Transcript Document

An Introduction to Functional Magnetic Resonance Imaging (FMRI)
and Its Application to Psychiatry
Kristen A. McKiernan, Ph.D.
Michael C. Stevens Ph.D.
Neuropsychiatry Research Center
The Institute of Living
September 26, 2002
Presentation Overview
Kristen
The basic principles of FMRI
How do we get brain images
Research methods
Collecting data
Analyzing data
Michael
Clinical applications
Experimental approach
Example: An Oddball Task
Application to clinical groups
Where can we go from here
Typical FMRI Experimental Setup
The basic principles of FMRI
Necessary Equipment
4T magnet
RF Coil
gradient coil
(inside)
Bo
Magnet
Gradient Coil
RF Coil
Source: Joe Gati, photos
A Moment on Magnet Safety
The magnetic field strength of these magnets is EXTREMELY powerful
It is VERY important to keep metallic objects far away from the scanner area
Source: www.howstuffworks.com
Source: http://www.simplyphysics.com/
flying_objects.html
To avoid injuries:
Screen subjects (and researchers) carefully
Make sure anyone who will be near the magnet understands the importance of safety
and knows the safety procedures
The MAGNET is used to align protons in the direction of the
magnetic field (Bo)
Outside magnetic field
Hydrogen nuclei
Magnetic field is very strong and is continuously ON
1 Tesla (T) = 10,000 Gauss
Earth’s magnetic field = 0.5 Gauss
4 Tesla = 4 x 10,000  0.5 = 80,000X Earth’s magnetic field
Inside magnetic field
x 80,000 =
M
B0
Source: www.spacedaily.com
• spins tend to align parallel or anti-parallel to B0
• net magnetization (M) along B0
• spins precess with random phase
• only 0.0003% of protons/T align with field
Robarts Research Institute 4T
The GRADIENT COILS are used make small adjustments so that the
magnetic field (Bo) is as homogeneous as possible
The gradients generate small magnetic fields in 3 directions: x y z
Putting a body in magnetic field makes it non-uniform, so we adjust the 3
orthogonal weak magnets to make thee magnetic field as homogenous as
possible (i.e., equal strength across the field)
Gradient coil
The RADIO FREQUENCY (RF) Coil is used to apply a “pulse” of
radiofrequency waves that “excite” the protons
This means that the direction of magnetization is temporarily altered
Resonance frequency of
42.58 MHz/T for 1H
Bo
M
Equilibrium
+ RF pulse
=
(90o flip angle)
2-4 ms duration
Bo
M
Spins absorb energy,
become excited and “flip”.
Time to get back to Bo
varies for different tissues
We can measure this
Excitation
Why do this?? Can’t detect M if aligned along Bo
When M is in the transverse plane, it induces a voltage in the coil – the RF signal
Measuring this signal produces the raw MRI data that we analyze
So, I thought we were talking about BRAIN activity?
Introducing Hemoglobin – a magnetically susceptible molecule
Hemoglogin (Hgb):
- four globin chains
- each globin chain contains a heme group
- at center of each heme group is an iron atom (Fe)
- each heme group can attach an oxygen atom (O2)
- oxy-Hgb (four O2) is diamagnetic  no B effects
- deoxy-Hgb is paramagnetic  if [deoxy-Hgb]   local B 
Source: http://wsrv.clas.virginia.edu/~rjh9u/hemoglob.html, Jorge Jovicich
Hbr and the MRI Signal
Neural activity in the brain initiates a cascade of events:
•Metabolic changes:  in glucose and oxygen metabolism
•Physiological changes:  CBF,  CBV,  blood oxygenation level
These hemodynamic changes influence MRI signal intensity:
CBF brings more H2O molecules into the imaging area (a “slice” of brain tissue)
more protons align with Bo
 CBV brings more O2 into the area – much more than is needed
More HbrO2 means less
deoxy-Hbr in the capillaries and
veins (and less randomness in
magnetic field)
The level of deoxy-Hbr is what
affects the MRI signal
 deoxy-Hbr =  MRI signal
The BOLD Signal in FMRI
Using the dependence of the MRI signal on the level of O2 in the blood is the most common
FMRI technique. This type of MR signal is a Blood Oxygenation Level Dependent contrast
This is what the MRI BOLD signal looks like
It represents “activity” (function) of brain cells
Research Methods
Two Design Possibilities
• Block Design
– Useful for block tasks (PET studies)
– Analysis simple to implement
Imaging
Task1
Task2
Task1
Task2
30s
30s
30s
30s
• Event-Related Design
– Can replicate single trial studies
– Provides information about temporal response
Trial1
Trial2
30 s
30 s
Collecting Data and
Preparing for Analyses
Creating an Image
(4mm x 4mm x 6mm)
Blood flow
Voxel
Different voxels have different
hemodynamic properties
thus the density of the magnetic
field is different in each voxel
These differences, put together
in space, produce images
Creating a Time Series
(3D+time)
most
inferior slice
1 slice
most
superior slice
2-3 sec
for a
Volume
We decide on the thickness of each slice (4-7 mm) and number of
slices needed (whole brain or a specific region)
Take repeated volumes (50+) to get many samples of each voxel
Two Types of Images from Each Subject
IR-MPRAGE T1 Weighted Structural
provides detailed anatomical information
3D only
Gradient Echo, Echo Planar Image (EPI)
contains functional data used in
statistical analysis
3D + time
FMRI Data Analysis
Step 1: Subject Level Analysis
1. Model
(1 or more
Regressors)
or
2. Data
3. Fitting the
Model to the
Data at each
voxel
Regression
Results
Analysis Using AFNI software
9 voxels
Step 2: Group Level Analyses
To account for individual differences in brain size and anatomy, each subject’s 3D
brain volume is “warped” to best fit a standard brain
Once normalized we can refer to specific locations using the Talairach Coordinate
System
Subject data (ie statistical results) can then be combined
across subjects to get experimental results – these are
what you usually see reported
C
D
Presentation Overview
Kristen
The basic principles of FMRI
How do we get brain images
Research methods
Collecting data
Analyzing data
Michael
Clinical applications
Experimental approach
Example: An Oddball Task
Application to clinical groups
Where can we go from here
“…So what does it mean?”
(“…So what?”)
Image Interpretation…Is this all?
Clinical FMRI Applications
• In general, one approach is to compare brain
activity between psychiatric groups and normal
controls.
• But, that leaves a lot of room…
• How do you ask intelligent and meaningful
questions?
• The benefits of FMRI over other imaging
modalities primarily involve the combined
abilities to quantify both the spatial extent and
magnitude of that brain activity evoked by some
cognitive process.
Any question you can think of...
– “How does brain function differ between schizophrenic
patients and healthy controls?”
– OR “Do schizophrenic patients have a deficit in:
•
•
•
•
Attention
Working Memory
Language Use (i.e., auditory hallucinations)
Overall patterns of brain function on these tasks (functional
organization of brain activity)
– “How do antipsychotic medications affect brain function in
schizophrenic patients (acute and chronic)?”
– “Is the the relative effectiveness of certain medications
reflected in the hemodynamic measurement of brain
function?”
...FMRI can examine.
– “How do biomarkers, symptom profiles and diagnostic
classifications relate to patterns of brain function?”
– “What are the effects on the brain of long-term
antipsychotic medication treatment?”
– “How effective is cognitive rehabilitation at improving
brain function in schizophrenic patients?”
– “Are there cognitive function biomarkers in first-degree
relatives of schizophrenics that speak to etiological
factors (i.e., genetics)?”
– “How different is the cognitive function of first-break
schizophrenics with those having a chronic illness?”
Experimental Approach to FMRI
•
•
•
•
•
Theory
Hypotheses
Methods
Results
Interpretation
Experimental Approach to FMRI
• Theory - Schizophrenia is associated with
brain dysfunction related to attentional
orienting.
• Hypotheses - Evoked brain activity on an
attentional orienting response will show
reduced amplitude of response in brain areas
known to subserve attention in healthy normal
controls.
The oddball task
• Tones are presented and subject responds to low probability target
tones (e.g., 12.5% trials)
• First ERPs ever recorded were to the oddball task – stimulus
targets and omissions.
• Sokolov said salient stimuli are very robust elicitors of the
orienting response, more robust than novel stimuli
• Historically one of the most well characterized tasks in
psychopathology, schizophrenia in particular
• ERP studies have shown P3 component is reduced in
schizophrenia and in psychopathy
• ERP studies have shown that the P3 is reduced in nearly every
pathological condition – how can this be!
Three Stimulus Visual Oddball Task
T T T T T T T X T T T T T T C T T T T X T T T T T X X
T T T T T T T T T X T T T T T T X T T T X T C T T X T
Infrequent Target - “X” - Requires button press response
Infrequent Distractor - “C” - Ignored (no response)
14 - 9% “X”
9 - 9% “C”
97 - 82% “T”
Cognitive Processes Associated with Three-Stimulus
Oddball Task Paradigm (Polich & Kok, 1995)
Somato-Motor Cortex
– Preparation and Execution
Frontal and Parietal Cortex
– Response Inhibition
– Working Memory
– Self-Monitoring of Response Accuracy
(including orienting)
– Vigilance (sustained attention)
Occipital-Temporal Cortex
– Visual Object Recognition
– Long-Term Memory
Kiehl et al. (2001)
Hemodynamic response
to auditory oddball
stimuli
Healthy Control
Participants
Kiehl et al.
(2001)
Results of group data
Control subjects (n=11)
Schizophrenic patients (n=11)
PSYCHIATRIC DIAGNOSIS
First episode patient
Database of other first episode patients
Bipolar
Schizophrenia
Affective
PSYCHIATRIC TREATMENT
First episode patient
(with schizophrenia)
Database of other schizophrenia patients
Olanzapine
Risperidone
Haloperidol
ADHD Anterior Brain Deactivation
(Deactivation for ADHD subjects not seen in Controls)
CONTROL SUBJECTS
Z = 48 mm
Z = 54L/R
mm
Z = 48 mm
Z = 54 mm
In areas of superior frontal
gyrus and perhaps some medial
frontal gyrus, there is
deactivation to targets, which is
not seen in controls.
ADHD SUBJECTS
Normal Control Response to Targets
-30 mm
0 mm
+30 mm
+60 mm
R/L
Conduct Disorder Response to Targets
R/L
Difference Map: CD - NC
-30 mm
0 mm
+30 mm
+60 mm
R/L
X48 Y36 Z12
Left Insula
1.0
1
0.8
0.6
0.8
0.6
0.4
CD+
0.2
CD-
0.0
-0.2
-4 -3 -2 -1
0
1
2
3
4
-0.4
5
6
7
8
9
% Signal Change
% Signal Change
X19 Y38 Z12
Right Insula
0.4
CD+
0.2
CD-
0
-0.2
-4 -3 -2 -1
0
1
2
3
4
-0.4
Time Course
Time Course
5
6
7
8
9
What else has been done…?
(What else COULD be done?)
• You name it…
– Conduct Disorder, ADHD, psychopathy, Alzheimer’s Disease,
Learning Disabilities, stroke, epilepsy, autism, head injury,
alcoholism, drug addiction, bipolar illness, OCD, Generalized
Anxiety Disorder, PTSD, unipolar depression, etc.
– Memory, attention, language, working memory, motor function,
executive-function, visual perception, etc.
• Capitalizes on vast field of previous research and theory.
• Used in combination with other imaging and research
modalities.
Acknowledgements and
thanks to those who provided slides or figures
used in this presentation
NRC, IOL
Godfrey Pearlson, M.D.
Kent Kiehl, Ph.D.
Vince Calhoun, Ph.D.
Michael C. Stevens, Ph.D.
Kristen McKiernan, Ph.D.
Jin-Suh Kim, M.D.
External
Robert Cox, PhD
Jody Culham, PhD
These websites can provide additional information on FMRI
Robert Cox’s webpage:
http://afni.nimh.nih.gov/afni/edu/index.html
Jody Culham’s webpage:
http://defiant.ssc.uwo.ca/jody_web/fmri4dummies.htm
Doug Noll’s FMRI Primer
http://www.bme.umich.edu/~dnoll/primer2.pdf
Mark Cohen’s Basic MR Physics
http://porkpie.loni.ucla.edu/BMD_HTML/SharedCode/MiscShared.html
General questions related to FMRI:
http://www.radiologyresource.org/content/functional_mr.htm
Brain images from different clinical patients:
http://www.med.harvard.edu/AANLIB/home.html