Transcript document

Functional Magnetic Resonance
Imaging: Emerging Clinical
Applications
Heather A Wishart,PhD, Andrew J.Saykin,PsyD,
Thomas W.McAllister,MD
Introduction
 Magnetic Resonance Neuroimaging techniques
are shedding new light on brain mechanisms and
clinical management of various neurological and
neuropsychiatric disorders.
Introduction
 Brief Review of fMRI Imaging
 Use of fMRI in clinical practice Precautions
 Use of fMRI in clinical practice
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Neurosurgery candidates
Schizophrenia
Cognitive Impairment and Alzheimer’s Disease
Traumatic Brain Injury
Multiple Sclerosis
Research on Neuro-plasticity in the Adult Human
 Conclusions
Review of fMRI
 Most fMRI studies are based on the blood-oxygen-leveldependent (BOLD) method, where the MRI signal derives
from local changes in the ratio of deoxygenated to
oxygenated hemoglobin that occur during neural events.
 Deoxy- and oxy-hemoglobin differ in their magnetic
properties.
 Statistical parametric maps are derived and overlaid on
anatomical images reflecting statistically significant signal
changes in different brain regions (1-4% signal change
from control to event at conventional field strength.
 fMRI has high spatial and temporal resolution permitting
the observation of transient and prolonged neural events.
Use of fMRI in clinical
practice~precautions
 There are numerous technical issues that must be accounted for
when applying fMRI to the clinical population.
 The illness may make it impossible for the patient to
remain still (movement disorders). This artifact can be
addressed to some extent but may introduce other
forms of error during post processing.
 Patients with cognitive deficits may not be able to
follow the test instructions. Extensive training and
assurance during scanning may be useful and it is
important not to presuppose that the presence of a
neuropsychiatric disorder will necessarily adversely
affect scanning.
 Do group differences in brain activation reflect the
disease or the simple fact that they were performing
the task differently or incorrectly?
 This may be addressed by using different levels of
difficulty including those that can be completed
equally well by patients and control subjects.
Use of fMRI in clinical practice~precautions
 Other problems that require consideration include disease related
changes in the coupling of neural activity and the hemodynamic
response***, as well as the presence of medications that alter
psychological state or BOLD response in the patient group.
 Precautions must be taken at the individual level when
interpreting results for the planning of surgical interventions.
***FIG 1. A and B, Functional maps generated from the event-related, visually cued bilateral motor task for a
patient with occlusion of the right internal carotid artery. Two axial images are shown with a cross-correlation
threshold of r > 0.3. Note that the motor cortex ipsilateral to the lesion (right side) shows minimal or absent
activation as a result of the occluded right internal carotid artery (blue circle), a finding corroborated by the
blood flow velocity results of the transcranial Doppler US examination.1
Use of fMRI in clinical practice~precautions
 Other problems that require consideration include disease related
changes in the coupling of neural activity and the hemodynamic
response***, as well as the presence of medications that alter
psychological state or BOLD response in the patient group.
 Precautions must be taken at the individual level when
interpreting results for the planning of surgical interventions.
*** A and B, Functional maps generated from the block motor task for a right internal carotid artery
occlusion (same patients as in Figure 1). Two axial images are shown at the same anatomic level as
that obtained for the event-related maps in Figure 1, but with a cross-correlation threshold of r > 0.45.
Note the strong bilateral activation in the motor cortex. 1
Use of fMRI in clinical practice~precautions
 In other words the event-related scans made it
appear as though there was no activity ipsilateral
to the vascular occlusion, whereas the block
design consisting of 30 second active intervals
revealed bilateral activation as would have been
expected.
 “The vascular disease inherent to our
patient population may have curtailed the
increase in blood flow to the expected area
of activation that normally occurs
subsequent to motor activity”1
1:(Hemodynamic Response Changes in Cerebrovascular Disease: Implications for
Functional MR ImagingLeo M. Carusonea, Jayashree Srinivasanb, Darren R.
Gitelmanc,d, M. Marsel Mesulamd and Todd B. Parrisha,c)
Use of fMRI in clinical practice cont’d:
Neurosurgery Candidates
 fMRI is used in the assessment of individuals about to
undergo functional neurosurgery for example:[to identify
particular regions in the brain which can be considered
“functional organs at risk (fOARs)] (Medical Physics,
Vol.34, No.4 pp.1176-1184, April 2007)
 Resection (cut away) of seizure foci
 Neoplasms (metastatic cancer foci) Neoplasia is the scientific
term for the group of diseases commonly called tumor or cancer
(From Wikipedia)
 Vascular malformations
Use of fMRI in clinical practice
cont’d: Neurosurgery
Candidates
Resection of seizure foci
"fMRI gives the surgical
team an important
roadmap of the brain
function without contrast
injections or invasive
tests”(http://www.sciencedai
ly.com/releases/2005/06/050
628063632.htm)
Use of fMRI in clinical practice
"fMRI gives the surgical
cont’d:
Neurosurgery
team an important
roadmap of the brain
Candidates
function without contrast
injections or invasive
tests”(http://www.sciencedai
Neoplasms (metastatic cancer foci)
ly.com/releases/2005/06/050
628063632.htm)
Fig B.
Fig A.
Use of fMRI in clinical practice
cont’d: Neurosurgery
Candidates
Vascular malformations
"fMRI gives the surgical
team an important
roadmap of the brain
function without contrast
injections or invasive
tests”(http://www.sciencedai
ly.com/releases/2005/06/050
628063632.htm)
Use of fMRI in clinical practice
cont’d: Neurosurgery
Candidates
Vascular malformations
In a clinical setting two
problems must be solved.
First of all the exact
localization on the brain of the
cortical reorganization has to
be demonstrated. This is done
by means of a functional MRI.
This is a classical MRI scan
where two scans are
combined : a normal
brainscan and a scan
performed during auditory
exposure.
http://www.oorsuizen.be/neurochir_EN
.htm
Use of fMRI in clinical practice cont’d:
Neurosurgery Candidates
 fMRI is used in the assessment of individuals about to undergo
functional neurosurgery for example:[to identify particular
regions in the brain which can be considered “functional organs
at risk (fOARs)] (Medical Physics, Vol.34, No.4 pp.1176-1184, April
2007)
 Resection (Cut away) of seizure foci
 Neoplasms (metastatic cancer foci) Neoplasia is the scientific term for
the group of diseases commonly called tumor or cancer (From Wikipedia)
 Vascular malformations
 fMRI is used to Identify whether resection site is in or near
critical regions for language, memory, or movement.
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fMRI has been shown to have good agreement between Wada
(intracarotid amobarbital) tests and electrical stimulation mapping which
are invasive procedures.
fMRI yields additional intrahemispheric data and is not limited by
lateralization of functions.
TO THE EXTENT POSSIBLE ACTIVATED AREAS AROUND
LESION ARE AVOIDED DURING SURGERY
Use of fMRI in clinical practice cont’d:
Schizophrenia
 WHAT IS SCHIZOPHRENIA?
 is a psychiatric diagnosis that describes a mental disorder
characterized by abnormalities in the perception or
expression of reality. It most commonly manifests as
auditory hallucinations, paranoid or bizarre delusions or
disorganized speech and thinking in the context of
significant social or occupational dysfunction.
 The symptoms of schizophrenia are often divided into two
groups:Positive symptoms, for example, hallucinations and
delusions. Negative symptoms, for example, flat affect,
apathy and poverty of speech, social withdrawal, and
depression.
http://www.sfnsw.org.au/schizophrenia/symptoms.htm
Use of fMRI in clinical practice cont’d:
Schizophrenia
 fMRI has been used to extend scientific understanding of the
neural basis of Schizophrenia.
 Working memory cognitive deficits have been hypothesized to
be a key cognitive deficit in some sub-types of Schizophrenia.
 fMRI reveals reduced activation of frontal and parietal regions
on working memory tasks in the patient group.
Decreased brain activity in schizophrenia
subjects (S) compared to normal controls(N)
in an fMRI study examining executive
functioning.
Image courtesy of Prof. Philip Ward,
NISAD Cognitive Neuroscience Research
Panel.
(http://www.schizophrenia.com/disease.htm)
Use of fMRI in clinical practice cont’d:
Schizophrenia
 fMRI replicates previous findings of hypofrontality.
 These results also suggest that impaired activation of frontal
regions during working memory task is related to thought
disturbances: thought content- a result of fronto-parietal systems
dysfunction.
 Other studies have shown vis-à-vis medication-naïve patient
samples increased brain activation compared with healthy
control samples. (when medication and performance artifacts are
taken into account).
 An excessive recruitment of neural processing power during
reasoning tasks may be associated with Schizophrenia.
 Atypical antipsychotics may normalize this excessive activity.
Use of fMRI in clinical practice cont’d: Schizophrenia

In another study Muller et al. demonstrated excess subcortical
activation during a simple motor task in untreated Schizophrenics
compared to those treated with various antipsychotic agents and the
healthy controls.
Use of fMRI in clinical practice cont’d: Schizophrenia
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Zorrilla et al. recently found a group
difference in activation patterns underlying
memory for recent information in
schizophrenia.
“The medial temporal lobe includes a system
of anatomically related structures that are
essential for declarative memory (conscious
memory for facts and events). The system
consists of the hippocampal region (CA fields,
dentate gyrus, and subicular complex) and the
adjacent perirhinal, entorhinal, and
parahippocampal cortices.”
(http://arjournals.annualreviews.org/doi/abs/1
0.1146/annurev.neuro.27.070203.144130)
Medial temporal activation was inversely
related to subsequent recognition memory in
healthy control individuals, the opposite
pattern occurred in patients.
http://www.nada.kth.se/~asa/bilder/MTL.jpg
Use of fMRI in clinical practice cont’d: Schizophrenia
 Studies have also found:
 A failure in patient groups in the coupling of reaction time
and bilateral parietal activation that is seen in normal
subjects.
 In examining Schizophrenic patients’ deficit in interpreting
the mental state of others (“theory of mind”) Russell et al.
found less BOLD signal in the left inferior frontal gyrus in
patients.
http://content.answers.com/main/content/wp/en/thumb/0/00/250px-Inferior_frontal_gyrus.png
Use of fMRI in clinical practice cont’d: Schizophrenia
 Converging lines of evidence show an interplay of brain
structure and function and behavioral and environmental factors
in the causation of such disorders. (RECIPROCAL
DETERMINSM).
 Abnormalities of brain structure and function may lead to
symptoms (unidirectional view) but years of abnormal
functioning and exposure especially during childhood
development may lead to structural and functional
abnormalities.
 Bringing it together:
 Mesolimbic (projections from limbic system to forebrain)positive symptoms- shows higher activation in schizophrenics in
a hypofrontality (negative symptoms) setting. Normal subjects
only show this activation pattern in a threat situation.
(http://www.annalsnyas.org/cgi/content/abstract/877/1/562)
 QUESTION: (relative to the environment)
 Do you think that abnormalities in higher cognitive
functions (cortical) cause changes in mesolimbic activity
(motivation/emotion eg. Fear)? Or do changes in
mesolimbic activity subsequently cause functional and
structural changes in the cortex? (resulting in thought
disturbances)
Use of fMRI in clinical practice cont’d: Schizophrenia
 PROBLEM: In some studies activation for patients did not
remain stable across test-retest fMRI scans despite stable task
performance. Thus many sources of variation exist in fMRI
studies of schizophrenia.
Use of fMRI in clinical practice cont’d: Cognitive
Impairment and Alzheimer’s Disease
 What is Alzheimer's Disease?
 Alzheimer's disease (AD), also called Alzheimer disease or simply Alzheimer's,
is the most common type of dementia. Alzheimer's is a degenerative and
terminal disease for which there is no known cure.
 Research indicates that the disease is associated with plaques and tangles in the
brain
Histopathogic image of
senile plaques seen in
the cerebral cortex in a
patient with Alzheimer
disease of presenile
onset.
http://en.wikipedia.org/wiki/Image:Alzheimer_dementia_%283%29_presenile_onset.jpg
Use of fMRI in clinical practice cont’d: Cognitive
Impairment and Alzheimer’s Disease
 Episodic memory is
a component of
Declarative
memory (remember
medial temporal
slide?)
 Episodic memory
impairment is a
primary cognitive
feature of
Alzheimer's disease
(AD). Consistent
with pathologic and
structural imaging
fMRI shows
evidence of
reduced
hippocampal
formation
activation in AD
patients during
episodic memory
encoding.
http://3d-brain.ki.se/atlas/images/limbic.jpg
Use of fMRI in clinical practice cont’d: Cognitive
Impairment and Alzheimer’s Disease
 In a study of visual stimuli encoding, Kato et al. compared young and
older control individuals with mild AD patients and found that all
subjects activated the visual cortex, but the patients failed to activate the
entorhinal cortex as well as other temporal regions and frontal areas
involved in episodic memory. They also showed reduced
intrahippocampal functionality.
Use of fMRI in clinical practice cont’d: Cognitive
Impairment and Alzheimer’s Disease
 Reduced activation of frontal regions has been seen in AD patients during
episodic memory retrieval; within this group hippocampal volume was
related to preservation of frontal activation.
 AD patients show greater spatial extent of frontal activation compared
with control individuals on the same task. This increased activation was
directly related to the degree of atrophy in the same brain region.
 This supports the compensatory hyperactivation hypothesis which
suggests that greater neuronal recruitment is required in AD patients
to complete the same task as the control subjects even when their
accuracy was the same or lower than the control group.
 In neurologically intact individuals who carry a genetic risk for AD,
increased activation in temporal, parietal, and prefrontal regions has been
reported during episodic memory processing.
 fMRI may someday serve as a biomarker method to potentially identify
at-risk individuals early on in the disease process, and thus enable early
biomedical interventions as they become available.
Use of fMRI in clinical practice cont’d:
Traumatic Brain Injury (TBI)
 fMRI studies of mild TBI in acute post injury period have shown
differences in group activation associated with working memory despite
equivalent task performance. Patients showed lower activation in low
working memory demand condition and higher activation in high working
memory demand condition than the control group. These findings may
suggest TBI related neural processing changes corresponding to cognitive
changes in these patients. (corresponding to patients subjective
impressions of cognitive changes).
 Lateralization of brain activation during working memory have also been
demonstrated in moderate to severe TBI cases.
 Though both groups activated frontal, parietal, and temporal regions the
patients had a more dispersed activation and greater right hemisphere
activation in frontal lobes. This corroborates recent findings that PTSD
and TBI (with concussion) patients are likely to become severely
depressed if left untreated. Higher activity in the right frontal and parietal
lobe is associated with a later onset depression.
(http://cat.inist.fr/?aModele=afficheN&cpsidt=15694558,
&http://www.medicalnewstoday.com/articles/94564.php)
Use of fMRI in clinical practice cont’d:
Multiple Sclerosis (MS)
 WHAT IS MS?
MS is known as disseminated sclerosis or encephalomyelitis
disseminata) is an also known as disseminated sclerosis or
encephalomyelitis disseminata) is an autoimmune condition in which
the immune system attacks the central nervous system (CNS), leading
to demyelination. It may cause numerous physical and mental
symptoms, and often progresses to physical and cognitive disability.
fMRI studies of MS provide evidence of reallocation of brain processing
resources associated with motor, sensory, and cognitive abilities even in
patients with no impairment of functioning.
These changes are associated with the structural and neurochemical
alterations in the brain.
Studies have shown increased, spatially shifted or expanded activation during
motor tasks even when no motor deficit is present.
Use of fMRI in clinical practice cont’d:
Multiple Sclerosis (MS)
 Picture right (before MS)..Left with MS..Demonstrates areas which may
Cause lateralization and functional changes in the CNS.
http://www.msreversed.com/MRI/MRI_2004_12_(Small).jpg
Use of fMRI in clinical practice cont’d:
Neuroplasticity in the adult brain
 fMRI research suggests that the potential for adaptive plasticity (in
response to trauma etc.) in the adult brain may have been underestimated
for some time.
 BOLD fMRI neuroimaging techniques in MS and AD are advancing the
understanding of such plasticity.
 These studies have revealed changes in patterns of activation that include
displacement of foci, spatially expanded regions of activation around the
areas normally used for said function, activation of distal regions in and
outside the territory normally used for the task (may include diaschisis- a
sudden inhibition of function. This is produced by an acute focal
disturbance in an area of the brain, due to for example a stroke, at a
distance from the original seat of injury, but anatomically connected with
it through fibre tracts.)(http://en.wikipedia.org/wiki/Diaschisis)
 Some studies indicate hypoactivation in local networks relative to control
individuals.
 Further research is needed to determine the extent to which these changes
support normal function (the extent to which they are compensatory)
Conclusion
 fMRI’s application to clinical research and clinical practice in neurology
and psychiatry has the potential to improve understanding of brainbehavior relationships.
 Relative to conventional MRI, fMRI has the potential to provide a more
complete appreciation of both pathologic and reparative processes in the
brain.
 This information may be used in diagnosis, prognosis, and treatment
monitoring and may be used in some conditions as a biomarker.
 fMRI data will remain open to interpretation at the level of the individual
patient.
The end.