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Doubtless, the conscious brain integrates masses of information. But declaring that consciousness simply "emerges" when enough has accumulated, doesn't really explain how first person experience is implemented by neurons. Moreover, empirical observations challenge integrated information theory's (IIT) reliance on thalamo-cortical interactions as the information integrator. More likely, the cortex streams processed information to a still-enigmatic consciousness generator, one perhaps located in the brainstem.
Behavioural Brain Research 427 (2022) 113861
Available online 26 March 2022
0166-4328/© 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (
Might pain be experienced in the brainstem rather than in the
cerebral cortex?
Mark Baron
, Marshall Devor
Department of Cell and Developmental Biology, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel
The Center for Research on Pain, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel
Brain evolution
Mesopontine tegmentum
It is nearly axiomatic that pain, among other examples of conscious experience, is an outcome of still-uncertain
forms of neural processing that occur in the cerebral cortex, and specically within thalamo-cortical networks.
This belief rests largely on the dramatic relative expansion of the cortex in the course of primate evolution, in
humans in particular, and on the fact that direct activation of sensory representations in the cortex evokes a
corresponding conscious percept. Here we assemble evidence, drawn from a number of sources, suggesting that
pain experience is unlike the other senses and may not, in fact, be an expression of cortical processing. These
include the virtual inability to evoke pain by cortical stimulation, the rarity of painful auras in epileptic patients
and outcomes of cortical lesions. And yet, pain perception is clearly a function of a conscious brain. Indeed, it is
perhaps the most archetypical example of conscious experience. This draws us to conclude that conscious
experience, at least as realized in the pain system, is seated subcortically, perhaps even in the primitive
brainstem. Our conjecture is that the massive expansion of the cortex over the course of evolution was not driven
by the adaptive value of implementing consciousness. Rather, the cortex evolved because of the adaptive value of
providing an already existing subcortical generator of consciousness with a feed of critical information that
requires the computationally intensive capability of the cerebral cortex.
1. Functional localization in the brain
One of the central themes of human brain architecture, and a concept
that has stood the test of time, is that the brain is subdivided into distinct
territories that may collaborate, but that carry out different functions.
Functional borders are not always sharp and neighboring, and even
distant, regions may be highly interconnected. But in most instances
specic denable functions can be said to reside in, to be "seated in", or
to depend onactivity in particular parts of the brain. Here we will
consider such localization-of-function with respect to pain [1]. Pain,
perhaps the prototypical exemplar of conscious experience, is routinely
bundled within the near-universal presumption that the cortex, or the
thalamo-cortical complex, is the "organ of consciousness". Our main
message is that this presumption may be mistaken.
Pain as a sensory modality features a number of peculiarities that are
not widely appreciated and that set it aside from the other senses with
regard to localization. Specically, these peculiarities suggest that the
raw feel of something hurting may not be anchored in the cerebral
cortex, but somewhere else in the brain. Moreover, because the expe-
rience of pain is so intimately linked to arousal and the feeling of being
me, of being present, awake and aware (i.e., of being "conscious"), the
question of its residing elsewhere than in the cortex is not just a matter of
anatomical location. It has consequences for our understanding of the
evolution of consciousness itself.
The localization of visual perception, hearing, touch, smell etc., each
in its own neighborhood in the cerebral cortex, is the clearest example of
functional modularity in the brain. But localization-of-function extends
beyond the senses. Willed motor function, for example, is believed to be
seated in the motor cortex (precentral gyrus) notwithstanding the roles
played by other brain structures including the cerebellum, the corpus
striatum and the spinal cord [2]. Strokes affecting the motor cortex in
humans result in contralateral hemiparesis. And beyond sensation and
action, more elusive functions also appear to be localized in the brain,
although perhaps not so clearly bound to the cortex. Key examples are
motivation and emotions which are strongly linked to the hypothala-
mus, nucleus accumbens and amygdala, and perhaps not exclusively
* Correspondence to: Department of Cell and Developmental Biology, Institute of Life Sciences 3-533, The Hebrew University of Jerusalem, Edmond J. Safra
Campus at Givat Ram, Jerusalem 9190401, Israel.
E-mail addresses: (M. Baron), (M. Devor).
Contents lists available at ScienceDirect
Behavioural Brain Research
journal homepage:
Received 1 December 2021; Received in revised form 9 March 2022; Accepted 23 March 2022
Behavioural Brain Research 427 (2022) 113861
seated in the limbic cortex (orbital frontal cortex, cingulate gyrus and
elsewhere) [1]. And for some functions the jury is still out. We tend to
teach, for example, that memory is located in the hippocampal forma-
tion. But while the hippocampus surely plays a key role in the processes
of storage and retrieval, memories themselves likely exist in a more
distributed form, one for which the metaphor of a hologram has been
invoked because of the resistance of memories to erasure by lesions
[35]. Finally, while the concept of a center-of-consciousnessseems to
be outmoded, consciousness is almost universally believed to be
seatedin the cerebral cortex.
The primacy of the brain should not be taken for granted. In ancient
times complex human experience was believed to be seated in the heart
and later in diverse body organs including, the spleen (mood) and the
uterus (empathy). In Hebrew rahamim, the word for mercy, derives
from rehem, the womb. Only later did the brain, and principally the
cortex, become the consensus repository of mental life, at times in
exaggerated form. 19th century phrenology gave functional modularity
a bad name with the claim that personality traits, and even ethical
predilections, can be localized to bumps on the skull. But those days
have largely passed. Motor theories of perception not withstanding [6],
there is little dispute today that mental functions reside in the brain and
are largely modular [1].
2. Primacy of the cerebral cortex in conscious perception
Among contemporary opinion leaders there is a broad consensus that
conscious sensory perception, felt emotions and motivation, cognition
and the sense of agency (the perhaps illusory conviction that my will
determines my actions) are seated in the cerebral cortex [2,7,8]. This
includes both being "conscious of…” things and ideas, and also
phenomenal consciousness, the raw feel that I am present without
there necessarily being a connection to sensory experience, memory, or
thinking of anything in particular. Raw feelrefers to the sense that I"
am located behind the bridge of my nose, that my feeling of being
presentis unaffected when I close my eyes, or cover my ears, and that
I am not in oblivion (in non-dream sleep, anesthetized, comatose or
dead). My retina and my camera may capture an identical scene. But I
view the scene while the camera has no equivalent perceptual
The broad consensus that consciousness is a cortical function usually
species that it is dependent on thalamo-cortical networks, with their
highly interconnected multimodal information content. Among cortical
regions focus is nearly always placed on the neocortex and in particular,
higher order association cortices, with recent interest on a choice be-
tween prefrontal and more posterior (parietal-occipital) regions,
depending on the investigator [9,10]. After initial processing in the
spinal cord, and/or brainstem (including cerebellum), and sub-cortical
forebrain, information from all modalities and from all parts of the
body is relayed to the cerebral cortex. This occurs via a variety of
ascending pathways including ones that relay through the basal fore-
brain and zona incerta rather than the thalamus. However, as the thal-
amus includes the most comprehensive collection of cortical relay
nuclei, it has received the bulk of research attention and is widely
accepted as the primary access portal to the conscious brain [11,12]. By
this canonical model, information entering the cortex maintains arousal
and forms the primary substrate of perception and non-reexive deci-
sion-making, conscious and unconscious. This includes pain perception
and pain-related behavior.
2.1. Role of the brainstem in consciousness
It is appreciated, of course, that arousal nuclei in the mesopontine
brainstem and diencephalon play an essential role in causing the cortex
to transition between states of consciousness and unconsciousness,
particularly in the framework of sleep. This idea took center stage with
Moruzzi & Magouns aRAS (ascending Reticular Activating System),
later morphing into its contemporary elaborations [1316]. But the
contribution of the subcortical arousal system has always been viewed as
being permissive, enabling cortical function. Its supposed role is to
switch the cortex from a state of absence (unconscious oblivion) to one
of arousal, and to maintain this state until oblivion (sleep) resumes.
Arousalis a hypothetical intermediate brain-state that is a prerequisite
for the normal awake-state of conscious awareness, but something
less. A vegetative patient, in contrast to one in a deep coma, is said to
have arousal, but to be unconscious and incapable of perception,
including pain [17]. The brainstem arousal complex is often likened to a
power supply, or an on-off switch[9,18]. By the canonical model the
implementation of consciousness occurs in the cortex. As the eminent
neuroanatomist Alf Brodal stated, it would be entirely misleading to
consider the reticular formation the ‘seat of consciousness (quoted
from [19]).
A hybrid model, Penelds Centrencephalic Hypothesis, envi-
sioned a dialog between cortex and brainstem as the substrate for con-
sciousness, with the brainstem actually prioritized at one point in the
models development [20,21]. A contemporary approach which also
sees the brainstem and cortex as sharing duties has been championed by
Damasio [22]. Only a few dissenting voices have taken seriously the
prospect that primal, raw consciousness might be seated in the brain-
stem, and they have tended to have relatively small microphones
2.2. Cortical localization of consciousness
The canonical view that consciousness is seated in the cortex derives
from a number of fundamental observations, chief among them:
2.2.1. Big cortex
Across species there is a clear relation between large brains, actually
large brain/body ratios, and greater mental sophistication. Primates,
and particularly humans, are at the pinnacle of this trend. Along this
spectrum the brain structure that shows the largest proportional growth
is the cerebral cortex [2629].
2.2.2. Direct electrical stimulation
of exposed primary sensory cortices in awake humans consistently
gives rise to the corresponding sensation. Stimulating S1 (primary so-
matosensory cortex) evokes touch sensation, stimulating A1 (primary
auditory cortex) evokes sound and stimulating V1 (primary visual cor-
tex) evokes patterned light. In mapped senses such as touch and vision,
the site of stimulation corresponds to a specic location in sensory space
[30,31]. Likewise, epileptic seizures are often accompanied by a
sensation ("aura") that corresponds to the location of the epileptiform
activity. It should be noted, however, that the sensory experience is not
usually attributed to neurons active in primary cortices, but rather to
higher order cortical association areas that receive input from S1, A1
and V1. It is also noteworthy, but not a key feature of the consensus
model, that subcortical structures receive a copy of this information feed
via descending axons, particularly of lamina 5 pyramidal neurons in the
cortical association areas.
2.2.3. Sensory ngerprint and electroencephalography (EEG)
Sensory stimuli, be they visual, olfactory, taste or touch, give rise to
complex patterns of evoked neural activity across corresponding parts of
the cortex. In the event of painful stimuli, the pattern is referred to as the
pain matrix" (or alternatively "pain signature", or "pain ngerprint").
The evoked cortical activity is best illustrated using non-invasive im-
aging techniques such as fMRI (functional Magnetic Resonance Imag-
ing), or PET (Positron Emission Tomography) [32,33], but it is also
registered by surface or depth recording electrodes. In addition to
stimulus-evoked cortical responses, there are patterns of electrical ac-
tivity generated spontaneously within the cortex itself that correlate
with the ongoing state of arousal-awareness. Most notably,
M. Baron and M. Devor
Behavioural Brain Research 427 (2022) 113861
low-amplitude activity in the theta- (48 Hz), alpha- (814 Hz) and
higher frequency EEG bands is associated with conscious wakefulness in
contrast to high-amplitude slow-wave delta-band (0.54 Hz) activity
that associates with unconsciousness including NREM sleep, GABAergic
anesthesia and light coma. There are exceptions to this general rule,
however, especially in the presence of brain disorders and pharmaco-
logical interventions [34,35].
Lesions, and reversible block of neural activity, using local anesthetics
or cold-block for example, disrupt perception in the corresponding
sensory modality. The most dramatic example is vision. Individuals with
lesions including V1 report blindness, inability to see. However, some
residual visual function can often be detected such as intuition about the
shape of objects and object location (especially of moving objects), and
perhaps even the ability to catch such objects ("blindsight"). Perceptu-
ally the individual denies being able to see anything although careful
inspection may reveal borderline phenomenal vision [3639]. Just as
telling, a 2nd lesion may restore vision in animals blinded by destruction
of V1 (the Sprague effect[40]). In modalities other than vision,
damage to primary sensory cortex causes functional disruption that is
much less complete (e.g. [41]). It is important to note, however, that
whereas loss of a sensory modality may cause severe functional decits,
it does not render individuals less conscious. This holds for closing ones
eyes, visual loss due to V1 damage in adulthood or congenitally, and also
for combined loss of multiple senses such as vision, hearing and touch.
People are also not less conscious for lack of visual awareness in the
ultraviolet range, or for lack of awareness of magnetic and electric elds,
capabilities upon which some animals depend. The inability of humans
to sense and process such stimuli makes us less capable, but not less
conscious. Even major brain lesions affecting the cortex like surgical
hemispherectomy, prefrontal lobotomy and congenital cortical thin-
ning, although they do cause disabilities, spare consciousness and with it
often a considerable degree of sensory-motor, cognitive and emotional
functioning [42,43]. This is indisputable in the many patients with these
sorts of injuries who are capable of speech.
Broadly disseminated cortical damage that extends across functional
regions, such as occurs in cases of prolonged hypoxia (e.g. in drowning
victims), or developmental malformation (e.g. hydranencephaly) may
leave the individual in a "vegetative" state of unresponsive wakefulness.
Unlike coma, these individuals awaken in the morning, have alternating
periods of wakefulness and sleep, respond to pinch with an adaptive
nocifensive reex movements, and may even display familiar facial
expressions, vocalization and tears suggestive of consciousness and pain
perception [17,23,44]. But all this is believed by the broad neurological
community to be without awareness. Vegetative patients are considered
to have arousal but not consciousness. The individual is seen as
disconnected from the world, unconscious and most important in the
present context, incapable of experiencing pain.
3. The primacy of cortex cracks in the wall
On the face of it, the above body of evidence seems irrefutable. And
indeed, the idea that conscious perception is intimately linked to
thalamo-cortical function is not often disputed even by investigators
who accept that the brainstem may be more than just an on-off switch.
Nonetheless, two lines of thought might tend to shake ones condence.
The rst is the realization that for the most part, the observations listed
above with respect to the cortex apply just as well to subcortical struc-
tures along the ascending sensory pathways. Electrical stimulation of the
retina, or ectopic discharge originating there, also evokes localized vi-
sual percepts, and retinal lesions cause blindness. The same is true of the
diencephalic relay nuclei that convey visual signals from the retina to
the cortex. Few would take this as convincing evidence that conscious
visual perception occurs in the retina, lateral geniculate, or pulvinar
nucleus. The conventional interpretation, of course, is that the retina
feeds visual information via diencephalic relays to the visual cortex
where the magic of conscious perception occurs. But following this line
of reasoning one could ask whether the high-level areas of visual asso-
ciation cortex are necessarily the end of the relay chain. As noted, most
cortical areas, including high-order association cortices, provide
massive numbers of bers that descend to the subcortical forebrain and
brainstem. Indeed, ber counts in these descending projections may
outnumber those that ascend from the thalamus to the cortex [4547].
Can we be certain that visual, auditory and other sensory signals pro-
cessed and interpreted by the massive cortical computer are not then
delivered to a conscious operator resident subcortically?
A second line that might undermine condence in cortical primacy is
a list of peculiarities that are specic to pain processing. In the pain
system signals are normally generated in the periphery with the acti-
vation of nociceptor endings in the skin and other tissues by noxious
stimuli: mechanical, chemical or thermal. The resulting afferent drive
runs centrally past the para-spinal sensory ganglia and is delivered to
nociceptive-selective and wide dynamic range neurons in the spinal and
medullary dorsal horn where a rst stage of integration occurs. Much of
the resulting signal is distributed broadly in the brainstem and dien-
cephalon, relayed along ascending spino-bulbar, spino-cerebellar and
spino-thalamic pathways. A variety of secondary ascending relays for-
ward the signal to the cerebral cortex. In parallel, signals from a sub-
population of spinal nociceptive-selective neurons ascend in a separate
white-matter tract to synapse in the pontine parabrachial complex from
where they ascend to the amygdala followed by areas of limbic and
prefrontal cortex [48]. Somewhere along these intricate routes through
the pain matrix, the ow of information somehow transubstantiates in a
seemingly miraculous manner into conscious experience.
Pain is universally included among the primary sensory modalities
with functional localization no different in principle than functional
localization of vision, hearing and the rest. Indeed, among the senses,
pain is surely the most frequently chosen by philosophers and psychol-
ogists as an exemplar of phenomenal consciousness [7]. This choice is
well justied. More than sight and sound, pain features emotional and
hedonic vectors (suffering), and attention-riveting urgency, making it
particularly salient. However, there are features of the pain system that
are less-well appreciated, even among pain specialists, that set pain
aside from the other senses and raise questions as to whether raw pain
experience is in fact seatedin the cortex. Consider the following:
4. Little-appreciated peculiarities of the pain system
4.1. Pain evoked by cortical stimulation
Direct electrical stimulation of primary sensory cortices in awake
humans, in all modalities, evokes the corresponding sensory experience:
vision, audition, touch, smell etc. [30,31]. The one exception is pain.
There is no recognized P1 (primary pain cortex) as there is a V1, an S1
etc. Wilder Peneld wrote “… no removal of cortex anywhere can pre-
vent pain from being felt and only very rarely does a patient use the
word pain to describe the result of cortical stimulation…”. He
continued, It is obvious therefore that the pathway of pain conduction
reaches the thalamus and consciousness without essential conduction to
the cortex. More recent studies report much the same [30,49]. The
closest approaches to an exception are studies from two groups in France
that reported pain evoked from depth electrodes placed in the insular
cortex and dorsal operculum (S2). Even in these groups the estimate is
that pain was evoked in no more than ~1.4% of stimulation trials
[5053]. To be sure, neurons in S1, S2 and the insula are strongly
activated by pain-provoking stimuli such as pinch and heat [54]. These
areas are prominent parts of the pain matrix (Fig. 1A). But direct elec-
trical stimulation here, as in other parts of the pain matrix, almost al-
ways evokes a sensation of touch, pressure and/or vibration, but rarely
pain [30,31]. The fact that information about noxious stimuli reaches
the neocortex implies that this information is used in the generation of
adaptive behavioral responses. The same is true of the cerebellum which
also receives prominent noxious input. A sudden cramp will impair your
M. Baron and M. Devor
Behavioural Brain Research 427 (2022) 113861
tennis swing, but the cerebellum is not considered a player in the gen-
eration of pain perception [9]. In general, the activation of a brain area
by painful stimuli in no way proves that the area in question must be a
substrate for generating conscious pain experience.
The occasional instances in which pain has been reported following
cortical stimulation also need consideration. Stimulating the insula
causes abdominal contractions, documented by balloon sensors placed
in the gut [55]. This might cause pain by activating primary afferent
nociceptors in the periphery, especially if gastric inammation were
present. Considering that the French patients studied had epilepsy,
stimulation might also have kindled hard-to-detect after-discharge in
strategic subcortical loci. Surprisingly, the two French groups found
pain responses in different parts of the insula (posterior vs. anterior).
Finally, others have looked for and not found such pain responses (e.g.
[55]). In a personal communication addressed to the senior author
neurosurgeon Mitchel S. Berger (UCSF, 2/2009) stated: Ive operated
on more than 175 insular tumors, and although I have not mapped all of
them, I can tell you that even when patients are awake, I have never seen
pain being evoked by stimulating, touching or even resecting the pos-
terior insula (quoted with permission). In contrast, pain sensation is
readily evoked in animals and humans by conventional electrical stim-
ulation at various subcortical locations along ascending pain pathways,
most notably the somatosensory thalamus (PO, VPM, VPL) and the
parabrachial complex [56,57].
4.2. Not looking in the right place?
Perhaps P1 cortex has evaded discovery to date because one has not
looked in the right place. Non-invasive functional imaging in humans
reveals large expanses of cortex that are activated by sensory stimuli
which are reported by the subjects to be painful. However, this pain
matrix overlaps to a considerable degree with cortical areas activated by
non-painful touch stimuli. Indeed, as shown in Fig. 1, it also overlaps the
matrix of regions activated by auditory and visual stimuli [33,58,59].
The high degree of overlap is a concern for interpreting such functional
images. To what extent do these activations reect the particular
perceptual experiences reported by the subjects (pain, touch, sound and
vision) rather than features common to all of them, such as arousal and
attention? There are particular locations, such as S1, the anterior
cingulate cortex (ACC) and the dorsal operculum (S2), at which the
degree of fMRI activation has been shown to correlate with the intensity
of pain reported, the degree of unpleasantnessexperienced, and the
degree to which manipulations such as hypnotic suggestion and placebo
can modulate the pain experience [60,61]. Such correlations come
Fig. 1. The cortical pain matrix, obtained in response to a pain-provoking noxious stimulus, closely resembles the matrix obtained from a similar non-painful
tactile stimulus, and from auditory and visual stimuli. All images show Blood Oxygenation Level Dependent (BOLD) signatures in the human brain in response to
8 trials of each of the 4 stimuli, in pseudo-random order, delivered over 8 min. The nociceptive somatosensory stimulus (red) was a 5 msec pulse of radiant heat from
an infrared Nd:YAP laser, ~7 mm beam diameter, targeting the dorsum of the right foot. This evoked a painful pinprick sensation. The non-nociceptive somato-
sensory stimulus (purple) was a 1 msec electrical pulse applied to the right ankle at an intensity adjusted to elicit a non-painful paresthesia. The auditory stimulus
(blue) was a 50 msec right-sided 800 Hz tone. The visual stimulus (green) was a bright white disk (~9
) projected above the right foot for 100 msec. L: left, R: right.
Signicant clusters are overlaid onto an average structural MRI scan. Note the large amount of spatial overlap between the responses elicited by stimuli in all four
modalities. Image reprinted from NeuroImage, Vol. 54/Issue 3, Mouraux, Andr´
e ., Diukova, Ana., Lee, Michael C., Wise, Richard G., Iannetti, Gian Domenico., A
multisensory investigation of the functional signicance of the "pain matrix", Pages 22372249., Academic Press (2011), with permission from the senior author and
Elsevier publishers.
M. Baron and M. Devor
Behavioural Brain Research 427 (2022) 113861
closer to indicating specicity. However, direct electrical stimulation in
awake patients has been attempted at these cortical locations too and as
noted, pain sensation was almost never evoked. We suspect the reported
correlations have little to do with cortical processing. Rather, they may
simply reect effects of attention, placebo etc. on the magnitude of the
nociceptive signal ascending from the spina cord. Ascending nociceptive
signals are strongly modulated by pathways that descend from the
midbrain periaqueductal gray (PAG) and the medulla to control the
spinal gate. Descending control is known to be engaged by contextual
variables including hypnosis, placebo, nocebo etc., and to secondarily
affect the magnitude of ascending neuronal activations traveling along
axonal chains to cortical areas including the ACC and S2 [6264]. Such
modulation has been extensively studied under the headings of diffuse
noxious inhibitory controls(DNIC) and conditioned pain modulation
(CPM; [65,66]).
4.3. Not stimulating in the right place?
One might similarly argue that P1 is located in a region of cortex
inaccessible to conventional surface stimulation. The insular cortex, for
example, is not visible upon acute brain exposure. One needs to remove
the overlying operculum to gain access, or to insert depth electrodes.
These invasive procedures are justied for purposes of clinical diagnosis
and treatment in the case of the insula and afford an opportunity for
research studies. But in other inaccessible regions there may be no such
medical justication. The orbital frontal cortex and the mesial temporal
lobe are examples of such buriedcortex. However, irrespective of
surface accessibility, essentially all cortical regions are subject to
epileptiform activity. Indeed, the temporal lobe and insula are particu-
larly frequent foci. Epileptic discharge in primary sensory cortices
routinely evokes an aura corresponding to the location of the discharge,
visual, auditory, or tactile. For example, as anticipated, epileptic sei-
zures in buried mesial temporal lobe tend to evoke olfactory sensations,
often foul-smelling odors [67,68]. But remarkably, reports of pain as an
aura of epileptic seizure activity are very rare, whether they occur in
these inaccessible cortices or elsewhere in the cerebral convexities. The
few instances that have been reported seem to favor the dorsal oper-
culum and underlying insular cortex. As noted, at least some of these
might be due to the spread of activity subcortically [6972].
4.4. Complexity of the cortical pain signature
It is sometimes argued that the failure of focal stimulation and of
endogenous epileptiform activity to evoke pain sensation indicates that
pain is a more complex experience than vision, hearing, touch and smell.
The crude, unpatterned discharges generated in the cortex by direct
electrical stimulation and by epileptic seizures are simply inadequate to
mimic the intricate activity patterns required to generate pain experi-
ence. Although the cortical ngerprints of different sorts of sensory
stimuli appear similar (Fig. 1), it is inevitable that at higher resolution
subtle differences exist that distinguish them. Indeed, a priori, distin-
guishable experiences must associate with distinguishable patterns of
neural activity, although we may need futuristic technologies to detect
the differences that matter. Might such subtleties account for the
different sensations experienced? Machine-learning algorithms and
deep-learning have already provided additional power in sorting fMRI
images on the basis of the presence or absence of pain [73]. The
detection of differences, however, does not in itself prove that these
differences are causative. Be that as it may, the crude electrical stimuli
applied to recognized primary sensory cortices by neurosurgeons, and
the disorganized activity present during seizures at these locations, are
perfectly able to evoke corresponding sensory experience in other mo-
dalities. Indeed, sometimes evoked sensations have incredibly complex
life-like qualities, such as recognizable images and specic tunes. The
one exception is pain [31].
4.5. Lesions
Why does pain differ in this way from vision, audition, smell and the
other senses in terms of response to stimuli and cortical seizure activity?
Although it stretches the bounds of credulity (Section 4.4 above),
perhaps pain is more complex than van Gogh, Mozart and Cabernet
Sauvignon, requiring perfect matrix delity. The requirement for precise
patterning, however, goes hand-in-hand with loss of resilience if the
pattern is disrupted. Thus, if precise matrix patterning is required to feel
pain, even minor disruption of patterning should cause the subjective
experience of pain to vanish. In fact, conditions that surely disrupt the
cortical pain matrix such as brain tumors and traumatic or vascular le-
sions are common, and they do not cause blindnessto pain (analgesia).
Quite the contrary, cortical injury is frequently followed by increased
pain, e.g. post-stroke pain [74,75]. Surgical removal of the cortical
representation of a painful body part (e.g. in S1) has been attempted
repeatedly without much success and is no longer used as a therapeutic
modality in chronic pain patients, notwithstanding the occasional
anecdotal report of a surgical resection or a stroke being followed by
pain relief [76,77]. This includes lesions of the insular cortex, the only
tentative candidate for P1 (discussed in Section 4.1). Complete
destruction of the insula does not eliminate pain sensation [7883].
4.6. Pain without a cortex
Curiously, experimental animals that have undergone complete
surgical decortication and even complete decerebration (removal of
cortex and subcortical forebrain), particularly as neonates, retain a
remarkable degree of adaptive behavior, including pain behavior. This
includes locomotion, play behavior, pup rearing and complex noci-
fensive behaviors. Nocifensive behavior goes far beyond spinal exor
reexes. It includes vocalization, squirming and targeted defensive
maneuvers associated with pain in intact animals. Indeed, without
special testing it can be difcult to distinguish decorticate rats from
intact ones [25,8488]. Unfortunately, in the absence of a denitive
marker of pain experience it is impossible to know for sure if such
nocifensive behaviors indeed reect phenomenal suffering or just the
output of unconscious central pattern generating circuitry. The same
question applies to human patients in an unresponsive wakeful state
(vegetative state), advanced Alzheimers disease and children born with
hydranencephaly [23]. There is no region in the cortex at which surgical
excision results in loss-of-consciousness (LOC), even of an entire hemi-
sphere [43]. Traumatic cortical injury caused by a high-velocity bullet
or shrapnel often does cause LOC presumably with loss of pain. Likewise
for major subdural bleeds and concussion. The mechanism in these
cases, however, is most likely elevated intracranial pressure causing
secondary subtentorial injury to the brainstem. Along the same lines,
thalamic lesions that cause LOC invariably extend into the brainstem
5. Big cortex the evolutionary forces at play
Among the arguments placing consciousness in the cerebral cortex,
the evolutionary argument is probably the most resonant. There is a
clear directional arrow over eons showing that enlargement of brain/
body ratio accompanies increased intelligence and behavioral sophisti-
cation. This correlation is particularly robust for enlargement of the
neocortex and it is clearly meaningful. The few exceptions to the rule
probably represent species resident in unusual ecological niches in
which the brain was shaped by unusual demands [26,27,29]. But has the
larger community of neuroscientists interpreted this correlation
correctly? Is the emergence of consciousness in fact the ultimate fruit of
cortical expansion, or could there be a different need that led to the
dramatic increase in computational power rendered by the big cortex of
advanced mammals, notably mankind?
A part of the increase in brain size represents the extra housekeeping
M. Baron and M. Devor
Behavioural Brain Research 427 (2022) 113861
duties needed to maintain a larger body with its greater area of skin,
length of the intestine, muscle mass and so forth. Having covered these
needs, however, it also makes evolutionary sense to invest in increased
computational power to achieve other ends [9294]. Specically,
cortical expansion, and the extra computational power that it makes
available, is expected to improve many skills and hence to promote an
individuals adaptability to thrive in most ecological niches. Advances in
the realms of sensory processing, motor performance, memory, detec-
tion of emotional subtleties, cognition and predictive abilities are all
likely to be rewarded in the Darwinian battleground. This trend features
prominently in brain evolution from lower vertebrates to primates.
Consider the following examples, all made possible by a bigger cortex:
1) Benets accrued when visual processing dependent on the midbrain
tectum, which specializes in the detection of movement and looming
objects, was enhanced by cortically-based object recognition,
including the capacity to better recognize potential predators and
individual conspecics.
2) The emergence of the pyramidal system in higher mammals
permitted the ne digital motor control needed for sophisticated tool
3) A big cortex increases the ability to predict and plan for future needs.
Additionally, it permits increased sophistication of social in-
teractions including the emergence of language.
Interestingly, these are the very same steps that have featured in the
evolution of electronic computing capabilities as we have moved in
recent decades from adding machines to systems capable of face
recognition and robots that dance. All this, however, falls within the
sphere of engineering. In animals advanced computation may (some-
how) be beneted by conscious perception. But this does not yet apply to
machines. What modern advances in computational power have not
brought about (to the best of our knowledge) is any emergence of sub-
jective experience. Deep Blue, the rst silicon-based chess champion,
was just as unconscious as a 1960 s adding machine, and neither expe-
rience pain. Nor would this be changed by installing a temperature
transducer and having the computer ash ouchat 45 C. Its true that
we have no way to prove that Big Blue, or the adding machine, are not
conscious. But we know precisely how both were built and operate, and
nothing that might support consciousness was included in their design.
At present, we have absolutely no idea how neuronal impulses and
neurotransmitters generate the raw feel of being conscious. Indeed, the
question remains open as to whether this explanatory gap can, even in
principle, be bridged with ever more computational power. The even-
tual construction of conscious machines may require something very
5.1. The role of cortical information in pain processing
The evidence touched upon above, revolving around brain stimula-
tion, epilepsy, imaging, and lesions, calls into question the widely and
rmly held belief that pain perception is something that happens in the
cerebral cortex. In contrast, none of these points undermine the case for
pain experience being seated in the subcortical forebrain and/or the
brainstem. Direct electrical stimulation at appropriate subcortical lo-
cations in humans and animals readily evokes pain experience and pain
behavior, subcortical seizure activity can be painful, appropriate
subcortical regions are activated in functional imaging and pathway
lesions can relieve pain [31,56,95]. What is more, localized microin-
jection of minute quantities of opiates into the brainstem PAG yields
selective whole-body analgesia and microinjecting GABAergic anes-
thetics into the brainstem MPTA (mesopontine tegmental anesthesia
area) yields LOC including insensitivity to noxious stimuli [9699]. Most
telling of all, localized lesions in the dorsal mesopontine tegmentum
readily induce LOC in animals and humans, and lesions limited to the
MPTA render animals relatively insensitive to otherwise clinically
effective doses of anaesthetics delivered systemically [90,91,100102].
The prospect touched upon above, that pain is a more complex sense
than vision, hearing etc. is jarringly counterintuitive (Section 4.5).
Consider that the information needed to detect that a stimulus to the lips
is a cactus plant, not a gentle kiss, is present at the rst central synapse in
the trigeminal brainstem, and it is immediately available for an adaptive
action response with no further signal processing. In contrast, it requires
a great deal of sophisticated computation to distinguish, based on con-
trasts falling on the retina, whether one is facing a passing cloud or a
rhinoceros charging (Fig. 2). The latter type of distinction demands
heavy investment in signal processing resources, just the kind of prob-
lem that our cortex specializes in. Computations needed for this type of
pattern recognition are also the sort in which articial intelligence
routines such as deep learning excel. Whatever sort of computation is
required to generate a conscious me, and to experience pain rather
than simply to respond reexively, it is surely different. However such
an algorithm might operate, there is no a priori reason to predict that it
would also be good at distinguishing clouds from charging beasts. The
fundamental nature of the problem is different.
The survival value of a brain capable of high-quality object recog-
nition is transparent and provides a satisfying explanation for the
cortical expansion that occurred over the course of vertebrate evolution.
But it does not explain the evolutionary advantage of rendering the
object recognized in the form of a conscious experience. Identifying the
retinal image as a rhinoceros rather than a cloud should be enough to
trigger an appropriate behavioral response, at least in organisms that
share a habitat with rhinos or that otherwise know how to deal with risks
of this sort. The philosophersunconscious "zombie", and the android
robots that populate science-ction lms, are human-like if with an
uncanny emotional feel. But moving beyond Hollywood fantasy, an
unconscious person who is sleep-walking can also carry out complex acts
such as getting dressed and driving a car, devoid of awareness. A famous
instance is the Kenneth Parks case in which Mr Parks was acquitted on
murder charges because his actions were carried out when he was
asleep, unconscious and hence not responsible for his actions (https://
Fig. 2. Noxious stimuli that activate afferent nociceptive neurons innervating
the skin and deep tissues, be they chemoreceptors detecting spicy peppers, or
mechanoreceptors detecting sharp spines, deliver an aversive sensory signal to
the brain. This can be interpreted as painful with minimal further signal pro-
cessing, already in the trigeminal brainstem. Unlike the pain system, contrasts
falling on the retina require complex image processing, and comparison with
previously encountered images and contexts, before their signicance to the
well-being of the organism can be established. This process requires the
immense computational processing rendered by the cerebral cortex. We pro-
pose that the outcome of this processing is then delivered by descending
pathways to brainstem circuitry shared with noxious and other sensory input
where it becomes consciously perceived. In this case, the percept is a distant
cloud or a rhinoceros charging.
M. Baron and M. Devor
Behavioural Brain Research 427 (2022) 113861
html by Toronto Globe and Mail, Chicago Tribune 1988; Parks, R v. 1992. 2
SCR 871). Autonomous machines are already with us in high-end ap-
plications (e.g. Mars landers) and are scheduled soon to take to our
streets in the form of self-driving cars. Again, we face the question of the
evolutionary benet of consciousness. In what way would conscious
perception improve the performance of the lander or the car? Sophis-
ticated machine vision is already able to identify objects and even to
distinguish individual faces, utterly without consciousness. So why
would brains need conscious perception in order to get along in the
We are not satised that an answer to this question is in hand.
However, the very existence of consciousness as a product of brain
evolution implies that there is an adaptive benet to enriching auton-
omous actions of the zombieor the sleep-walker with willed sensory-
motor acts, and to supplement nocifensive reex action with pain
experience [103]. Perhaps the answer lies in the realm of response to the
unexpected. But whatever it might be, in awake humans the cortical
processor normally does deliver its output to consciousness. Although "I"
may not always attend to the high-resolution feed generated by my
cortex, or take optimal advantage of it, it is usually accessible to me.
There are exceptions, however. When tasks are stereotyped and over-
learned, such as highway driving or playing piano, the unconscious
zombiemay take over executive control of my body for extended
periods of time. Nonetheless, control tends to transfer back to the
conscious "me" rapidly and seamlessly when routine is broken.
5.2. Where is pain? Where is consciousness?
As pointed out, all the information needed for nociception to become
pain is available at the 1st central synapse in the dorsal horn and tri-
geminal brainstem. There is no need for prior signal processing depen-
dent on heavy computational resources. Thus, in principle, the adaptive
advantages of rendering pain as a subjective experience could have
emerged at a much earlier stage of evolution than visual perception,
perhaps even before development of a neocortex. This supposes, of
course, that raw consciousness is built on a platform that does not
require intense computational power. Our conjecture is that the unique
isodendritic structure of neurons in the reticular core of the brainstem,
shared by lower vertebrates and primates [104106], might be ideally
suited for integrating nociceptive input about force, heat, sting etc. from
data streams arriving from all parts of the body. Massive integration of
information of this sort is precisely the process called for by some the-
ories on the emergence of consciousness [9]. Why could not this inte-
gration be implemented in the brainstem for the modality of pain?
In the sense of evolving earlier and not requiring an on-line super-
computer, pain experience probably is more primitivethan visual
experience as simple intuition usually tells us (Fig. 2). But the utterly
mysterious neural process underlying subjectivity is likely the same for
pain and vision, and equally sophisticated. The fact that contemporary
computer science experts gured out how to implement face recognition
using silicon chips (and only very recently), but have not yet gured out
how to implement consciousness, may ultimately prove to be an insig-
nicant quirk and not a reection of the relative difculty of the two
problems. The ash of insight that led to the deep learning algorithms
may be no different in kind from the insight that will eventually explain
raw consciousness. Or perhaps it is easier, or even essential, to imple-
ment sentience using biological components rather than silicon. Perhaps
one will need to wait until the critical technology appears.
We are aware that at this point in the discussion not many readers
will feel the need to question the consensus opinion that visual
perception, touch and hearing are seated in the cortex. But as a thought
experiment, and in light of the empirical observations laid out above, we
ask the reader to suspend credulity for a moment and grant the possi-
bility that pain, including its emotional vector of suffering, might be a
special case that is seated subcortically. Be aware, however, that
granting this premise does not suspend the fact that, by denition, pain
is a function of a conscious brain. From these two premises, that pain
implies conscious perception and that pain is implemented in the
brainstem, it follows as a logical corollary that consciousness must be
implemented subcortically, at least with respect to pain.
5.2.1. Role of cortical processing of nociceptive signals
In a world where the raw experience of pain plays out in the brain-
stem, what might be the role of the pain matrix, the widespread pattern
of cortical activity associated with painful stimuli (Fig. 1)? What does
having a neocortex add to the more primitive raw feelof an event
being painful? The likely answer is that in higher mammals, and espe-
cially in humans, the experience of pain goes far beyond its raw feel
[107]. Specically, both the intensity of pain evoked by noxious stimuli
and the suffering attached to such stimuli are powerfully modulated by
its behavioral signicance and the context in which noxious stimuli
appear. Is an abdominal pain an indicator of impending childbirth, or
might it be cancer? Emotional context, fear, pleasure, afliation and
implications for the future (cognitive and emotional) are all strong
modulators of pain experienced in higher mammals, although surely less
so in amphibians and lizards. In humans, words from an authoritative
source (doctor, spiritual leader, hypnotist etc.), or prior beliefs no matter
how acquired (homeopathy, crystals) can be powerfully modulating
factors (placebo, nocebo, distraction). Perhaps the most dramatic gating
of pain occurs at times of emergency. There are innumerable instances of
accident victims, soldiers and injured parents extricating themselves and
loved ones from mortal danger with no pain felt during the process
[108110]. Pain comes later. It is noteworthy that the bulk of neuro-
physiological evidence indicates that pain is modulated in this way by
the engagement of high cortical functions, but that the actual modula-
tion is implemented by descending pathways that target brain structures
at mesopontine levels and below (Section 5.1). This is also where pain
modulation by opiates and by general anesthetics are believed to operate
Beyond modulation aimed at suppressing present pain, cortical
processing is also essential for facing the future. The capacity to learn,
remember and plan ahead for circumstances that carry a risk of
encountering pain all involve highly complex considerations whose so-
lutions depend on the advanced computational power that a big cerebral
cortex makes available. The capacity to anticipate future contingencies
based on currently available signals, like planning chess moves many
plays in advance, would have increased progressively with the ever-
growing capacity of the evolving cortical computer. And evolving in-
telligence (in both senses) provided by a big cortex would have consti-
tuted an ever more important and adaptive input to the conscious agent
seated in the brainstem.
We conclude that whatever the adaptive value of consciousness
might be, its contribution to the survival and well-being of the organism
would be enhanced by briengs provided by the cortex. Pain focuses
urgent conscious attention on matters related to survival while the
cortex provides the high-quality intelligence information needed for
better action plans. Routine action, even if complex, can run autono-
mously below the surface, unconsciously. The very existence of con-
sciousness implies that it plays an adaptive role even if the nature of the
value added remains obscure. In extremis, intense pain or intense
emotional engagement has the ability to turn consciousness off entirely,
e.g. to induce loss-of-consciousness in the form of psychogenic syncope
[112]. This returns the unconscious cortical machine to the driversseat
until the crisis is over.
6. The bottom line
The picture we are trying to paint is that, at least with regard to pain,
the evolutionary drive that fostered expansion of the cerebral cortex was
not to implement conscious experience, a capacity probably already in
place in the brainstem in lower mammals and perhaps before [113].
M. Baron and M. Devor
Behavioural Brain Research 427 (2022) 113861
Rather, evolutionary expansion of the cortex was adaptive because it
provided the already conscious brainstem with high-quality information
feed (Fig. 2).
CRediT authorship contribution statement
Mark Baron: Conceptualization, Writing original draft, Writing
review & editing. Marshall Devor: Conceptualization, Supervision,
Writing original draft , Writing review & editing, Visualization,
We thank Harry Rappaport and Yosef Grodzinsky for helpful dis-
cussions and comments, Giandomenico Iannetti for permission to
reprint Fig. 1, and Anne Minert for drafting Fig. 2. The senior authors
research work is supported by the Fund for Research on Anesthesia at
the Hebrew University of Jerusalem and the Hebrew Universitys Sey-
mour and Cecile Alpert Chair in Pain Research. Author MB is recipient of
a Dr. Willem Been Legacy Fellowship. The authors declare no conicts of
interest with respect to this paper.
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Background In the Wada test, one hemisphere is selectively anaesthetised by unilateral intracarotid injection of a fast-acting anaesthetic agent. This gives a unique opportunity to observe the functions and physiological activity of one hemisphere while anaesthetising the other, allowing direct comparisons between brain states and hemispheres that are not possible in any other setting. Aim To test whether potential measures of consciousness would be affected by selective anaesthesia of one hemisphere, and reliably distinguish the states of the anesthetised and non-anesthetised hemispheres. Methods We analysed EEG data from 7 patients undergoing Wada-tests in preparation for neurosurgery and computed several measures reported to correlate with the state of consciousness: power spectral density, functional connectivity, and measures of signal diversity. These measures were compared between conditions (normal rest vs. unilateral anaesthesia) and hemispheres (injected vs. non-injected), and used with a support vector machine to classify the state and site of injection objectively from individual patient's recordings. Results Although brain function, assessed behaviourally, appeared to be substantially altered only on the injected side, we found large bilateral changes in power spectral density for all frequency bands tested, and functional connectivity changed significantly both between and within both hemispheres. Surprisingly, we found no statistically significant differences in the measures of signal diversity between hemispheres or states, for the group of 7 patients, although 4 of the individual patients showed a significant decrease in signal diversity on the injected side. Nevertheless, including signal diversity measures improved the classification results, indicating that these measures carry at least some non-redundant information about the condition and injection site. We propose that several of these results may be explained by conduction of activity, via the corpus callosum, from the injected to the contralateral hemisphere and vice versa, without substantially affecting the function of the receiving hemisphere, thus reflecting what we call “cross-state unreceptiveness”.
A common observation in EEG research is that consciousness vanishes with the appearance of delta (1 – 4 Hz) waves, particularly when those waves are high amplitude. High amplitude delta oscillations are very frequently observed in states of diminished consciousness, including slow wave sleep, anaesthesia, generalised epileptic seizures, and disorders of consciousness such as coma and vegetative state. This strong correlation between loss of consciousness and high amplitude delta oscillations is thought to stem from the widespread cortical deactivation that occurs during the “down states” or troughs of these slow oscillations. Recently, however, many studies have reported the presence of prominent delta activity during conscious states, which casts doubt on the hypothesis that high amplitude delta oscillations are an indicator of unconsciousness. These studies include work in Angelman syndrome, epilepsy, behavioural responsiveness during propofol anaesthesia, postoperative delirium, and states of dissociation from the environment such as dreaming and powerful psychedelic states. The foregoing studies complement an older, yet largely unacknowledged, body of literature that has documented awake, conscious patients with high amplitude delta oscillations in clinical reports from Rett syndrome, Lennox-Gastaut syndrome, schizophrenia, mitochondrial diseases, hepatic encephalopathy, and nonconvulsive status epilepticus. At the same time, a largely parallel body of recent work has reported convincing evidence that the complexity or entropy of EEG and magnetoencephalogram or MEG signals strongly relates to an individual’s level of consciousness. Having reviewed this literature, we discuss plausible mechanisms that would resolve the seeming contradiction between high amplitude delta oscillations and consciousness. We also consider implications concerning theories of consciousness, such as integrated information theory and the entropic brain hypothesis. Finally, we conclude that false inferences of unconscious states can be best avoided by examining measures of electrophysiological complexity in addition to spectral power.
The sensory neocortex is a critical substrate for memory. Despite its strong connection with the thalamus, the role of direct thalamocortical communication in memory remains elusive. We performed chronic in vivo two-photon calcium imaging of thalamic synapses in mouse auditory cortex layer 1, a major locus of cortical associations. Combined with optogenetics, viral tracing, whole-cell recording, and computational modeling, we find that the higher-order thalamus is required for associative learning and transmits memory-related information that closely correlates with acquired behavioral relevance. In turn, these signals are tightly and dynamically controlled by local presynaptic inhibition. Our results not only identify the higher-order thalamus as a highly plastic source of cortical top-down information but also reveal a level of computational flexibility in layer 1 that goes far beyond hard-wired connectivity.
Although pain is defined as a sensory and emotional experience, it is traditionally researched and clinically treated separately from emotion. Conceptual and mechanistic relationships between these constructs highlight the need for better understanding of their bi-directional influences and the value of bridging the pain and emotion research and clinical communities.