphere inhibition on the stroke hemisphere is increased.
Reduced laterality might not merely reflect more severe
stroke or passive changes in inhibition, however. Some
studies suggest that changes in laterality of brain function
might nonetheless be important to whatever behavioral recovery
is achieved after stroke, even if the final behavior is
subnormal.9 Indeed, a number of cases have been published
in which brain activity is virtually restricted to the nonstroke
hemisphere, contralateral to results in controls for motor
tasks. Figure 2b provides an additional example.
Shifts in the site of activation have also been reported after
stroke in all directions. The most common changes described
in the motor system have been a ventral or a posterior shift in
the contralateral (stroke hemisphere) activation site during
task performance by the stroke-affected hand. Some data
suggest that, at least for hand motor recovery, a ventral shift
might be associated with better recovery of function. A
posterior shift in activation site has been described in motor
studies of stroke recovery across multiple imaging modalities
and has also been described in the motor system of patients
with multiple sclerosis or spinal cord injury, but its clinical
significance remains to be defined.
Studies have described changes in activation size in many
brain areas in the setting of stroke recovery. TMS studies
converge on the conclusion that progressive expansion in the
area of excitable primary motor cortex within the stroke
hemisphere during the period of stroke recovery is a feature
of patients with superior motor outcomes. In some serial
functional imaging studies, the correlate of better clinical
outcome has been increased activation in key strokehemisphere
areas (Figure 2a), but in other studies, the
correlate has been reduction in such activation. These differences
across fMRI studies might arise from divergence in
time after stroke at which investigations are performed, in the
task used to activate the brain, in the patient populations
enrolled, or in other variables. One unifying conclusion
across these studies is that the best outcomes are associated
with the greatest return to the normal state of brain function.
Indeed, when our laboratory applied the very same fMRI
probe (tapping the affected index finger at 2 Hz across a
25-degree range of motion with eyes closed in a 1.5-T
magnet), we found that, compared with age-matched controls,
activation volume is decreased with stroke10 and increased
with spinal cord injury.11 Together, these observations suggest
that a particular brain mapping method will have the best
clinical validity when applied to a specific patient population.
Increased activity along the rim of a cortical infarct has
been described in fMRI and PET studies. These observations
might correspond to several physiological events or to the
Figure 1. Changes in bilateral brain areas after unilateral stroke
have been grouped into 3 time periods. First, in the initial hours/
days after a stroke, brain function and behavior can be globally
deranged, and few restorative structural changes have started.
Second, a period of growth then begins, lasting several weeks.
Structural and functional changes in the contralesional hemisphere
precede those of the ipsilesional hemisphere, and at
such times activity in relevant contralesional areas can even
exceed activity in the lesion hemisphere. This growth-related
period may be a key target for certain restorative therapies.
Third, subsequently, there is pruning, reduction in functional
overactivation, and establishment of a static pattern of brain
activity and behavior. The final pattern may nevertheless remain
accessible to plasticity-inducing, clinically meaningful interventions.
An excess of growth followed by pruning has precedence
in human neurobiology, being a recapitulation of normal developmental
events. Supranormal and subnormal activity levels in
the ipsilesional and contralesional hemispheres correlate with
features of behavioral outcome in specific patient populations,
as described above. CBF indicates cerebral blood flow; CMRO2,
cerebral metabolic rate of oxygen; and Rx, treatment.
Cramer Functional Imaging in Stroke Recovery 2697
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increased levels of growth-related proteins measured along
the rim of experimental infarcts introduced into animals.
Diaschisis may also be an important process related to behavioral
recovery after stroke. Brain areas connected to, but spatially distant
from, the region of infarction show numerous changes after stroke.
For example, we found several patients with a behavioral deficit
early after stroke associated with failure to activate the brain area
underlying that behavior despite normal resting cerebral blood flow
in the area and lack of injury to the area; behavioral recovery was
associated with restitution of brain activity.12 While numerous
methods have been used to describe diaschisis, this process may be
measured directly with the use of [18
F]fluorodeoxyglucose PET.
Summary
Functional imaging of stroke recovery is a unique source of
information that might be useful in the development of
restorative treatments. A number of features of brain function
change after stroke. Current studies have defined many of the
most common events. Key challenges for the future are to
develop standardized approaches to help address certain
questions, determine the psychometric qualities of these
measures, and define the clinical utility of these methods.
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Figure 2. fMRI activation maps are
superimposed on brain anatomy, with
significance of activation indicated on
the color bar. Images are in radiological
convention. a, Activation volume in the
stroke hemisphere during movement of a
stroke-affected limb is related to degree
of behavioral recovery. Patients with
chronic stroke underwent fMRI scanning
while alternating rest with tapping the
index finger on the right, affected hand.10
Six patients had full recovery, and 5 had
excellent but only partial motor recovery.
Note that activation volume in the supplementary
motor area (green arrowheads)
was independent of degree of
recovery. However, the patients with partial
recovery showed activation volume in
the left primary sensorimotor-premotor
cortex (green arrows) that was 37% of
the volume activated in patients with full
recovery. Each pair of slices is at the
level of Talairach zϭ40 and zϭ57. b,
After stroke, activation can shift almost
entirely to the nonstroke hemisphere,
especially for larger strokes. Top row
shows a control subject alternating rest
with unilateral (right) contraction of the
risorius, a lower face muscle. Activation
is approximately equal in the right and
left primary sensorimotor cortex. Bottom
row shows a patient with a moderate to
large infarct (70 cm3
) that destroyed 52%
of the normal contralateral face motor
representation. The patient alternated
rest with unilateral (left) risorius contraction.
Activation is almost entirely in the
left (nonstroke) hemisphere, ipsilateral to
movement. This change in brain activation
pattern reflects greater injury but
may nevertheless be important to maintenance
of function.
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