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 CenterThe Institute of Living
September 26, 2002
Kristen MichaelThe basic principles of FMRI Clinical applicationsHow do we get brain images Experimental approachResearch methods Example: An Oddball Task Collecting data Application to clinical groups Analyzing data Where can we go from here
Presentation Overview
Typical FMRI Experimental Setup
The basic principles of FMRI
Necessary Equipment
Magnet Gradient Coil RF Coil
Source: Joe Gati, photos
RF Coil
4T magnet
gradient coil(inside)
Bo
A Moment on Magnet SafetyThe magnetic field strength of these magnets is EXTREMELY powerfulIt is VERY important to keep metallic objects far away from the scanner area
To avoid injuries:Screen subjects (and researchers) carefullyMake sure anyone who will be near the magnet understands the importance of safetyand knows the safety procedures
Source: www.howstuffworks.com Source: http://www.simplyphysics.com/flying_objects.html
The MAGNET is used to align protons in the direction of the magnetic field (Bo)Outside magnetic field
Inside magnetic field
• 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
x 80,000 =
4 Tesla = 4 x 10,000 0.5 = 80,000X Earth’s magnetic field
Robarts Research Institute 4T
Magnetic field is very strong and is continuously ON
Source: www.spacedaily.com
1 Tesla (T) = 10,000 Gauss
Earth’s magnetic field = 0.5 Gauss
B0M
Hydrogen nuclei
The GRADIENT COILS are used make small adjustments so that themagnetic 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
+ RF pulse =(90o flip angle) 2-4 ms duration
Bo M Bo M
Spins absorb energy, become excited and “flip”.Time to get back to Bovaries for different tissuesWe can measure this
Why do this?? Can’t detect M if aligned along BoWhen M is in the transverse plane, it induces a voltage in the coil – the RF signalMeasuring this signal produces the raw MRI data that we analyze
EquilibriumExcitation
Resonance frequency of42.58 MHz/T for 1H
Source: http://wsrv.clas.virginia.edu/~rjh9u/hemoglob.html, Jorge Jovicich
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
Introducing Hemoglobin – a magnetically susceptible molecule
So, I thought we were talking about BRAIN activity?
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 whataffects 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 likeIt represents “activity” (function) of brain cells
Research Methods
Two Design Possibilities
• Block Design– Useful for block tasks (PET studies)– Analysis simple to implement
• Event-Related Design– Can replicate single trial studies– Provides information about temporal response
Task1Task1Task2Task2Task1Task1Task2Task2ImagingImaging 30s30s 30s30s 30s30s 30s30s
30 s30 s 30 s30 s
Trial1Trial1 Trial2Trial2
Collecting Data and Preparing for Analyses
Creating an Image
Blood flow Voxel
Different voxels have differenthemodynamic propertiesthus the density of the magneticfield is different in each voxel
These differences, put togetherin space, produce images
(4mm x 4mm x 6mm)
Creating a Time Series(3D+time)
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
2-3 secfor aVolume
1 slice
mostinferior slice
mostsuperior slice
IR-MPRAGE T1 Weighted StructuralGradient Echo, Echo Planar Image (EPI)
3D only 3D + time
Two Types of Images from Each Subject
provides detailed anatomical informationcontains functional data used in
statistical analysis
FMRI Data Analysis
Step 1: Subject Level Analysis
1. Model1. Model(1 or more(1 or moreRegressors)Regressors)
oror
RegressionRegressionResultsResults
2. Data2. Data
3. Fitting 3. Fitting the Model the Model to the Data to the Data at each at each voxelvoxel
Analysis Using AFNI software
9 voxels
Step 2: Group Level AnalysesStep 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
Kristen MichaelThe basic principles of FMRI Clinical applicationsHow do we get brain images Experimental approachResearch methods Example: An Oddball Task Collecting data Application to clinical groups Analyzing data Where can we go from here
Presentation Overview
“…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 responseInfrequent 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
Hemodynamic response to auditory oddball stimuli
Healthy ControlParticipants
Kiehl et al. (2001)
Kiehl et al. (2001)
Control subjects (n=11) Schizophrenic patients (n=11)
Results of group data
PSYCHIATRIC DIAGNOSIS
First episode patient
Database of other first episode patients
Schizophrenia AffectiveBipolar
PSYCHIATRIC TREATMENT
First episode patient(with schizophrenia)
Database of other schizophrenia patients
Risperidone HaloperidolOlanzapine
ADHD Anterior Brain Deactivation(Deactivation for ADHD subjects not seen in Controls)
ADHD SUBJECTS
CONTROL SUBJECTS
In areas of superior frontal gyrus and perhaps some medial frontal gyrus, there is deactivation to targets, which is not seen in controls.
Z = 48 mm Z = 54 mm
Z = 48 mm Z = 54 mm
L/R
Normal Control Response to Targets
Conduct Disorder Response to Targets
-30 mm 0 mm +30 mm +60 mm
R/L
R/L
-30 mm 0 mm +30 mm +60 mm
Difference Map: CD - NC
R/LX19 Y38 Z12Right Insula
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Time Course
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X48 Y36 Z12Left Insula
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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
NRC, IOL External
Godfrey Pearlson, M.D. Robert Cox, PhD
Kent Kiehl, Ph.D. Jody Culham, PhD
Vince Calhoun, Ph.D.
Michael C. Stevens, Ph.D.
Kristen McKiernan, Ph.D.
Jin-Suh Kim, M.D.
thanks to those who provided slides or figuresused in this presentation
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 Primerhttp://www.bme.umich.edu/~dnoll/primer2.pdf
Mark Cohen’s Basic MR Physicshttp://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