Notes on placebo

How could the PFC do this?

The two areas of the PreFrontal Cortex most involved in anticipation are the Dorso-Lateral PreFrontal Cortex (DLPFC) DLPFC_1 and the OrbitoFrontal Cortex (for flexible incentive learning) OFC_1 [17,27]. The DLPFC appears to maintain information needed for cognitive control of the body [17], while the OFC is thought to be involved in configuring control mechanisms and in learning based on reward information [27]. The OFC communicates with the DLPFC and the Anterior Cingulate Cortex Anterior Cingulate Cortexto generate and maintain expectation or anticipation. [17].


How could the ACC do this?

The rostral Anterior Cingulate Cortex (rACC) rACC_1 is also thought to be involved in generating and maintaining expectations, and the Peri-Aqueductal Gray, PAG_1 and other parts of the brain are involved as well. The rACC shows activation on brain scans relative to "control conditions", and because it's been shown to track changes in reported pain induced by hypnosis [17]. It is also known to have a high concentration of opioid receptors, supporting the finding that the rostral ACC is more reliably activated by endogenous opioids, than is the caudal ACC, which is activated by pain itself. [15] There is also evidence that the opioid-receptor-containing Peri-Aqueductal Gray of the midbrain shows increased activity during anticipation of relief [17]. The peri-aqueductal gray alters neuronal activity in the rostral ventral medulla, which has 'on' and 'off' cells that are either excited or inhibited by the presence of endogenous or exogenous opioids [14]. Because the orbitofrontal cortex has dense connections with the rACC and with the brainstem, and because the ACC has fiber tracts projecting directly to the peri-aqueductal gray, it is hypothesized that these regions belong to a network that uses cognitive cues to activate an endogenous opioid network [15]. Other areas of cortex and subcortex show increased activity during anticipation of pain relief as well: the primary Sensory cortex, the secondary Sensory cortex, the primary Motor cortex --
RED = primary sensory cortexRED = primary SENSORY cortex,
BLUE = primary motor cortexBLUE = primary MOTOR cortex
-- and the dorsal amygdala Amygdala [17].


Why not a placebo for all diseases?

Placebos are unlikely to work for ailments such as Alzheimer's disease, where the brain is incapable of anticipation or expectation, since the nerve cells for that capability are no longer present or functioning.


Why would the thalamus be involved?

Since the thalamus thalamus.medium.size is the major 'way-station' in the pathway for sensing pain, decreased activity in the thalamus during the experience of placebo-induced pain reduction is assumed to come from a blocking or inhibition of pain transmission through the thalamus.



References for these notes

2. Leuchter F et. al.: changes in brain function of depressed subjects during treatment with placebo. Am J Psychiatry 2002; 122-129

13. Kirsch I, Sapirstein G: Listening to Prozac but hearing placebo : A meta-analysis of antidepressant medication. Prevention and Treatment 1998; 1(0002a)

14. Fields HL, Price DD: Toward a neurobiology of placebo analgesia, in The Placebo Effect: An Interdisciplinary Exploration. Edited by Harrington A. Cambridge, Mass., Harvard University Press, 1997 p.93-116

15. Petrovic P et. al.: Placebo and opioid analgesia – imaging a shared neuronal network. Science 2002; 295(5560): 1737-1740

17. Wager TD et. al.: Placebo-induced changes in fMRI in the anticipation and experience of pain. Science 2004; 303(5661): 1162

20. Amanzio M, Benedetti F: Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated systems. Journal of Neuroscience 1997; 19(1): 484-494

22. Benedetti F et. al.: Somatotopic activation of opioid system s by target-directed expectations of analgesia. Journal of Neuroscience 1999; 19(9): 3639-3648

23. Johansen O, et. al.: Placebo and Nocebo Responses, cortisol, and circulating beta-endorphin. Psychosomatic Medicine 2003; 65: 786-790

27. de la Fuente-Fernandez et. al.: Placebo mechanisms and reward circuitry; clues from Parkinson's disease. Biological Psychiatry, 2004.

 
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