emissions from fossil fuel burning ( 29) and is
comparable in magnitude to the cumulative
carbon losses to the atmosphere due to human-driven land use change during the past two
centuries ( 30). A transfer of carbon of this magnitude from forest soils to the atmosphere in
response to warming would amplify the mitigation challenge already faced by society. It is also
important to recognize that a global-scale, microbially mediated feedback could be very difficult,
if not impossible, to halt.
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Supported by U.S. Department of Energy grants DE-SC0010740
and DE-SC0016590 and by NSF grants DEB 1237491 (Long-Term
Ecological Research) and DEB 1456528 (Long-Term Research in
Environmental Biology). We thank the team of scientists who
worked with us on the study over the past 26 years, including
J. Aber, T. Ahrens, C. Baldino, J. Blanchard, M. Bradford,
L. Burrows, A. Burton, S. Butler, C. Catricala, R. Hanifin, T. Hill,
J. Johnson, H. Lux, J. Mohan, S. Morrisseau, K. Newkirk,
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Materials and Methods
Figs. S1 to S4
References ( 31–35)
22 March 2017; accepted 23 August 2017
Interactions between brain and spinal
cord mediate value effects in
A. Tinnermann,1 S. Geuter,1,2 C. Sprenger,1, 3 J. Finsterbusch,1 C. Büchel1
Value information about a drug, such as the price tag, can strongly affect its therapeutic
effect. We discovered that value information influences adverse treatment outcomes
in humans even in the absence of an active substance. Labeling an inert treatment
as expensive medication led to stronger nocebo hyperalgesia than labeling it as
cheap medication. This effect was mediated by neural interactions between cortex,
brainstem, and spinal cord. In particular, activity in the prefrontal cortex mediated
the effect of value on nocebo hyperalgesia. Value furthermore modulated coupling
between prefrontal areas, brainstem, and spinal cord, which might represent a flexible
mechanism through which higher-cognitive representations, such as value, can modulate
early pain processing.
Patients in randomized placebo controlled clinical trials frequently discontinue their participation because of side effects. Yet, after unblinding, it turns out that some of these patients were part of the placebo
group and thus never received any active medi-
cation (1). This is a case of the adverse nocebo
effect (2, 3) that can be seen in contrast to the
placebo effect. The placebo effect with respect to
pain involves an opioidergic mechanism ( 4–7)
and recruits the descending pain modulatory
system ( 5), which targets the spinal cord dorsal
horn ( 8). Placebo effects can be manipulated by
providing value information (e.g., price) about a
treatment ( 9–11). Although higher-priced treat-
ments lead to higher placebo effects ( 11), they
might also lead to an increase in perceived side
effects. We thus investigated whether value in-
formation about a medical treatment can fur-
ther modulate behavioral nocebo effects and the
underlying neural network dynamics.
How can a medial prefrontal value signal
( 10, 12) interfere with central pain processing
and modulate expectation-induced pain per-
ception? One possibility is that this modulation
is mediated through functional interactions
between key structures of the descending pain
pathway (fig. S8) ( 13). Because nocebo hyper-
algesia also modulates activity at the spinal
level ( 14), we followed this lead and investigated
whether nocebo hyperalgesia is mediated through
interactions within a cortico-subcortico-spinal
network ( 15), in analogy to other forms of cog-
nitive pain modulation ( 16, 17). However, simul-
taneous functional magnetic resonance imaging
(f MRI) measurements of neural activity in the
brain and spinal cord are technically challeng-
ing ( 18). To investigate the dynamics from cortex
to spinal cord, we developed an fMRI method
( 19, 20) that allows the measurement of neural
activity in the entire central pain system, com-
prising the cortex, brainstem, and spinal cord
(figs. S2 and S3).
To study the influence of value on nocebo
hyperalgesia, we induced negative treatment
expectations and experiences in two groups of
participants ( 21). As the nocebo treatment, we
introduced two alleged medical creams that did
not contain any active ingredient and provided
different value information by labeling one cream
as cheap and the second one as expensive. To
support the cheap versus expensive impression,
we designed two paper medical-cream boxes that
contained design elements for expensive (blue
box) and cheap (orange box) medication, respectively (Fig. 1A). A sample of 66 participants that
did not take part in the nocebo and value-manipulation experiment estimated actual pharmacy prices of the creams on the basis of the
appearance of the boxes. The price of the blue
box was estimated to be significantly higher than
the price of the orange box (Fig. 1B; for statistical
1Institute of Systems Neuroscience, University Medical
Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
2Institute of Cognitive Science, University of Colorado–
Boulder, Boulder, CO 80309, USA. 3Computational and
Biological Learning Laboratory, Department of Engineering,
University of Cambridge, Cambridge CB2 1PZ, UK.
*Corresponding author. Email: firstname.lastname@example.org