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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