nocebo effect (Fig. 4B and fig. S7). However,
the correlation pattern differed between treatment group and PAG cluster. The PAG cluster
interacting with the rACC was located ventrally, whereas the PAG cluster showing coupling
with the spinal cord was located laterally
(Fig. 4, B and C). Overlaying these two PAG
clusters onto the previously reported PAG activity revealed that the latter PAG cluster
overlapped with both coupling-related PAG subregions (fig. S7). This functional segregation of
the PAG is in line with studies showing intrinsic rACC coupling with the ventral PAG ( 27).
Conversely, neuronal tracing studies in rats
revealed that connections from the spinal cord
targeted more lateral aspects of the PAG ( 28).
These findings indicate that coupling along the
descending pain pathway is a key mechanism
to convey value information to early pain-processing areas. Furthermore, distinct subregions within the PAG interact with different
pain-processing areas, which might represent a
flexible mechanism to modulate pain perception along different levels of the descending
In summary, we show that expensive medi-
cation increases the risk for developing nocebo-
related side effects. Moreover, our fMRI protocol
allows us to assess how value information about
a medical treatment modulates the entire cen-
tral human pain system. Two regions of the de-
scending pain pathway, namely the rACC and
the PAG, facilitated expectation-induced pain
modulation and conveyed the difference in
nocebo effects between cheap and expensive
treatment. Furthermore, modulation of cou-
pling within the rACC-PAG-spinal axis might
represent a flexible mechanism through which
higher-cognitive representations such as value
interact with the descending pain pathway to
modulate pain processing between early sub-
cortical areas and nociceptive processing at the
spinal level. We did not observe increased ac-
tivity in other cortical pain-sensitive areas un-
der nocebo, which is in line with another study
( 29) that instead observed increased nocebo
activations in subcortical and limbic regions
such as the thalamus, amygdala, and hippo-
campus. This could indicate that expectation
modulation might predominantly involve the
spinoreticular tract, which comprises regions
that showed increased activity in the expensive
nocebo group, such as the brainstem, amygdala,
and prefrontal cortex ( 30).
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A. T., S.G., and C.B. were supported by the German Research
Foundation (DFG, Deutsche Forschungsgemeinschaft), SFB 936,
project A06. C.S. and C.B. were supported by the European
Research Council grant ERC-2010-AdG_20100407, and S.G. was
supported by the DFG Fellowship (GE 2774-1/1). The authors
declare no conflicts of interest. All raw data are archived at the
Institute of Systems Neuroscience in the University Medical Center
Hamburg-Eppendorf. Results reported in the paper are available in
the supplementary materials. We thank M. Menz for helpful
methodological discussions and L. Kampermann for assisting with
the thermode data. Furthermore, we thank H. Blank, M. Feldhaus,
B. Horing, and L. Kampermann for helpful comments on the
manuscript. We also thank our radiographers for their contribution in
collecting the fMRI data.
Materials and Methods
Figs. S1 to S8
Tables S1 and S2
References ( 32–56)
15 May 2017; accepted 22 August 2017
- 40 40
z = - 10
Nocebo effect (ΔVAS)
Nocebo effect (ΔVAS)
60 40 20 0 - 20
60 20 0 - 20
Fig. 4. Connectivity along the descending pain pathway. (A) Key candidates for showing
expectation-induced modulation in connectivity displayed on a single-subject anatomical image.
(B) Coupling strength between rACC and ventral PAG (red) and between spinal cord and right lateral
PAG (blue) correlated with behavioral nocebo effects (for statistical results, see fig. S7). (C) Schematic
segregation of anatomical PAG subregions ( 27, 31) overlaid on an average structural image for illustration
purposes: the lateral PAG (blue), the ventral PAG (red), and the dorsal PAG (green).