1. Public Health Julie C. Chapman, PsyD Director of Neuroscience War Related Illness & Injury Study Center Veterans Affairs Medical Center Washington, DC Assistant Professor of Neurology Georgetown University School of Medicine Clinical and Advanced Neuroimaging: A Primer for Providers Patrick Sullivan, MA Neuroimaging Lead, Chapman Laboratory War Related Illness and Injury Study Center Veterans Affairs Medical Center Washington, DC

2. Public Health Disclaimer The views expressed in this presentation are those of the author and DO NOT reflect the official policy of the Department of Veterans Affairs or the United States Government

3. Public Health What is Neuroimaging? Since we cannot generally take photographs of the brain in vivo, imaging technologies allow us to view the brain indirectly.

4. Public Health Neuroimaging in Clinical Practice  Which professions utilize clinical neuroimaging?  Radiology  Neurology  Psychiatry  Physiatry  Neuropsychology  Neurosurgery  What is clinical neuroimaging used to assess?  Tumor  Stroke  Brain Injury  Neurodegenerative disease

5. Public Health Neuroimaging Methods: Conventional vs. Advanced Brain scans used in clinical practice.  X-ray (Skull films)  Computed Tomography (CT): often used to image acute conditions  Magnetic Resonance Imaging (MRI)  Nuclear Medicine  Positron Emission Tomography (PET): Used often by Oncology and Cardiology for clinical purposes Conventional

6. Public Health Neuroimaging Methods: Conventional vs. Advanced Experimental brain scans used in research (Sometimes used clinically by Neurosurgeons)  Advanced Magnetic Resonance Imaging (MRI) include:  Diffusion Tensor Imaging (DTI)  functional Magnetic Resonance Imaging (fMRI)  Nuclear Medicine (Research & Clinical):  Positron Emission Tomography (PET) (brain)  Single-Photon Emission Computed Tomography (SPECT) Advanced

7. Public Health Structural vs. Functional Neuroimaging Methods  Examine brain anatomy (brain structures)  X-ray  Computed Tomography (CT)  Magnetic Resonance Imaging (MRI): Clinical scans DTI  Examine brain function (brain in action)  Functional Magnetic Resonance Imaging (fMRI)  Positron Emission Tomography (PET)  Single-Photon Emission Computed Tomography (SPECT) Structural MethodsFunctional Methods

8. Public Health Ionizing Radiation  Radiation with enough energy to remove an electron from an atom or molecule  Exposure to ionizing radiation causes damage to tissues, can result in mutation, can contribute to cancer.  Lifetime exposure limits  X-ray/Computed Tomography: Ionizing Radiation  PET/SPECT: Ionizing Radiation  MRI: NON-ionizing Radiation

9. Public Health Structural Imaging Methods

10. Public Health X-Rays  Ionizing Radiation  Measures density of tissue  Used to take one-view pictures  Limitations  Resolution (spatial): ability to distinguish changes in image across different spatial locations.  Contrast: intensity differences

11. Public Health Computed Tomography (CT)  Ionizing Radiation  CT uses an x-ray that moves around body/brain to create a 3-dimensional map.  Uses a computer to integrate information  Can distinguish between gray/white matter and CSF  Limitations  Resolution (spatial): ability to distinguish changes in image across different spatial locations.  Contrast: intensity differences

12. Public Health Magnetic Resonance Imaging: MRI  MRI Benefits over X-ray & CT scans  Non-ionizing radiation  Better resolution  Better contrast

13. Public Health MRI: How is the picture made?  How do we get from magnet to image? Image from Chapman Lab WRIISC-DC

14. Public Health Magnetic Resonance Imaging Components Diagram from Magnet Lab Florida State University

15. Public Health Magnetic Resonance Imaging The Basics  Magnetic:  The scanner has a powerful magnet that is always on  This magnet produces a constant and very large electromagnetic current: Static Magnetic Field  Outside the scanner, atomic nuclei in the brain (or body) spin randomly  Once inside the scanner, these nuclei align their spins in the direction of the static magnetic field

16. Public Health MRI Pulse Sequences  A pulse sequence is a group of computerized instructions that command the scanner hardware to emit a brief series of radiofrequency waves (and activate the gradient coils)  The pulse sequence is geared to the resonant frequency of atomic nuclei in the brain (or body). Images from Chapman Lab WRIISC-DC

17. Public Health Magnetic Resonance Imaging The Basics  Resonance: Radiofrequency coils turn on only during image acquisition  Radiofrequency coils transmit the pulse sequence (brief series of radiofrequency [RF] waves). These waves PERTURB the alignment of nuclei with the static magnetic field.  The pulse sequences are geared to the resonant frequencies of the nuclei. Different tissue types respond uniquely to these disruptions allowing us to differentiate between tissues.  **Eventually the nuclei return to their alignment with the static magnet field and as they do, they give off the MR signal which is received by the RF coils.**

18. Public Health Magnetic Resonance Imaging The Basics  Imaging: Gradient Coils turn on only during image acquisition  Gradient coils control the MR signal making it vary in different spatial locations  In addition to specifying the RF waves, the pulse sequence also instructs which gradient coils will activate at what time and for how long, making the MR signal vary over different locations  This difference in MR signal over spatial locations is key to constructing the image

19. Public Health Hardware: Radiofrequency Coils & Gradient Coils Diagram from Magnet Lab Florida State University Radiofrequency Coils both transmit the pulse sequence and receive the resulting MR signal. For this reason, they are also called “Transceiver Coils”. Gradient Coils (X, Y, & Z) cause the MRI signal to vary across spatial locations, assisting with image production.

20. Public Health Gradient Coil Orientations  X Coil: Varies signal left to right: Sagittal Plane  Y Coil: Varies signal top to bottom: Coronal Plane  Z Coil: Varies signal head to toe, names interchangeable:  Transverse Plane OR  Axial Plane OR  Horizontal Plane Diagram from Wellesley College

21. Public Health Planes of Orientation In Neuroimaging Axial, Transverse or Horizontal Sagittal Coronal Images from Chapman Lab WRIISC-DC

22. Public Health Contrasts  Contrasts: the intensity difference in tissues measured by an imaging system  Pulse sequences highlight these different contrasts  Selected Types of Contrasts:  Static Contrasts: sensitive to properties of atomic nuclei T 1 -weighted, T 2 -weighted, proton density  Motion Contrasts: sensitive to movement of atomic nuclei Diffusion Weighted Imaging, Perfusion Imaging

23. Public Health Processing Quantitative MRI  The pulse sequence gives us a basic picture  To get good quantitative data, the images have to be cleaned up and normalized (via template) Images from Chapman Lab WRIISC-DC

24. Public Health Analyzing Quantitative MRI  Once processed, structures within images can be analyzed (i.e., for size or intensity)  The smallest square-shaped element in a 2-D picture is a “pixel”. In a 3-D image, it is called a voxel  Voxels are usually grouped together into one or more regions-of-interest (ROI) for analysis Image from Chapman Lab WRIISC-DC

25. Public Health Volumetric Analysis A method to estimate the volume of specific brain structures or regions. Picture from Athinoula A. Martinos Center for Biomedical Imaging

26. Public Health Volumetric Analysis The volume of specific brain structures or regions can be compared between patients or groups Gross structure can be assessed by analysis of structural MRI Athinoula A. Martinos Center for Biomedical Imaging Images from Chapman Lab WRIISC-DC

27. Public Health Volumetric Analysis  Manually drawn  High anatomic validity (gold standard)  Extensive use of algorithms/atlas templates  Reduction of anatomic validity Manual MethodsAutomated Methods

28. Public Health Volumetric Analysis  Time-intensive  Inter-rater reliability concerns  Allows high throughput & efficient workflow  Eliminates multiple rater effects Manual MethodsAutomated Methods

29. Public Health Automated Volumetric Analysis  Uses an algorithm to:  Strip away skull and facial tissue in the image  Find border between the gray matter and subcortical white matter  Find border between the gray matter and the pia. Image from Chapman Lab WRIISC-DC

30. Public Health Automated Volumetric Analysis  Registers image to atlas template  automatically parcels brain into regions based on:  Atlas template  Anatomic properties of the subject brain. Images from Chapman Lab WRIISC-DC

31. Public Health Use of Volumetric Analysis  Automated programs accept standard clinical MRI images and produce objective results independent of rater effects.  The automatically parceled brain regions are each measured for total volume.

32. Public Health Use of Volumetric Analysis  These amounts can be averaged into groups and group differences can be computed.  Volumetric differences are seen in many disease conditions such as TBI, Alzheimer’s, epilepsy, and depression

33. Public Health Diffusion Tensor Imaging (DTI)  DTI measures the movement of water molecules in axonal bundles, also called tracts, fiber tracts or fasciculi.  DTI analysis yields quantitative metrics  Allows white matter tracts to be visualized and characteristics estimated in vivo

34. Public Health What is a Tensor?  MRI divides the brain into thousands of voxels.  At each voxel, DTI creates a “ellipsoid” as a measurement area.  The activity within the ellipsoid can describe the direction and magnitude of water diffusion  A Tensor is a mathematical method of characterizing activity within multi-dimensional geometric objects (like the ellipsoid). Image from Biomedical Imaging and Intervention Journal

35. Public Health Brownian Motion

36. Public Health Anisotropic DiffusionIsotropic Diffusion

37. Public Health DTI Metrics  Most Commonly Metrics Used:  Fractional Anisotropy (FA): Directionality of diffusion  Mean Diffusivity (MD): Diffusion averaged in all directions  Axial Diffusivity (AD): Magnitude of diffusion parallel to the axonal tract (diffusing down the length of axons)  Radial Diffusivity (RD): Magnitude of diffusion perpendicular to the axonal tract (diffusing across the width of the axon)

38. Public Health Axial vs. Radial Diffusivity Radial Diffusivity Axial Diffusivity

39. Public Health Strengths and Limitations of DTI  Measures white matter in vivo  Non-invasive, no ionizing radiation  Can be combined with functional and behavioral measures  Is relatively fast (~8 minutes per scan)  Regions with complex white matter configurations can confound the measurement  Is less informative about grey matter  Sensitivity to motion artifacts  Measure is indirect, diffusion is only a correlate of fiber integrity StrengthsLimitations

40. Public Health Major Functional Imaging Methods

41. Public Health Changes in Functional Activity: Positron Emission Tomography (PET)  Positron Emission Tomography (PET) was the first neuroimaging technique to allow functional localization.  Radioactively labeled isotopes are transmitted into the bloodstream.  Metabolism is observed. Public Domain image courtesy of Jens Langer

42. Public Health Changes in Functional Activity: Metabolism and Brain Function  Greater metabolism associated with higher activity in a given brain area.  Differences in brain activity can result from a range of factors including:  transient neurocognitive conditions  long-term changes in quantities of neurotransmitters receptors, or neurons  permanent structural damage.

43. Public Health Strengths and Limitations of PET  Allows us to measure brain function in real time  Different tracers can be specified for different needs  Can be combined with structural imaging as well as cognitive and behavioral measures  Uses ionizing radiation which must be limited over the lifetime  Tracer selection is limited unless a cyclotron is owned  Labeled isotope decays quickly, limiting time of scan  Measure is indirect, metabolism is only a correlate of neural activity StrengthsLimitations

44. Public Health Changes in Functional Activity: functional MRI (fMRI)  Good temporal resolution  Non-invasiveness  Lack of ionizing radiation  fMRI has supplanted PET as the most used functional neuroimaging technique. Public Domain image

45. Public Health Changes in Functional Activity: BOLD fMRI  Like PET, fMRI is measuring neural activation indirectly.  Activation detected through a natural phenomenon: “Blood-oxygen-level dependent” (BOLD) signal.  BOLD signal measures deoxygenated hemoglobin, which increases in areas of high neural activity.

46. Public Health Changes in Functional Activity: Statistical Aspects of fMRI  The colored areas do not strictly represent anatomy, but instead show significant differences in levels of BOLD activation across 2 (or more) groups.  These statistical maps are overlaid onto structural MRI images to help visualize where activity changes are taking place in the brain.

47. Public Health Strengths and Limitations of fMRI  Allows us to measure brain function in real time  Can be combined with structural imaging as well as cognitive and behavioral measures  Superior temporal resolution (compared to PET) allows activity to be correlated with a series of 1-2 second events, rather than over longer blocks of time  Non-invasive, no ionizing radiation  Measure is indirect, BOLD is only a correlate of neural activity  Hemodynamic response for a 1 second activity can last for over 10 seconds, confounding results  More susceptible than PET to motion artifacts StrengthsLimitations

48. Public Health Contact Us ADDRESS: Veterans Affairs Medical Center 50 Irving Street NW, MS 127 Washington, DC 20422 PHONE: (202) 745-8000 Ext. 7553 EMAIL: Julie.Chapman@va.gov OR Chapman.Research@va.gov VISIT OUR WEBSITE: http://www.warrelatedillness.va.gov/dc/