1. How does blood flow inform us about brain function? Cerebrovascular anatomy & neural regulation of CNS blood flow Neurovascular coupling HST 583 Brad Dickerson, M.D. bradd@nmr.mgh.harvard.edu

2. How does blood flow inform us about brain function? Cerebrovascular anatomy & neural regulation of CNS blood flow Cerebral blood flow: intro Cerebrovascular anatomy Neurotransmitter systems & neural regulation

3. Blood flow and the organ of thought “…blood supply to any part of the cerebral tissue is varied in accordance with the activity of the chemiccal changes which underlie the functional action of that part…” -- Roy & Sherrington, 1890 “We must suppose a very delicate adjustment whereby the circulation follows the needs of the cerebral activity. Blood very likely may rush to each region of the cortex according as it is most active, but of this we know nothing.” -- W. James, 1890

4. Blood flow and the organ of thought Slide courtesy of M. Raichle

5. Blood flow and the organ of thought The brain requires blood for: General support of maintenance functions, like every organ - requires energy (ATP) Specific localized support of functional activity related to neural activity - requires energy (ATP) Blood supplies substrates for energy production: Glucose and oxygen ~750 ml/min

6. The route of blood to the head

7. The route of blood within the head

8. 10 mm Circle of Willis

9. The route of blood within the head

10. T1 T2

11. The route of blood within the head

13. Scale of the circulatory system Aorta: 2.5 cm (~1 in) Large arteries (e.g., carotid):.5 - 1 cm Arterioles: 10 - 50 um Capillaries: 5 - 10 um (RBC)

14. Scale of the circulatory system Large arteries (e.g., carotid):.5 - 1 cm Arterioles: 10 - 50 um

15. Scale of the circulatory system Capillaries: 5 - 10 um (RBC)

16. Scale of the circulatory system Venules/veins

17. The route of blood within the head

28. Pial arteriolar anastomoses 1 mm From Edvinsson, 1993

30. AP view: Vertebral artery angiogram

32. 5 mm Cortical capillary vasculature

33. 5 mm Cortical neural structure

34. 5 mm Cortical capillary vasculature Grey matter has 2-4 times the capillary density of white matter

35. Cerebellar Vasculature

36. Inferior Olivary Nucleus and Inferior Cerebellar Peduncle 2 mm From Duvernoy, 1995

37. Cerebellar Histology Blue = myelin Pink = neuropil 1 mm From Duvernoy, 1995

38. 100  m 500  m From Duvernoy, 1995

39. Cerebellar Cortical Histology

40. Molecular Layer Purkinje Cells Granular Layer 50  m Cerebellar histology and vascularization From Duvernoy, 1995

41. Capillary density in rat brain is proportional to metabolic rate Low levels of CBF Hypothalamus, cerebellum, medulla High levels of CBF Cochlear nucleus, mammillary body, cortex Low levels of CMRglu Hypothalamus, cerebellum, medulla High levels of CMRglu Cochlear nucleus, mammillary body, cortex From Edvinsson, 1993

42. Flow of CSF

43. CSF return to venous blood

44. Large vessels in subarachnoid space

45. Blood Brain Barrier What cerebral capillaries have: –Tight continuous quintuple-layered intercellular junctions –low wall thickness (0.2 um) –higher mitochondrial content – thick basement membrane What cerebral capillaries don’t have: –fenestrations –lots of vesicles –fluid-filled bulk transport channels

46. Blood Brain Barrier Allows passage/transport of small molecules (H2O, O2, CO2), lipophilic molecules (EtOH, heroin), passive transport of glucose, active transport of amino acids/NT precursors Prevents passage of larger molecules (dopamine), charged molecules, etc

47. Measurement of blood flow to the brain Aorta 90cm/s, ICA 40cm/s, arterioles 10- 250mm/s, capillaries 1mm/s Transcranial doppler ultrasound

48. Cerebral autoregulation CBF remains constant over wide range of change in arterial pressure

49. Flow is regulated by arteriolar smooth muscle Arterioles: 10 - 50 um

50. Sites of CBF Regulation Large diameter vessels (ANS) Smaller diameter arterioles, venules (neurogenic) –Must have smooth muscle with appropriate innervation and receptor site to act upon –If signaling is at capillary level, message must move upstream to supplying arteriole

51. Changes in cerebral blood flow can be prompted by Change in hemical mileu/blood gases –Arterial hypercarbia/tissue acidosis/hypoxemia Neurotransmitter systems –Autonomic nervous system Sympathetic (NE, Neuropeptide Y) Parasympathetic (ACh, VIP) –Dopamine vs noradrenaline –Serotonin Localized neural activity

52. from hypothalamus and brain stem Global perfusion increase

53. NE (fast, short acting) & NPY (slow, longer lasting) From Wilson-Pauwels, 1997 from hypothalamus and brain stem Sympathetic innervation of blood vessels

54. NoradrenergicDopaminergic from hypothalamus and brain stem Sympathetic innervation of cortical pial vessels

55. Neurotransmitter systems