Neural correlates of placebo effect: Review and future implications

Abstract

Experimental and clinical research has documented expectancy related symptom improvement in a variety of conditions, leading to a growing interest in the placebo effect. Despite significant treatment outcomes, placebo-induced effects have been regarded as nonspecific psychological factors associated with the subjective experience of healing that operates different than the actual drug agent . However, neuroimaging research revealed more complex regulation of the placebo response, which indicates a top-down regulation of the symptom improvement enhanced by the expectancy effects. It appears that, placebo response is not solely function of higher order control processes, but also involves diverse disease-specific neurobiological mechanisms. In the current review, neural mechanisms underlying placebo effect have been addressed focusing on the analgesia, Parkinson’s disease and major depression. Along with the opiate system, dopaminergic and serotonergic functions in the brain are discussed in relation with the three target conditions. Last, potential implications of the placebo research are discussed with respect to experimental and clinical practice. 

Keywords

• placebo effect,pain,antidepressants,Parkinson's disease,treatment expectancy

Plasebo etkisinin nöral temelleri: Geçmiş bulguların gözden geçirilmesi ve çıkarsamalar

Öz

İyileşme beklentisi ile ilişkili hastalığa-özgü semptomlardaki iyileşme literatürde sıkça gösterildiğinden plasebo etkisine olan ilgi giderek artmaktadır. Her ne kadar tedavi etkinliği plasebo gruplarında belirgin olsa da, bu etkinin asıl maddeden ziyade, hastanın iyileşme beklentisi ve öznel iyilik değerlendirmesinin bir sonucu olarak düşünülmektedir. Öte yandan, beyin görüntüleme çalışmaları daha karmaşık bir sürecin var olduğuna işaret etmektedir. Denetimli kontrol mekanizmalarının yönettiği plasebo etkisinin iyileşme beklentisi ile güçlendiği görüşü giderek ağırlık kazanmaktadır. Bu bağlamda görünen odur ki, plasebo etkisi tek bir sistem üzerinden değil, hastalık temelli mekanizmalar aracılığı ile ortaya çıkmaktadır. Bu derleme çalışmasında da, plasebo etkisinin nöral boyutlarının sıkça incelendiği ağrı, Parkinson ve depresyon olgularına ilişkin bulgulara odaklanılmış ve opiat sistemi ile dopaminerjik ve serotonerjik işlevler incelenmiştir. Bu doğrultuda da, geçmiş bulguların gözden geçirilmesinin ardından plasebo etkisinin gelecek çalışmalardaki rolü tartışılmıştır.

Anahtar Kelimeler

• Plasebo etkisi,ağrı,antidepresanlar,Parkinson,tedavi beklentisi

Kaynakça

1. 1. Levine JD, Newton CG, Howard LF. The mechanism of placebo analgesia. The Lancet 1978;312(8091): 654-657.
2. 2. Finniss, DG., et al. Biological, clinical, and ethical advances of placebo effects. The Lancet 2010;375(9715): 686-695.
3. 3. Colloca L, Miller, FG. How placebo responses are formed: A learning perspective. Philosophical Transactions of the Royal Society of London B: Biological Sciences 2011;366(1572), 1859-1869.
4. 4. Benedett F. Placebo effects: from the neurobiological paradigm to translational implications. Neuron 2014;84(3): 623-637.
5. 5. Moerman DE. From Meaning, Medicine, and the placebo effect(v.28). Cambridge: Cambridge University Press;2002.
6. 6. Birch S. A review and analysis of placebo treatments, placebo effects, and placebo controls in trials of medical procedures when sham is not inert. Journal of Alternative & Complementary Medicine 2006;12(3): 303-310.
7. 7. Colloca L, Benedetti F. Placebos and painkillers: is mind as real as matter? Nat Rev Neurosci 2005;6:545–552.
8. 8. Tracey I. Getting the pain you expect: mechanisms of placebo, nocebo and reappraisal effects in humans. Nat Med 2010;(16):1277–1283.

9. 9. Petrovic P, Kalso E., Petersson KM, Ingvar M et al. Placebo and opioid analgesia--imaging a shared neuronal network. Science 2002; 295(5560):1737-1740. 10. Zubieta, JK, et al. Placebo effects mediated by endogenous opioid activity on μ-opioid receptors. J Neurosci 2005;25(34):7754-7762.
10. 11. Lieberman MD, Jarcho JM, Berman S, Naliboff BD, Suyenobu BY, Mandelkern M, Mayer EA. The neural correlates of placebo effects: A disruption account. Neuroimage 2004; 22(1):447-455.
11. 12. Wager, TD., et al. Placebo-induced changes in FMRI in the anticipation and experience of pain. Science, 2004, 303.5661: 1162-1167.
12. 13. Ochnser KN, Gross JJ. The cognitive control of emotion. Trends Cogn Sci 2005; 9(5): 242-249.
13. 14. Etkin A, Egner T, Kalisch R. Emotional processing in anterior cingulate and medial prefrontal cortex. Trends Cogn Sci 2011;15(2): 85-93.
14. 15. Nemoto H, Nemoto Y, Toda H, Mikuni M, Fukuyama et al. Placebo analgesia: A PET study. Exp Brain Res 2007, 179.4: 655-664.
15. 16. Benedetti F. How the doctor’s words affect the patient’s brain. Evaluation & the Health Professions 2002, 25.4: 369-386.
16. 17. Amanzio M, Benedetti F. Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific subsystems. J Neurosci 1999 19;1: 484-494.
17. 18. Montgomery, GH, Kirsch I. Classical conditioning and the placebo effect. Pain 1997: 72;1: 107-113.
18. 19. Scott DJ, et al. Individual differences in reward responding explain placebo-induced expectations and effects. Neuron 2007;55(2): 325-336.
19. 20. Faria V, Fredrikson M, Furmark T. Imaging the placebo response: A neurofunctional review. Eur Neuropsychopharmacol 2008;18(7): 473-485.
20. 21. Diamond SG, Markham CH, Treciokas, LJ. Double‐blind trial of pergolide for Parkinson's disease. Neurology 1985;35(3): 291-291.
21. 22. Goetz CG, Leurgans S, Raman R, Stebbins,et al. Objective changes in motor function during placebo treatment in PD. Neurology 2000;54(3): 710-710. 23. Lindstone SCC, Stoessl AJ. Understanding the placebo effect: contributions from neuroimaging. Mol Imaging Biol 2007;9(4): 176-185.
22. 24. De La Fuente‐Fernández, R, et al. Biochemical variations in the synaptic level of dopamine precede motor fluctuations in Parkinson's disease: PET evidence of increased dopamine turnover. Ann Neurol 2001, 49.3: 298-303.
23. 25. De La fuente-Fernández R, Phillips AG, Zamburlini M, Sossi V, Calne DB., Ruth, T. J., & Stoessl, AJ. Dopamine release in human ventral striatum and expectation of reward. Behav Brain Res 2002;136(2): 359-363.
24. 26. Strafella AP, Ko JH, Monchi O. Therapeutic application of transcranial magnetic stimulation in Parkinson's disease: The contribution of expectation. Neuroimage 2006;31(4): 1666-1672.
25. 27. Kirsch I. Response expectancy theory and application: A decennial review. Appl Prev Psychol 1997;6(2): 69-79.
26. 28. Lindstone SC, et al. Effects of expectation on placebo-induced dopamine release in Parkinson disease. Arch Gen Psychiatry 2010, 67.8: 857-865.
27. 29. Zubieta J, et al. μ-Opioid receptor-mediated antinociceptive responses differ in men and women. JNeurosci 2002;22(12): 5100-5107.
28. 30. Zubieta, J, et al. Regional mu opioid receptor regulation of sensory and affective dimensions of pain. Science 2001 293(5528): 311-315.
29. 31. Martikainen IK, Hagelberg N, Mansikka H, Hietala J, Någren K, et al. Association of striatal dopamine D2/D3 receptor binding potential with pain but not tactile sensitivity or placebo analgesia. Neurosci Lett 2005;376(3): 149-153.
30. 32. De La fuente-Fernández R, Stoessl AJ. The placebo effect in Parkinson's disease. Trends Neurosci 2002;25(6): 302-306.
31. 33. Lindstone, SC, Stoessl AJ. Understanding the placebo effect: Contributions from neuroimaging. . Mol Imaging Biol 2007;9(4): 176-185.
32. 34. Boileau I, Dagher A, Leyton M, Welfeld K, Booij L, et al. Conditioned dopamine release in humans: a positron emission tomography [11C] raclopride study with amphetamine. J Neurosci 2007;27(15): 3998-4003.
33. 35. Volkow, ND., et al. Effects of expectation on the brain metabolic responses to methylphenidate and to its placebo in non-drug abusing subjects. Neuroimage 2006;32(4): 1782-1792.
34. 36. Kirsch I, Sapirstein G. Listening to Prozac but hearing placebo: A meta-analysis of antidepressant medication. Prevention & Treatment 1998;1(2): 2a.
35. 37. Ioviena N, Papakostas GI. Correlation between different levels of placebo response rate and clinical trial outcome in major depressive disorder: a meta-analysis. J Clin Psychiatry 2012;73(10): 1300-1306.
36. 38. Khan A, Brown, WA. Antidepressants versus placebo in major depression: an overview. World Psychiatry, 2015, 14.3: 294-300.
37. 39. Mayberg HS, Brannan SK, Tekell JL, Silva JA, Mahurin RK, et al. Regional metabolic effects of fluoxetine in major depression: Serial changes and relationship to clinical response. Biol Psychiatry 2000;48(8): 830-843.
38. 40. Mayberg HS, Silva JA, Brannan SK, Tekell J, Mahurin RK. Helen S, et al. The functional neuroanatomy of the placebo effect. Am J Psychiatry 2002;159(5): 728-737.
39. 41. Schulz, V. Clinical trials with hypericum extracts in patients with depression–results, comparisons, conclusions for therapy with antidepressant drugs. Phytomedicine 2002;9(5): 468-474.
40. 42. Wager, TD., et al. Placebo-induced changes in FMRI in the anticipation and experience of pain. Science 2004;303(5661): 1162-1167.
41. 43. Benedetti F, Mayberg HS, Wager TD, Stohler CS, & Zubieta JK. Neurobiological mechanisms of the placebo effect. J Neurosci 2005;25(45):10390-10402.
42. 44. Hunter AM, Leuchter AF, Morgan ML, Cook IA.. Changes in brain function (quantitative EEG cordance) during placebo lead-in and treatment outcomes in clinical trials for major depression. Am J Psychiatry 2006;163(8): 1426-1432.
43. 45. Oken, BS. Placebo effects: Clinical aspects and neurobiology. Brain 2008;131(11): 2812-2823.