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General Introduction to Functional MRI Introduction to Physics, Physiology, Data Analysis, and Experimental Design in fMRI from a Behavioral Science Perspective Robert Savoy The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy Functional Magnetic Resonance Brain Imaging First, a few words about keeping... A Broad Perspective Robert L. Savoy, Ph.D. Athinoula A. Martinos Center for Biomedical Imaging of the Massachusetts General Hospital Harvard University HyperVision, Inc, Lexington, MA <[email protected]> A Broad Perspective Robert Savoy Functional Magnetic Resonance Brain Imaging Before we start on fMRI design... A few words about the “Big” issues A few words MultiModal Imaging A Broad Perspective Robert Savoy Functional Magnetic Resonance Brain Imaging Approaches to Understanding the Digital Computer • Quantum Mechanics • Materials Science • Components • Resistors, Capacitors, Transistors, Diodes • Chip Diagrams • Local Counters, Flip-Flops • Wiring • Global Hardware Circuitry) • Software • Networks A Broad Perspective Levels of Explanation Data Separation Algorithmic Separation Robert Savoy Functional Magnetic Resonance Brain Imaging Approaches to Understanding the Human Brain • Neurochemistry • Neuroanatomy • Neurophysiology • Single and Multiple Cell Recordings • • • • Columnar Wiring Brain Mapping Psychology Sociology A Broad Perspective Levels of Explanation Data Separation Algorithmic Separation Robert Savoy Functional Magnetic Resonance Brain Imaging MultiModal Imaging (a view oriented around MRI) Optical Microscopy PET High Field MultiChannel phMRI MEG EEG MRI Computational Neuroanatomy TMS MRS DTI DSI functional MRI DOT NIRS Intracranial Electrodes A Broad Perspective Robert Savoy Functional Magnetic Resonance Brain Imaging MultiModal Imaging and Approaches to Understanding the Human Brain • Neurochemistry Optical Microscopy • Neuroanatomy • Neurophysiology PET • Single and Multiple Cell Recordings • Columnar Wiring phMRI • Brain Mapping • Psychology • Sociology A Broad Perspective High Field MultiChannel MEG EEG MRS MRI Computational Neuroanatomy TMS DTI DSI functional MRI DOT NIRS Intracranial Electrodes Robert Savoy Functional Magnetic Resonance Brain Imaging MultiModal Imaging and Approaches to Understanding the Human Brain • Neurochemistry Optical Microscopy • Neuroanatomy • Neurophysiology PET • Single and Multiple Cell Recordings • Columnar Wiring phMRI • Brain Mapping • Psychology • Sociology A Broad Perspective High Field MultiChannel MEG EEG MRS MRI Computational Neuroanatomy TMS DTI DSI functional MRI DOT NIRS Intracranial Electrodes Robert Savoy Functional Magnetic Resonance Brain Imaging MultiModal Imaging and Approaches to Understanding the Human Brain • Neurochemistry Optical Microscopy • Neuroanatomy • Neurophysiology PET • Single and Multiple Cell Recordings • Columnar Wiring phMRI • Brain Mapping • Psychology • Sociology A Broad Perspective High Field MultiChannel MEG EEG MRS MRI Computational Neuroanatomy TMS DTI DSI functional MRI DOT NIRS Intracranial Electrodes Robert Savoy Functional Magnetic Resonance Brain Imaging MultiModal Imaging and Approaches to Understanding the Human Brain • Neurochemistry Optical Microscopy • Neuroanatomy • Neurophysiology PET • Single and Multiple Cell Recordings • Columnar Wiring phMRI • Brain Mapping • Psychology • Sociology A Broad Perspective High Field MultiChannel MEG EEG MRS MRI Computational Neuroanatomy TMS DTI DSI functional MRI DOT NIRS Intracranial Electrodes Robert Savoy Functional Magnetic Resonance Brain Imaging MultiModal Imaging and Approaches to Understanding the Human Brain • Neurochemistry Optical Microscopy • Neuroanatomy • Neurophysiology PET • Single and Multiple Cell Recordings • Columnar Wiring phMRI • Brain Mapping • Psychology • Sociology A Broad Perspective High Field MultiChannel MEG EEG MRS MRI Computational Neuroanatomy TMS DTI DSI functional MRI DOT NIRS Intracranial Electrodes Robert Savoy Functional Magnetic Resonance Brain Imaging MultiModal Imaging and Approaches to Understanding the Human Brain • Neurochemistry Optical Microscopy • Neuroanatomy • Neurophysiology PET • Single and Multiple Cell Recordings • Columnar Wiring phMRI • Brain Mapping • Psychology • Sociology A Broad Perspective High Field MultiChannel MEG EEG MRS MRI Computational Neuroanatomy TMS DTI DSI functional MRI DOT NIRS Intracranial Electrodes Robert Savoy Functional Magnetic Resonance Brain Imaging MultiModal Imaging and Approaches to Understanding the Human Brain • Neurochemistry Optical Microscopy • Neuroanatomy • Neurophysiology PET • Single and Multiple Cell Recordings • Columnar Wiring phMRI • Brain Mapping • Psychology • Sociology A Broad Perspective High Field MultiChannel MEG EEG MRS MRI Computational Neuroanatomy TMS DTI DSI functional MRI DOT NIRS Intracranial Electrodes Robert Savoy Functional Magnetic Resonance Brain Imaging We will focus on fMRI, but... Integration Optical Microscopy PET High Field MultiChannel phMRI MEG EEG MRI Computational Neuroanatomy TMS MRS DTI DSI functional MRI DOT NIRS Intracranial Electrodes Levels of Explanation Data Separation Algorithmic Separation A Broad Perspective Across Modality Across Function Unity through Topic Simultaneous Data Acquisition Ultimate Unity through Conceptual Integration and Modeling of Brain Function Robert Savoy Functional Magnetic Resonance Brain Imaging On to an introduction specific to Functional MRI A Broad Perspective Robert Savoy Personal Introduction • Thanks to many people... • My Eclectic background; Exptl. Psych.; Vision • General interests: 70% out? Integrating FNI data The Goals of this Workshop Thorough introduction to the basics of the physics, experimental psychology, data analysis, and practical constraints underlying fMRI-based research. Discussion of basic data analysis theory and tools. Starting to think about your experiments. The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy Why Is fMRI So Exciting? • Repeated studies on single subjects • Better temporal resolution than the nearest non-invasive volumetric imaging alternative • Better, and ever-improving, spatial resolution ================================== • Large installed machine base • Remarkably flexible tool at its core • Potential for complementing other tools, with greater temporal resolution The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy Introduction to fMRI: Outline • Set the Stage History and Basics of Functional MRI • Practical Issues Functional MRI is Complicated • Applications Selected Examples • Research Themes Challenges in Human Brain Mapping The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy Introduction to fMRI: Outline • Set the Stage History and Basics of Functional MRI • Practical Issues Functional MRI is Complicated • Applications Selected Examples • Research Themes Challenges in Human Brain Mapping The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy Practicalities NMR MRI Computers for Everything Experimental Task Hemodynamics Data Analysis Animal Brain Mapping Clinical Applications Partial List of Other Modalities: Direct Stimulation • DOT • EEG • ERP Lesions • MEG • Optical • PET Structural MRI • TES • TMS The MGH/MIT/HMS Athinoula A. Martinos Center Psychophysiological Laboratory Functional Neuroanatomy Comparing Brains Computational Neuroanatomy HyperVision, Inc. Robert Savoy What is the real challenge? What is your question? Why should I believe your answer? What is the nature of an answerable question, using fMRI? What would that answer look like? The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy Practicalities NMR MRI Psychophysiological Laboratory Experimental Task Hemodynamics Data Analysis Functional Neuroanatomy Comparing Brains Experimental Design The MGH/MIT/HMS Athinoula A. Martinos Center Computational Neuroanatomy HyperVision, Inc. Robert Savoy Basics of Functional MRI • Hemodynamics • Roy and Sherrington • History • BOLD / Flow The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy First Examples with Humans The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy Basics of Functional MRI • Hemodynamics • Roy and Sherrington • History • BOLD / Flow • Instrumental Source of the Data • NMR 8 Magnetic Fields and Relaxation • MRI • Contrast • Flexibility of Tool Maximum Signal (minimal contrast) No Signal (no contrast) "Inject Signal" (90° saturation rf-pulse) The MGH/MIT/HMS Athinoula A. Martinos Center Time HyperVision, Inc. Robert Savoy MRI in a Slide: MRI In a Slide 8 Magnetic Fields and Relaxation ■ ■ ■ ■ ■ To Obtain the NMR Signal: Three Magnetic Fields µ The magnetic field of a nucleus with spin B0 The main magnetic field, used to align nuclei B 1 The radio-frequency field, used to flip nuclei Relaxation: Two ways for the signal to go away T1 Longitudinal: The nuclei re-align with B0 T 2 Transverse: The nuclei get out-of-phase To Select Slices and Make Images: Three More Fields G The gradient fields x, G y, G z Shim Fields To make better images Shielding Fields To protect us from all of the above! The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy Signal decays exponentially Maximum Signal Fading... Fading... Gone Singal Decays Expontntially Time "Inject Signal" (90° saturation rf-pulse) The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy Rate of decay varies across voxels Different Rates of Decay "Inject Signal" (90° saturation rf-pulse) The MGH/MIT/HMS Athinoula A. Martinos Center Time HyperVision, Inc. Robert Savoy Image contrast varies with time Faces Contrast for fMRI Maximum Signal (Little Contrast) Intermediate Signals (Useful Contrasts) Maximum Signal (minimal contrast) (90° saturation rf-pulse) (90° saturation rf-pulse) (No Contrast) No Signal (no contrast) "Inject Signal" "Inject Signal" Minimum Signal Time Time So, we must WAIT for dephasing to occur, in order to get T2 or T2* contrast. But while we are waiting, various bad things happen: imaging artifacts appear The MGH/MIT/HMS Athinoula A. Martinos Centersignal decreases; HyperVision, Inc. Robert Savoy Proton Density; T1-Weighted; T2-Weighted; MRA contrast enhanced; 95% The MGH/MIT/HMS Athinoula A. Martinos Center a b c d HyperVision, Inc. Robert Savoy Basics of Functional MRI • Hemodynamics • Roy and Sherrington • History • BOLD / Flow • Instrumental Source of the Data • NMR • MRI • Contrast • Flexibility of Tool • Combining Hemodynamics and MRI The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy The Chain of Ideas Increased Neural Activity Increased Local Cerebral Blood Flow Decreased Deoxyhemoglobin Concentration in Veins (BOLD) Change in Magnetic Susceptibility Change in NMR Signal The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy Deoxygenated blood attenuates signal in T2*-weighted MR images O2 Figure from Rick Hoge MRI volume element The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy Decrease of Venous Deoxyhemoglobin Concentration During Increased Perfusion O2 Figure from Rick Hoge The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy Close up on a few hydrogen nuclei, the Larmor frequencies of each, and how they add up += O2 += MRI volume element The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy Basic Time Course of the Hemodynamic Response Hemodynamic Delay and Dispersion Stimulus 1 sec Time Neuronal Response Hemodynamic Response 6-8 sec The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy 1000 msec ε = 20 seconds 10 100 msec 34 msec 20 (60 - ε) seconds 50 Time (seconds) 80 2.5 Consisent latency (2 sec) (~2 sec)totoonset onsetofof MR response 2 1.5 Stimulus Duration 1000 msec : black 100 msec : grey 34 msec : white Peak Percent Increase 1 in MR Signal 0.5 Strength 0 -0.5 Duration of Response to Very Brief Stimuli 34 msec 100 msec 1000 msec 15 20 The MGH/MIT/HMS Athinoula A. Martinos Center Time 25 (seconds) 30 HyperVision, Inc. 35 Robert Savoy Functional MRI is Complicated • Technology is Complicated • Roy and Sherrington quotation The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy On the Regulation of the Blood-Supply of the BRAIN C.S. Roy and C.S. Sherrington Journal of Physiology 11, 85 (1890) In modern English: We think different investigators get contradictory results because the technology for measuring cerebral hemodynamics is complicated. The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy On the Regulation of the Blood-Supply of the BRAIN C.S. Roy and C.S. Sherrington Journal of Physiology 11, 85 (1890) One of the marked characteristics of the literature dealing with the cerebral circulation is, we think, the contradictory nature of the results which have been obtained by different investigators. There is no reason, we imagine, for doubting that the cause of these discrepancies is to be found in the great difficulty of avoiding the sources of error which plentifully surround the subject, and in overcoming certain technical difficulties which we shall presently have to refer to. The ease with which one can obtain results upon certain points, on taking up the subject, is itself, we believe, apt to make the inquirer careless in controlling sources of error, which, it may be noted, are some of them not at first sight obvious. We must on this account say more about the technology of our subject than would be necessary were the subject a simpler one. The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy Functional MRI is Complicated • Technology is Complicated • Roy and Sherrington quotation • Good written resources are available (e.g., textbooks on fMRI) The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy Functional MRI is Complicated • Technology is Complicated • Link between neural activity and hemodynamics • Still not well-understood • Possible role of dopamine • Latest work with monkeys and fMRI + invasive recording • “Initial Dip”; Post-Stimulus Undershoot; Arteries, Veins & Capillaries • Models (Buxton; Mandeville & Weisskoff; Hoge) • Recent Book: Functional Magnetic Resonance Imaging: Principles and Techniques, by Richard Buxton, Cambidge Univ. Press (2001). Strong emphasis on the connection between basic physiology and the MR physics. The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy Tightening the Links • Regulation of the cerbral microcirculation during neural activity: is nitric oxide the missing link? by C. Iodecola. Trends in Neuroscience, 16 (6), 206 (1993) • Neurogenic control of cerebral microcirculation: is dopamine minding the store? by C. Iadecola Nature Neuroscience, 1 (4), 263 (1998) • Neurophysiological investigation of the basis of the fMRI signal. by N.K. Logothetis, et al. Nature, 412, 150 (2001) • Imaging function in the working brain with fMRI. by R.S. Menon. Current Opinion in Neurobiology, 11, 630 (2001) This is still a controversial area. SEE FOR EXAMPLE a recent article by Devor, et al.: The Journal of Neuroscience, December 31, 2008 • 28(53):14347–14357 Chapter 6 in the Huettel textbook is good general introduction. The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy Functional MRI is Complicated • Technology is Complicated • Link between neural activity and hemodynamics • Experimental Design: A variety of techniques The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy Basic Time Course of the Hemodynamic Response Hemodynamic Delay and Dispersion Stimulus 1 sec Hemodynamic Delay and Dispersion Stimulus Time Neuronal Response Hemodynamic Response Time 30 sec Neuronal Response Hemodynamic Response 34-38 sec 6-8 sec The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy Blocked versus Mixed-Trial Paradigm Buckner: Blocked/Spaced/Rapid BLOCKED: SPACED MIXED TRIAL: RAPID MIXED TRIAL: The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy Blocked versus Mixed-Trial Paradigm Buckner: Blocked/Spaced/Rapid BLOCKED: SPACED MIXED TRIAL: RAPID MIXED TRIAL: The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy Blocked versus Mixed-Trial Paradigm Buckner: Blocked/Spaced/Rapid BLOCKED: SPACED MIXED TRIAL: RAPID MIXED TRIAL: The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy Basic Time Course of the Hemodynamic Response Hemodynamic Delay and Dispersion a Stimulus 1 sec Time Neuronal Response Hemodynamic Response 6-8 sec The MGH/MIT/HMS Athinoula A. Martinos Center b HyperVision, Inc. Robert Savoy Blocked versus Mixed-Trial Paradigm Buckner: Blocked/Spaced/Rapid BLOCKED: SPACED MIXED TRIAL: RAPID MIXED TRIAL: The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy Functional MRI is Complicated • Technology is Complicated • Link between neural activity and hemodynamics • Experimental Design: A variety of techniques • Data Analysis: Endless time sink • 5+1 Lectures by Doug Greve on Data Analysis • The saga of Michael Chee • Recent (2009) controversy in the literature, based on statistics: Nature News: Published online 13-Jan-2009: “Brain imaging studies under fire” by Alison Abbott”, based on paper by Vul, et al.: “Voodoo Correlations in Social Neuroscience” Perspectives on Psychological Science 23-Dec-2008. Not to mention the saga of the dead salmon brain activations (Bennett, et alia, OHBM Poster, June 2009. The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy SPM: Statistical Parametric Mapping. (From the Department of Cognitive Neurology) The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy Functional MRI is Complicated • Technology is Complicated • Link between neural activity and hemodynamics • Experimental Design: A variety of techniques • Data Analysis: Endless time sink • MR Physics and Hemodynamics, Experimental Design, and Data Analysis are Tightly Coupled The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy Functional MRI is Complicated • • • • • Technology is Complicated Link between neural activity and hemodynamics Experimental Design: A variety of techniques Data Analysis: Endless time sink MR Physics and Hemodynamics, Experimental Design, and Data Analysis are Tightly Coupled • Each part of the chain implies limits and opportunities. The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy This concludes... The MGH/MIT/HMS Athinoula A. Martinos Center HyperVision, Inc. Robert Savoy