Esther M. Sternberg, M.D., Director,

1. BRAIN - IMMUNE CONNECTIONS in HEALTH & DISEASE Esther M. Sternberg, M.D., Director, Integrative Neural Immune Program National Institute of Mental Health/NIH Author: The Balance Within The Science Connecting Health and Emotions

2. Can BelievingMake You Well

3. Does Stress Make You Sick?

4. What isStress?

5. There are many parts to “Stress”: • Initiating event • Perception • Response • Effect

6. Emotions Disease

7. Emotions Health = Balance Disease

8. Yellow bile Phlegm The Four Humors Black bile Blood

9. Gregor Reisch, Margarita Philosophica cum Additionibus Novis Basel 1517

10. Anatomical Dissecting Theater, Padua: ca. 1550

11. Anatomical View of the Brain: ca.1670 Thomas Willis, The Remaining Medical Works of Thomas Willis London, 1679

12. Emotions ‘Accept nothing as true which you have not verified yourself.’ Rene´ Descartes, 1644 Disease = Abnormal Anatomy Disease

13. Anatomical Dissecting Instruments Andreas Vesalius, De Humani Corporis Fabrica. Venice, 1568

14. Neuroendocrine Immune Interactions EM Sternberg, Nature Reviews Immunology 2006

15. IL IL Antibodies The immune system signals the nervous system via many routes. CYTOKINES Nerve cell death and survival

16. Infectious • NeuroAids • Toxoplasmosis Degenerative • Alzheimer’s Inflammatory/autoimmune • Multiple Sclerosis Vascular • Stroke Traumatic • Nerve trauma Diseases in which Cytokine-Induced Neurodegeneration May Play a Role:

17. 17Kd BBB CYTOKINES IL IL Antibodies Stress response Sickness Behavior Fever Sleep Memory, cognition, mood The immune system signals the nervous system via many routes. CYTOKINES Nerve cell death and survival

18. Cytokines can signal the brain: • Leaky areas in BBB: • OVLT, ME • Signaling via Vagus • Active Transport • Second Messengers: • NO, PGs

19. What isStress?

20. There are many parts to “Stress”: • Initiating event • Perception • Response • Effect

21. “The chief and primary cause of …the very rapid increase of nervousness is modern civilization, which is distinguished from the ancient by these five characteristics: steampower, the periodical press, the telegraph, the sciences and the mental activity of women.” American Nervousness, Its Causes and Consequences, George M. Beard, 1881

22. Hans Selye (ca. 1960) Stress=non specific response of the body to any demand.

23. The stress response is more specific than Selye predicted. D. Goldstein et al.; P. Sawchenko et al.

24. There Are Many Kinds of Stress. • Psychological – performance, hierarchy, relationship, loss • Physical– pain, exercise • Physiological – infection, disease, nutritional deprivation, sleep deprivation, hemorrhage, hypoxia, heat/cold

25. CRH ACTH Adrenals Glucocorticoids The Brain’s Hormonal Stress Response: Hypothalamic Pituitary Adrenal (HPA) Axis.

26. CRH NE Adrenals Adrenalin Nerve Pathways of the Brain’s Stress Response: Sympathetic Nervous System Response

27. Inverted U-shaped Curve Performance and the Stress Response Peakperformance Total relaxation Extreme stress

28. Brainstem Stress Area (LC) Single Neuron Recordings G. Aston-Jones

29. How Do You Turn Bad Stress Into Good Stress? By Controlling Stress and Making It Work For You.

31. DEMANDS HI STIMULATION RELAXED CONTROL PASSIVE STRESSED

32. We Can Learn to Control Some Parts of Our Stress Response. • Training/practice • Biofeedback • Stress reduction programs • Meditation/Yoga/Prayer • Psychotherapy • Exercise • Social support • Lifestyle change (Mediterranean)

33. Stressors Have Different Effects Depending on: • Dose • Pattern • Duration • Gender

34. Total Load of Stress = “Allostatic Load”

35. Too much Infection Too little Inflammation Immune disease results when theNeuroendocrine Stress Responseis out of balance:

36. Effects of Glucocortioids on Innate Immunity

37. Effects of Glucocortioids on Cell-mediatedImmunity

38. Effects ofGlucocortioids on Differentiation of TH Cells

39. General structure of nuclear hormone receptors:

40. Molecular mechanism of Glucocorticoid/GR Effects on Transcription

41. CRH ACTH IL IL Antibodies Adrenals Glucocorticoids Normally the immune system activates the brain’s stress response.

42. IL IL Antibodies Adrenals Glucocorticoids And the Brain’s Stress Response Tunes Down the Immune System. CRH ACTH

43. CRH ACTH IL Antibodies Adrenals Glucocorticoids How Stress Makes You Sick: IL

44. Prolonged wound healing J. Kiecolt-Glaser, et al. • Increased severity and incidence of viral infection S. Cohen, et al.; J. Kiecolt-Glaser, et al. • Decreased antibody production to vaccine J. Sheridan, et al.; J. Kiecolt-Glaser, et al. Conditions Associated with Chronic Stress:

45. Too much Infection Too little Inflammation Immune disease results when theNeuroendocrine Stress Response is out of balance:

46. Lewis Rats • Streptococcal cell wall arthritis • Lactobacillus cell wall arthritis • Collagen arthritis • Adjuvant arthritis • Experimental allergic encephalomyelitis • Autoimmune myasthenia gravis • Autoimmune myasthenia gravis • Experimental autoallergic sialadenitis • Experimental autoimmune thyroiditis • Experimental autoimmune adrenalitis • Experimental autoimmune uveitis • Experimental autoimmune orchitis • Autoimmune myocarditis • Autologous immune-complex nephritis • Mercuric chloride-induced nephritis

47. Fischer Rats • Streptococcal cell wall arthritis • Lactobacillus cell wall arthritis • Collagen arthritis • Adjuvant arthritis • Experimental allergic encephalomyelitis • Autoimmune myasthenia gravis • Autoimmune myasthenia gravis • Experimental autoallergic sialadenitis • Experimental autoimmune thyroiditis • Experimental autoimmune adrenalitis • Experimental autoimmune uveitis • Experimental autoimmune orchitis • Autoimmune myocarditis • Autologous immune-complex nephritis • Mercuric chloride-induced nephritis

48. EM Sternberg et al PNAS 1989

49. I n f l a m m a t o r y / A u t o i m m u n e D i s e a s e T h y r o i d i t i s S c l e r o d e r m a S L E L o w H o r m o n a l S t r e s s R e s p o n s e A r t h r i t i s , E A E , S e p t i c S h o c k , I n f l a m m a t i o n R h e u m a t o i d A r t h r i t i s , S L E , S j o g r e n ’ s , D e r m a t i t i s , A s t h m a F i b r o m y a l g i a , C F S, IBS Illnesses Associated with Blunted Hormonal Stress Response

50. Cortisol Responses in Human Autoimmune Disease EO Johnson et al. MA Gutierrez et al. A Buske Kirschbaum et al. A Buske Kirschbaum et al.