Shulman and Rothman PNAS, 1998

2. Shulman and Rothman PNAS, 1998 In this period of intense research in the neurosciences, nothing is more promising than functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) methods, which localize brain activities. These functional imaging methodologies map neurophysiological responses to cognitive, emotional, or sensory stimulations. The rapid experimental progress made by using these methods has encouraged widespread optimism about our ability to understand the activities of the mind on a biological basis. However, the relationship between the signal and neurobiological processes related to function is poorly understood, because the functional imaging signal is not a direct measure of neuronal processes related to information transfer, such as action potentials and neurotransmitter release. Rather, the intensity of the imaging signal is related to neurophysiological parameters of energy consumption and blood flow. To relate the imaging signal to specific neuronal processes, two relationships must be established… The first relationship is between the intensity of the imaging signal and the rate of neurophysiological energy processes, such as the cerebral metabolic rates of glucose (CMRglc) and of oxygen (CMRO2). The second and previously unavailable relationship is between the neurophysiological processes and the activity of neuronal processes. It is necessary to understand these relationships to directly relate functional imaging studies to neurobiological research that seeks the relationship between the regional activity of specific neuronal processes and mental processes.

3. Shulman and Rothman PNAS, 1998 Psychology Image Signal Mental Neuroenergetics Neuronal CMRglc CMRO2 CBF Neuroscience

4. Let’s back up…What do we know for sure about fMRI?

5. Hemoglobin Molecule 280 million Hb molecules per red blood cell

6. Different magnetic properties of hemoglobin and deoxyhemoglobin L. Pauling and C. Coryell The Magnetic Properties and Structure of Hemoglobin, Oxyhemoglobin and Carbonmonoxy hemoglobin, PNAS, vol. 22, pp. 210-216, 1936.

7. Hemoglobin Molecule

9. Blood Oxygenation Level Dependent Imaging Baseline Task from Mosley & Glover, 1995

10. Brain or Vein?

12. Virchow-Robin Space Large Vessel Contributions to BOLD Contrast

13. Intravascular Perivascular Extravascular

14. 3 z = 1.64 Large Small Isotropic Diffusion Weighted Spiral Imaging at 4T Courtesy of Dr. Allen Song, Duke University

15. a b 9 sec 9 sec

16. BOLD activation (b factor = 0) Diffusion-weighted (b factor = 54) Diffusion-weighted (b factor = 108) ADC masked by BOLD activation Subject 41057, Slice 12, 4.0 Tesla

17. BOLD activation (b factor = 0) Diffusion-weighted (b factor = 54) Diffusion-weighted (b factor = 108) ADC masked by BOLD activation Subject 41037, Slice 183, 4.0 Tesla

18. BOLD activation (b factor = 0) Diffusion-weighted (b factor = 54) Diffusion-weighted (b factor = 108) ADC masked by BOLD activation Subject 41037, Slice 177, 4.0 Tesla

19. BOLD activation (b factor = 0) ADC masked by BOLD activation Subject 41037, Slice 177, 4.0 Tesla

20. Negative dips

21. Phosphorescence Decay Time (Oxyphor R2 oxygen tension-sensitive phosphorescent probe) Vanzetta and Grinvald, Science, 286: 1555-1558, 1999

22. Phosphorescence Decay Time (Oxyphor R2 oxygen tension-sensitive phosphorescent probe) Vanzetta and Grinvald, Science, 286: 1555-1558, 1999

23. Vanzetta and Grinvald, Science, 286: 1555-1558, 1999 deoxy Hb Oxy Hb

24. Berwick et al, JCBFM, 2002 Optical imaging of rat barrel cortex Hb02= oxyhemoglobin, Hbr = deoxyhemoglobin, Hbt = total blood flow

25. Functional Imaging of the Monkey Brain N. Logothetis, Nature Neuroscience, 1999

26. Early Response in fMRI Hu, Le, Ugurbil MRM, 1997

27. Early Response in fMRI Hu, Le, Ugurbil MRM, 1997

28. What triggers blood flow?

29. Arterioles (10 - 300 microns)precapillary sphinctersCapillaries (5-10 microns)Venules (8-50 microns)

30. Tissue factors • K+ • H+ • Adenosine • Nitric oxide

31. Neuronal Control of the Microcirculation C. Iadecola, Nature Neuroscience, 1998 Commentary upon Krimer, Muly, Williams and Goldman-Rakic, Nature Neuroscience, 1998

32. Pial Arteries Noradrenergic Dopamine 10 m Krimer, Muly, Williams, Goldman-Rakic, Nature Neuroscience, 1998

33. Dopamanergic terminals associated with small cortical blood vessels 10 m Krimer, Muly, Williams, Goldman-Rakic, Nature Neuroscience, 1998

34. Dopamanergic terminals associated with small cortical blood vessels 2 m 400 nm 2 m 400 nm Krimer, Muly, Williams, Goldman-Rakic, Nature Neuroscience, 1998

35. Perivascular iontophoretic application of dopamine 18-40 s 40-60 s Krimer, Muly, Williams, Goldman-Rakic, Nature Neuroscience, 1998

36. Let’s back up again…Why isn’t all the oxyHb used up?

37. Uncoupling…

38. glucose glucose Glucose 6 phosphate Net +2 ATP Fructose – 1,6-phosphate pyruvate lactate TCA cycle O2 Net +36 ATP CO2 + H20

39. Shulman and Rothman PNAS, 1998

40. Shulman and Rothman PNAS, 1998 Proposed pathway of glutamate / glutamine neurotransmitter cycling between neurons and glia, whose flux has been quantitated recently by 13C MRS experiments. Action potentials reaching the presynaptic neuron cause release of vesicular glutamate into the synaptic cleft, where it is recognized by glutamate receptors post-synaptically and is cleared by Na+ -coupled transport into glia. There it is converted enzymatically to glutamine, which passively diffuses back to the neuron and, after reconversion to glutamate, is repackaged into vesicles. The rate of the glutamate-to-glutamine step in this cycle (Vcycle), has been derived from recent 13C experiments.

41. Sibson et al. PNAS, 1998

42. Heeger, Nature Neuroscience 2002

43. Ito et al. JCBFM, 2001

44. Relationship of BOLD to neuronal activity

45. Attwell and Laughlin, JCBFM, 2001 Brain Energetics

46. Attwell and Laughlin, JCBFM, 2001 Brain Energetics

47. Rees et al. Nature Neuroscience 2000

48. Heeger, Nature Neuroscience 2000

49. Lauritzen, JCBFM, 2001

50. Lauritzen, JCBFM, 2001 Climbing Fiber Stimulation