identified as a gate controlling mechanical
itch (9). Consequently, ablation or silencing
of the NPY+ neurons leads to disinhibition of
unidentified excitatory neurons, resulting in
mechanical itch through a pathway distinct
from that which produces chemical itch.
Together, these studies suggest a mecha-
nism by which Merkel cell signaling modu-
lates itch: Normally, LTMR nerve fibers
that receive input from Merkel cells form
excitatory synapses onto NPY+ interneu-
rons, counteracting the direct excitatory
input from LTMRs and other nerve fibers
onto excitatory itch-transmitting interneu-
rons. Similar to the well-established gate
theory for pain (10), increasing direct excit-
atory input to the inhibitory NPY+ neurons,
through increased recruitment of LTMRs
by means of painful scratch, would inhibit
this circuit, reducing itch. Conversely, loss
of Merkel cell–derived LTMR activity (here,
through loss of Merkel cell number) would
lead to disinhibition of the inhibitory path-
way and result in alloknesis.
Several questions remain, particularly
in the context of treating human disease.
Is the loss of Merkel cells with age con-
served in humans, and, if so, how can this
be prevented? Itching is the most common
skin complaint among elderly patients and
is frequently associated with dry skin (11).
The current study suggests a mechanism by
which painful scratch temporarily alleviates
itch, by inducing enough activity through
remaining Merkel cells to favor the inhibi-
tory pathway of the gate. Enticing thera-
peutic routes for treating alloknesis involve
either finding a way to prevent Merkel cell
loss in the first place or noninvasively in-
creasing activity in remaining Merkel cells,
thus avoiding the damage that results from
the painful itch-scratch cycle. It is also un-
known whether this pathway is a potential
avenue for the treatment of other itch dis-
orders involving dry skin, such as eczema.
Finally, what is the identity of the excitatory
itch-transmitting interneuron? Completing
our understanding of this circuit by iden-
tifying this excitatory neuron as well as the
nerve fibers that innervate it is a necessary
first step toward selectively silencing them
for the treatment of itch. j
REFERENCES
1. P. Perez, J. Bao, Aging Dis. 2, 231 (2011).
2. X. Ding et al., Prog. Retin. Eye Res. 28, 1 (2009).
3. J. Feng et al., Science 360, 530 (2018).
4. V. E. Abraira, D. D. Ginty, Neuron 79, 618 (2013).
5. B. Coste et al., Science 330, 55 (2010).
6. R. Ikeda et al., Cell 157, 664 (2014).
7. S.-H. Woo et al., Nature 509, 622 (2014).
8. S. Maksimovic et al., Nature 509, 617 (2014).
9. S. Bourane et al., Science 350, 550 (2015).
10. R. Melzack, P. D. Wall, Science 150, 971 (1965).
11. L. Garibyan et al., Dermatol. Ther. 26, 92 (2013).
10.1126/science.aat5617
SCIENCE sciencemag.org
NEUROSCIENCE
The controversial correlates
of consciousness
New data suggest that the prefrontal cortex ignites
networks supporting consciousness
By George A. Mashour
T
he mechanism of consciousness is
one of the most fundamental, ex-
citing, and challenging pursuits in
21st-century science. Although the
field of consciousness studies at-
tracts a diverse array of thinkers
who posit myriad physical or metaphysical
substrates for experience, consciousness
must have a neural basis. But where in the
brain is conscious experience generated?
It would seem that, given this remarkable
era of technical and experimental prowess
in the neurosciences, we would be homing
in on the specific circuits or precise neu-
ronal subpopulations that generate experi-
ence. To the contrary, there is still active
debate as to whether the neural correlates
of consciousness are, in coarse terms, lo-
cated in the back or the front of the brain
(1, 2). On page 537 of this issue, van Vugt et
al. (3) provide evidence that the prefrontal
cortex is one of the brain regions that me-
diates visual consciousness. Additionally,
Joglekar et al. (4) provide evidence that the
prefrontal cortex is important for igniting
neural networks that contribute to visual
signal processing. Both studies support a
model for consciousness that involves dis-
tributed and reciprocal interactions across
the cortex.
The investigation of nonhuman pri-
mates by van Vugt et al. was motivated by
a joint consideration of signal detection
theory and global neuronal workspace
theory. Signal detection theory attempts to
explain the processing of stimuli that are
around the threshold of perception and the
reasons why sometimes we perceive such
stimuli and other times we do not. Global
workspace was originally a psychological
framework for consciousness that has, in
the past decade, become more neurobio-
logically informed (5). Global neuronal
workspace theory posits that a subset of
excitatory neurons and long-range tracts
Center for Consciousness Science, Department of
Anesthesiology, Neuroscience Graduate Program, University
of Michigan Medical School, University Hospital, 1H247, 1500
East Medical Center Drive, SPC-5048, Ann Arbor, MI 48109-
5048, USA. Email: gmashour@med.umich.edu
Published by AAAS
in the cortex, including prominent involve-
ment of the prefrontal cortex, amplify,
sustain, and broadcast specific representa-
tions for widespread cognitive processing.
Van Vugt et al. hypothesized that the
threshold required for signal detection
and the neural activity required for the
broadcasting of information through the
neuronal workspace would be the same.
Downloaded from http://science.sciencemag.org/ on May 6, 2018
Neuronal activity in the visual cortex (ar-
eas V1 and V4, in the back of the brain;
see the figure) and dorsolateral prefrontal
cortex (in the front of the brain) of awake
monkeys was recorded to establish neural
correlates of visual stimuli that were per-
ceived and reported with a specific eye
movement. Reported stimuli were associ-
ated with strong and sustained prefrontal
cortex activity, whereas nonreported stim-
uli were associated with weak and tran-
sient prefrontal activity. The investigators
also assessed where information was lost
“…there is still active debate
as to whether the neural
correlates of consciousness
are, in coarse terms,
located in the back or the
front of the brain.”
for nonreportable stimuli and found that
propagation failures could occur at vari-
ous stages in the feedforward pathways en
route to the front of the brain. It was con-
cluded that stimuli cross the threshold for
reportable signal detection when a critical
trigger (or “ignition”) for broadcasting oc-
curs in the prefrontal cortex. This empiri-
cal conclusion was supported by a model
in which reciprocal activity between fron-
tal and parietal cortices enables the signal
to become a self-sustained representation.
But how do the long-range excitatory
neurons of the global neuronal workspace
amplify sensory signals without corrupt-
ing them or leading the brain into unbri-
dled activation? Joglekar et al. examined
4 MAY 2018 • VOL 360 ISSUE 6388 493
INSIGHTS | P E R S P E C T I V E S
Processing consciousness
Visual processing (left) becomes consciously accessible (right) after “ignition” in the frontal cortex leads to reciprocal
interactions that allow the representation of a stimulus to become self-sustaining and widely broadcast.
Feedforward visual processing
The processing of visual information in the feedforward
direction is thought to remain subliminal or, at least,
inaccessible to further cognitive processing.
Parietal
cortex (Par)
Primary
visual
cortex
Thalamic
input
V1 V4 Par
a model of feedforward (back-to-front)
and feedback (front-to-back) processing in
nonhuman primate brain networks. They
demonstrate that excitatory feedback con-
nections can amplify signals but are bal-
anced by local inhibitory processes. This
“global balanced amplification” fits cur-
rent empirical data and is novel because it
integrates local, feedforward, and feedback
processing as well as the inhibitory neuro-
nal brakes that appropriately
constrain the network. Fur-
thermore, Joglekar et al. mod-
eled sensory input to area V1
in the visual cortex and found
that weak signals activate lo-
cal cortex whereas stronger
signals lead to activation of
prefrontal cortex and a rever-
beration of cortical networks,
all of which are consistent
with global neuronal work-
space theory. These modeling
data support the hypothesis of
van Vugt et al. that the thresh-
old of signal detection is the
same threshold that activates
prefrontal cortex and ignites a reciprocally
connected cortical network.
How do these data inform the current
controversy regarding the location of the
neural correlates of consciousness? To
answer this question, it is necessary to
consider the distinction between phenom-
enal consciousness and access conscious-
ness (6). Phenomenal consciousness is the
purely qualitative aspect of experience,
whereas access consciousness shares that
experience with other cognitive systems for
further action (for example, memory, mo-
494 4 MAY 2018 • VOL 360 ISSUE 6388
tex in humans (10), potentially
representing a failure of igni-
tion. General anesthetics also
show dose-dependent effects on
Activated global neuronal workspace local and long-range process-
Once a signal triggers the frontal cortex, a network
ing, two critical elements of
reverberation is thought to allow visual representation to be
both conscious and available to other cognitive systems. global balanced amplification.
At lower doses, local network
connectivity is enhanced while
the long-range connections of
Frontal the global neuronal workspace
cortex are disrupted; higher anesthetic
(Front) doses suppress both local and
long-range connectivity (11).
Thus, general anesthetics could
Thalamic
Monkey brain input
prevent ignition in the pre-
frontal cortex while mitigating
signal strength, depending on
the dose. This independent line
of investigation on the neural
correlates of unconsciousness
Downloaded from http://science.sciencemag.org/ on May 6, 2018
provides further evidence sup-
Front V1 V4 Par Front porting the conclusions of the
two studies.
tor activity, or report). The empirical data Many questions remain. How do the
of van Vugt et al. were focused explicitly on studies of van Vugt et al. and Joglekar et
reportable conscious events and provide al. apply to sensory processing outside of
further support to the hypothesis that the the visual system or to endogenous experi-
prefrontal cortex is important for access ences (such as dreams) that do not require
consciousness. The study does not speak external sensory input at all? How does
directly to the question of phenomenal this work in nonhuman primates trans-
consciousness, but the authors do allude to late to humans or to animals that have a
evidence that prefrontal cortical neurons less developed prefrontal cortex? Further,
can represent consciously perceived visual how do these presumed correlates of con-
stimuli even in the absence sciousness inform the actual causes of
of report (7). Furthermore, consciousness? Solving—or dissolving—
a recent study on dream- controversies related to the neural corre-
“The studies… ing found that, although lates will require transparent definitions
help to explain the neural correlates of phe- of consciousness (access, phenomenal) and
nomenal consciousness ap- carefully designed paradigms (report, no
a related and peared to be primarily in the report) as well as techniques that causally
long-standing posterior cortex, dreaming manipulate neural circuits with the depen-
during rapid eye movement dent variable being a principled, possibly
scientific issue, sleep was also associated behavior-independent measure of con-
namely, the with high-frequency activity
in the frontal and prefrontal
sciousness. Only rigorous neuroscientific
investigation will be able to reveal if the
mechanisms cortices (8). In other words, brain can ultimately explain both itself and
anterior cortex might also its most precious function. j
of general contribute to the pure expe-
anesthetics.” rience that constitutes phe-
REFERENCES
1. M. Boly et al., J. Neurosci. 37, 9603 (2017).
nomenal consciousness. 2. B. Odegaard et al., J. Neurosci. 37, 9593 (2017).
The studies of van Vugt et al. and 3. B. van Vugt et al., Science 360, 537 (2018).
Joglekar et al. also help to explain a related 4. M. R. Joglekar et al., Neuron 98, 222 (2018).
and long-standing scientific issue, namely, 5. S. Dehaene, J.-P. Changeux, Neuron 70,
200 (2011).
the mechanisms of general anesthetics. 6. N. Block, Trends Cogn. Sci. 9, 46 (2005).
Models in which a reciprocally interact- 7. T. I. Panagiotaropoulos et al., Neuron 74,
ing frontal and parietal cortex is deemed 924 (2012).
GRAPHIC: A. KITTERMAN/SCIENCE
necessary for access consciousness align 8. F. Siclari et al., Nat. Neurosci. 20, 872 (2017).
9. G. A. Mashour, A. G. Hudetz, Trends Neurosci. 41, 150
with the finding that diverse general anes-
(2018).
thetics depress metabolism and/or disrupt 10. U. Lee et al., Anesthesiology 118, 1264 (2013).
connectivity in frontal-parietal networks 11. Z. Huang et al., J. Neurosci. 38, 2304 (2018).
(9). Indeed, there is evidence that diverse
general anesthetics preferentially suppress
feedback connectivity from the frontal cor- 10.1126/science.aat5616
sciencemag.org SCIENCE
Published by AAAS
The controversial correlates of consciousness
George A. Mashour

Science 360 (6388), 493-494.

DOI: 10.1126/science.aat5616

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