The dynamic mechanisms of placebo induced analgesia: Evidence of sustained and transient regional involvement

Abstract

Previously, we demonstrated that placebo analgesia (PA) accompanies reductions in neural activity during painful stimulation. This study investigated areas of the brain where the neural activity was increased during PA. The literature has associated PA with two potential mechanisms of action; one sustained (e.g., engaged for the duration of PA), the other, transitory (e.g., a feedback mechanism). We propose that PA results from the engagement of two complementary pain-modulation mechanisms that are identified with fMRI data as a main effect for condition or a time *condition interaction. The mechanism with sustained activity should activate the emotional regulation circuitry needed for memory formation of the event. The mechanism with transient activity should process cognitive and evaluative information of the stimuli in the context of the placebo suggestion to confirm the expectations set by it. To identify regions involved with these mechanisms, we re-analyzed fMRI data from two conditions: baseline (B) and PA. Results support the presence of both mechanisms, identified as two neural-networks with different temporal characteristics. Regions with sustained activity primarily involved the temporal and parahippocampal cortices. Conversely, brain regions with transient activity included linguistic centers in the left hemisphere and frontal regions of the right hemisphere generally associated with executive functioning. Together, these mechanisms likely engage analgesic processes and then simply monitor the system for unexpected stimuli, effectively liberating resources for other processes. Identifying brain regions associated with pain-modulation with different temporal profiles is consistent with the multidimensionality of PA and highlights the need for continued investigation of this construct.

Figure 1

A) Mean pain ratings for the 7, 20-second rectal distensions produced by a balloon barostat in the baseline (B) and placebo analgesic (PA) conditions. Note: the pain ratings in the B condition increased over time whereas the pain ratings in the PA condition were relatively stable.B) Mean pain ratings (standard deviation) of the last five stimuli were (B= 52.0 (12.7) and PA= 32.8 (14.9).

Figure 2

Brain regions identified as having i) a main effect for condition (Placebo >Baseline), and ii) a main effect for time (first three stimuli [Early] > [Late] last three stimuli). Brain regions circled in blue are (from top to bottom): bilateral temporal lobes, left precuneus, and the right amygdala.

Figure 3

Brain regions identified as having a significant time*condition interaction (i.e., Early [PA] > all other cells). Brain regions circled in blue are (from top to bottom): right subcallosal gyrus, left lentiform nucleus, and left temporal lobe. The graphs on the right show the amount of signal change across time (early to late). Note: In both conditions, the Late signal intensity values reflect the amount of change that has occurred from the Early time-period, which have been rescaled to a value of zero.