Developmental perspectives is the fetus conscious

1. Developmental Perspectives:
is the Fetus Conscious?
Roland Brusseau, MD, FAAP
Children’s Hospital Boston
Boston, Massachusetts
Advances in prenatal care, including diagnostic studies and imaging
techniques, have allowed many serious anatomic fetal anomalies to be
identified in earlier gestation, affording the possibility of fetal therapy
and treatment before irreversible damage occurs. Although the
anesthetic management for these fetal interventions often depends on
the type of fetal lesion involved, it has been accepted practice to provide
anesthesia and analgesia to both the mother, via maternal general
anesthesia and maternal analgesic administration, and to the fetus, via
placental transfer.1 The general anesthesia and analgesia provide ideal
surgical conditions, minimize pain for the mother, reduce the fetal stress
response, and may potentially ameliorate fetal pain.2 However, the
development of minimally invasive techniques for fetal intervention
have called into question the need to provide any maternal anesthetic at
all and, by extension, any fetal anesthetic. This has brought the question
of the potential for fetal pain to the fore.3,4
Although discussions of fetal pain are complicated and controversial,
there is little disagreement about the capacity of the fetus to generate a
physiochemical stress response from early gestation. Indeed, human
fetal endocrine responses to stress have been demonstrated from as
early as 18 weeks gestation.5 Such a response to nociceptive stimuli in
and of itself would not seem to qualify as a fetal experience of pain. Pain,
according to the International Association for the Study of Pain, is an
unpleasant sensation which may be associated with actual or potential
REPRINTS: ROLAND BRUSSEAU, MD, FAAP, DEPARTMENT OF ANESTHESIOLOGY, PERIOPERATIVE AND PAIN MEDICINE,
CHILDREN’S HOSPITAL BOSTON, 300 LONGWOOD AVENUE, BOSTON, MA 02115. E-MAIL: ROLAND.BRUSSEAU@
CHILDRENS.HARVARD.EDU
INTERNATIONAL ANESTHESIOLOGY CLINICS
Volume 46, Number 3, 11–23
r 2008, Lippincott Williams & Wilkins
11

2. 12 ’ Brusseau
tissue damage, possibly including physical and emotional components.6
Pain is clearly a subjective phenomenon—one that typically accompanies
nociception—but can also arise without any nociceptive stimulus.
Nociception, on the other hand, is a neurophysiologic term and denotes
specific activity in nerve pathways. It functions as the transmission
mechanism for physiologic pain, but does not necessarily subserve or
describe psychologic pain states.7
Pain, as a subjective phenomenon, would seem to require some
degree of conscious activity to separate it from simple nociception and its
concomitant stress response. Some sort of integrating process, or
processes, is required to render noxious stimuli into a form of
coordinated experience. Therefore, an investigation of the generation
of fetal pain states may itself serve as a surrogate for an investigation of
consciousness, or at least the implied possibility of consciousness. But
simply to demonstrate the possibility of fetal pain is not a satisfactory
criterion for establishing fetal consciousness—clearly one can have
consciousness without pain but the concept of pain occurring without
consciousness would seem to run contrary to our current understanding
of pain as a subjective experience. Therefore, a discussion of conscious-
ness itself is mandated if we are to suggest that there is such a
phenomenon as fetal pain. Subsequently, further investigation of fetal
pain may indeed cast light back on some of the mysteries of the
developmental aspects of consciousness and help us to appropriately ask
and then perhaps answer the query: is the fetus conscious?
’ Cortex, Subcortex, and Consciousness
Working some 5 decades ago, Penfield, a neurosurgeon, and Jasper,
a psychologist, demonstrated that the consciousness (as traditionally
understood) of some 750 patients undergoing radical cortical excisions
remained continuous and unimpaired both during and after the
procedures. Certain discrete cortical functions might be lost or
impaired, but consciousness remained.8 This led to a critical insight:
that the highest integrative functions of the brain are not organized at
the cortical level, but rather within a divergent system of subcortical
structures that process cortical and subcortical inputs. Subsequently,
Jasper found that consciousness might be disrupted in a manner typical
of certain generalized seizures—not by cortical stimulation but rather by
experimental stimulation of the midline thalamus, producing a change
from the usual adult electroencephalogram (EEG) to the familiar spike
and wave pattern of the absence seizure, suggesting that some form of
concordant EEG rhythm, or rhythms, is necessary to support the
conscious state.9 Consciousness, in their view, at minimum requires
certain (largely subcortical) structures and some form of coordinating
rhythm or rhythms.

3. Developmental Perspectives ’ 13
Asking a similar question about the minimal requirements for
consciousness, Merker10 cited the example of a common jellyfish, the
cubomedusa or Sea Wasp. The cubomedusa serves an example of a
primitive neural network—essentially a group of semi-independent
pacemakers with no cephalization or centralization. These pacemakers
allow the cubomedusa to respond with directional locomotor responses
to asymmetric sensory inputs. But, Merker asks, is the cubomedusa
conscious? He concludes that there is no reason to believe that what
amounts to the environmental guidance system provided by this neural
network involves, or generates, an experience of any kind. But where in
the spectrum of possibility between the cubomedusa and the awake
surgical patients of Penfield and Jasper may we identify a rubicon of
consciousness? What are the minimal criteria for consciousness? What
might a fetus require to be capable of consciousness?
Hameroff11 suggests that consciousness, in its most basic form, may
be considered equivalent to a ‘‘minimal awareness’’ without a require-
ment for memory, cognition, or organizational sophistication. This is
certainly more rudimentary than the phenomenal consciousness we
enjoy in wakefulness. However, Hameroff argues, the interesting
question lay not in discriminating degrees of self-referential cognition
(such as differentiating between human and chimpanzee) but rather in
illuminating the distinction between consciousness (understood as
minimal awareness) and nonconsciousness. This is the important
transition. Just as with the eye, where the development of photosensitive
pigments that transduce light energy into neural signals is the critical
development in the natural history of vision,12 here the critical step in
generating consciousness is bridging the gap between the individual
neuron (and concomitant neuroprocessing) and conscious experience.
Essentially the brain’s neural networks subdivide processing into
modalities (visual and tactile) and submodalities (temperature and
color) while perceptions are integrated and unified.13 It is out of such
integration, it would seem, that conscious states become possible.
Recalling Merker’s jellyfish, then, what apparently disqualifies the
cubomedusa from participation in conscious states is not so much its
simplicity but rather its lack of specific structural arrangements required
to support conscious function. It does not integrate or unify subproces-
sing modalities; it exists by reflex arc. This, however, raises a question: if
coordination of such subprocessing is essential to the generation of
conscious states, is its interruption essential to the generation of
unconscious states? Jasper’s induced thalamic seizures certainly suggest
such, and anesthetics provide further insight.
Anesthetics have long been acknowledged as reversible suppressors
of consciousness (as well as memory and movement), yet the mechan-
isms of such remain unclearly understood. Although the traditional view
has been that anesthetics blunt neural function globally, recent evidence

4. 14 ’ Brusseau
suggests that like the unconsciousness of the generalized seizure, the
anesthetized brain is anything but silent. Isoflurane has been shown to
inhibit pattern recognition (an integrating function) but not component
recognition, suggesting that subprocessing modalities remain intact
whereas integration fails.14 Indeed, multiple anesthetics have demon-
strated electrical uncoupling of rostrocaudal and intrahemispheric brain
regions15 and caudorostral information transfer.16 It is not clear,
however, whether anesthetics interrupt subcortical integrating
functions. Certainly, in the fetus or preterm neonate there is currently
no significant evidence that anesthetics do, or do not, disrupt subcortical
unities. Currently available technologies limit investigation of this
question. Nevertheless, the bulk of evidence from anesthesia demon-
strates that, as is the case with the cubomedusa, the brain is not silent—it
is simply not connected. As such, and in agreement with Penfield and
Jasper, it would seem that the presence of certain structures and
concordant rhythms become a sort of minimum requirement for
consciousness. Indeed, the very subcortical and cortical structures that
Penfield and Jasper suggest are involved in the generation of conscious
states, and their inherent electrical rhythms, are known to be present
in the term neonate and their development during fetal life is well
documented.
’ Fetal Neurodevelopment I: Structures and Rhythms
The development of the human brain and spinal cord begins as
early as the third postconceptual week, when the neural tube forms
from neuroectoderm. Neural crest cells migrate out laterally to form
peripheral nerves from 4 weeks, with the first synapses between them
forming a week later. Synapses within the spinal cord begin to develop at
8 weeks gestation, suggesting the first spinal reflexes may be present
from roughly 8 weeks forward.17 Between 8 and 18 weeks gestation is
the time of maximal neuronal development. After neural proliferation,
synaptogenesis occurs, first in peripheral structures and then more
centrally. Cortical development initiates from the subplate zone,
developing connections to both the thalamus and the neocortex.
Intensive differentiation of these neurons occurs between 17 and 25
weeks gestation, a process that is at least partly dependent on sensory
stimulation.18
The development of the nociceptive apparatus proceeds in parallel
with basic central nervous system development. The first essential
requirement for nociception is the presence of sensory receptors, which
develop first in the perioral area at around 7 weeks gestation. From
here, they develop in the rest of the face and in the palmar surfaces
of the hands and soles of the feet from 11 weeks. By 20 weeks, they
are present throughout all of the skin and mucosal surfaces.19 The

5. Developmental Perspectives ’ 15
nociceptive apparatus is initially involved in local reflex movements at
the spinal cord level without supraspinal integration. As these reflex
responses become more complex, they, in turn, involve brainstem
structures, through which other responses, such as increases in heart
rate and blood pressure, are mediated.20,21
The thalamus is the structure responsible for relaying afferent
signals from the spinal cord to various subcortical structures and the
cerebral cortex itself.22 Thus, if integrative thalamic function is
necessary for nociceptive perception (ie, pain) or any other higher
order sensory perception as the work of Jasper suggests, arguably it
cannot be until the thalamocortical connections are formed and
functional that the fetus may first attain something approaching
Hameroff ’s rudimentary consciousness. The thalamus is first identified
in a primitive form at day 22 or 23 postconception. Its connections grow
out in phases, initially only as far as the intermediate zone of the cerebral
wall, collecting below the cortical plate. Stimulation of the subplate zones
by thalamic neural connections stimulates aspects of cortical develop-
ment. As such, thalamic development largely precedes significant
cortical development. The final thalamocortical connections are thought
to be in place by around 26 weeks, although estimates differ.23 In fact,
there are thought to be transient cholinergic neurons with functioning
synapses connecting the thalamus and cortical plate from approximately
20 weeks.24 This time point could be taken as the absolute earliest time
in gestation when a fetus could be aware of nociceptive stimuli, or to feel
pain—provided there is some degree of functional maturity in addition
to this structural maturity.
As suggested by Jasper, the link between consciousness and electrical
activity within the brain can be measured and patterns defined using the
EEG. The presence of EEG activity would confirm a degree of functional
maturation in addition to structural maturation described above.
Although sporadic electrical activity has been detected in the fetal brain
as early as 43 days gestation,25 more coordinated electrical activity (in
the form of intermittent bursts) has been shown to be present in the
brainstem from 12 weeks, and the later-developing cerebral hemi-
spheres at 20 weeks. Before 25 weeks, the electrical activity on EEG
recordings is discontinuous, with periods of inactivity lasting up to 8
minutes. From 25 to 29 weeks, the periods of activity increase, such that
by 30 weeks, although EEG activity is still not continuous (indeed, in
some infants, it does not become continuous during quiet sleep until
several weeks after term), distinct patterns of wakefulness and sleep can
be recognized as the precursors of adult patterns.26
Nevertheless, it is arguable when electrical activity in the fetal brain
first becomes indicative of a state of consciousness or at least the
possibility thereof. If we require a cortical contribution to the generation
of conscious states, then the lack of cortical electrical activity detected

6. 16 ’ Brusseau
below 20 weeks sets the lowest possible limit. Given that cortical
electrical activity at this time is exceedingly discontinuous, 20 weeks
would seem a very liberal estimate. Should greater continuity of cortical
electrical activity be required, 30 weeks gestation may represent a more
reasonable threshold. However, if one were to argue that a minimal
form of consciousness might be possible without cortical involvement,
then certainly one would have to consider thalamic development as a
benchmark for the possible generation of such a state. As described
above, thalamic structures seem to be in place somewhere between 20
and 30 weeks. However, the paucity of evidence demonstrating
continuous and coordinate thalamic electrical activity makes such a
distinction difficult. Nevertheless, the later-developing cortex does allow
electrical interrogation and as such allows indirect evidence of thalamic
function. Cortical electrical activity suggests intact thalamic function and
as such implies that thalamic electrical maturation is at least con-
temporaneous with the cortex, and indeed likely precedes cortical
development in this functional regard, as is also the case with its
structural development. Other evidence, however, points to a much
earlier maturation of thalamic processing function. Thalamic connec-
tions are intimately involved in the generation of the physiochemical
and endocrine responses to nociception that are seen as early as 18
weeks.20,27 This line of evidence would suggest an earlier threshold for
the possible development of consciousness. In general, however, by 34
weeks electrical activity is seen throughout the brain approximately 80%
of the time.28 As periods of continuous electrical activity gradually
lengthen, it would seem likely that no sudden event marks the
beginning of consciousness but that as the gaps between periods of
electrical activity gradually shorten, consciousness emerges incrementally.
’ Consciousness Without a Cortex
Returning to the notion that pain may function as a surrogate
marker for consciousness, inasmuch as an experience of pain pre-
supposes at least a minimal degree of consciousness, clinical data may
allow us further insight into the structures and functionalities required
for conscious perception. This, in turn, may offer greater insight into the
possibility of fetal consciousness. Consider the possibility that a cortex is
not required at all—what could this tell us about the generation of pain
states, and their consequential states of consciousness, in the uterine
fetus?
In keeping with the critical insights of Penfield and Jasper,
clinical evidence suggests that either ablation or stimulation of the
primary somatosensory cortex does not alter pain perception in adults
(demonstrated by Penfield and Jasper themselves), whereas both
thalamic ablation and stimulation have been shown to interrupt pain

7. Developmental Perspectives ’ 17
perception. Chronic deep brain stimulation of the periventricular gray
(PVG) for treatment of chronic pain states clearly demonstrates the
latter point. Stimulation of the PVG that leads to clinically observed pain
relief has been shown to attenuate field potentials in the ventroposter-
olateral thalamic nucleus for the duration of the stimulation; PVG
stimulation that fails to provide pain relief similarly has been shown to
fail to attenuate these thalamic field potentials.29 In keeping with this
evidence, we should consider that if cortical activity is not a prerequisite
for pain perception in adults, then by analogy neither would it be a
necessary criterion for fetuses. Further, if cortical function is not
necessary for pain perception, then it may not be required for the
generation of conscious states. Perhaps subcortical structures, including
the thalamus, are necessary and sufficient to support at least a minimal
form of consciousness. As previously discussed, fetal development of the
thalamus occurs much earlier than the sensory cortex, but functional
evidence for thalamic sensory processing is currently lacking. Never-
theless, significant cortical activity may be demonstrated as early as 28
weeks in preterm neonates exposed to tactile or painful stimuli,30
suggesting a degree of thalamic function before full gestation and, by
extension, implying the possibility of fetal conscious perception by that
gestational age; whether such is possible before 28 weeks, with or
without cortical contribution, remains an open question.
Clinical evidence for conscious perception mediated by such a
subcortical system comes from infants and children with hydranence-
phaly. These children are born with minimal or no cortical tissue, yet
have intact and functional subcortical structures.31–33 Despite the total
or near-total absence of cerebral cortex, these children clearly
demonstrate elements of consciousness: discriminative awareness
(including the ability to distinguish familiar from unfamiliar people
and environments), appropriate social interaction, functional vision,
orienting, apparent musical preferences, appropriate affective re-
sponses, and associative learning.34 Indeed, many of these children
are not diagnosed as newborns, as their behavior patterns are often
indistinguishable from those of unaffected newborns. It is important to
note that these are not hydrocephalic children who possess a thin rim of
intact, functional cortex but rather children with little or no cortex at all,
resulting from in utero cortical infarcts that were subsequently
reabsorbed. What little cortex may remain is generally nonfunctional
and without normal white matter connectivity.35
As such, it would seem these children demonstrate that anatomic
development or functional activity of the cortex may not be required for
conscious sensory perception. They may, and do in fact, respond to
painful or pleasurable stimuli in what may easily be argued to be a
conscious, coordinated manner, similar to intact children.36 Other
evidence for such a subcortical machinery of consciousness may be

8. 18 ’ Brusseau
derived from preterm neonates or adolescents with parenchymal brain
injury who have impaired cortical function, yet mount physiochemical
and behavioral responses to pain that are indistinguishable from those
of unimpaired controls.37,38 Also, patients in persistent vegetative states
present evidence for the conscious perception of self and environ-
ment,39 including the capacity to experience pain.40 Perhaps not
surprisingly, recovery from vegetative states has been shown to be
associated with the restoration of the connectivity of thalamocortical
networks,41 again documenting the critical roles of the thalamus and
subcortex in the generation of conscious experience.
The neurologic phenomenon of blindsight provides further insight
into the subcortical mechanisms of consciousness. Blindsight occurs in
humans (and has been reproduced in monkeys) when there is extensive
damage to cortical area V1, which produces a hemianopsia.42 In a
typical case, the patient can indicate, well above chance level, the
direction of movement of a spot of light over a certain range of speed—
all the while denying that he or she sees anything at all. Other patients
can distinguish large, simple shapes, or colors. What is remarkable about
this phenomenon is that the patient is, in fact, seeing, but simply is not
aware of it. As was the case with acortical pain states, there seems to be
no prerequisite for cortical function to produce this discrete, limited
consciousness. Recent functional magnetic resonance imaging of the
blindsight patients directly implicates the superior colliculus as being
active specifically when such patients correctly discriminate the direction
of motion of some stimulus without being aware of it at all.43 Similar
evidence for the role of subcortical processing in conscious sensory
perception comes from the related Sprague effect described in cats.44
Complete removal of the posterior visual areas of one hemisphere
renders the affected cat profoundly and permanently unresponsive to
visual stimuli in the field contralateral to the lesion; however, infliction of
further damage at the midbrain level—particularly at the superior
colliculus—restores the animal’s ability to orient and localize stimuli in
the formerly blind field.45 Notably, analogous correction of the neglect
caused by frontal cortical damage has been observed in human patients
after midbrain damage on the opposite side.46 The Sprague effect is
thought to be a brainstem-level consequence of unilateral cortical
inactivation, likely due to unbalanced cortical input leading to
unbalanced inhibitory inputs at the level of the superior colliuculus.47
The secondary brain stem lesioning is thought to correct this latter
imbalance at least partially, allowing the superior colliculus and related
structures to resume their usual contribution to functional behavior.48,49
It would seem that the superior colliculus, either by itself or in
conjunction with other subcortical structures (eg, the thalamus), is
capable of independent off-line processing and functionality that may
participate in a sort of minimal awareness.

9. Developmental Perspectives ’ 19
Blindsight aptly demonstrates what has been described as a sort of
off-line consciousness (a consciousness with only minimal awareness, as
described by Hameroff, but a form of consciousness nevertheless) that is
distinct from mere reflex; the patient with blindsight is seeing, but
simply is not aware of it. This exists in distinction to what would be an
on-line consciousness—which more aptly describes our subjective
experience of wakefulness. This has led to the philosophical construct
of the zombie, a creature who is supposed to act just as normal people
do but who is completely unconscious.50 Odd as this construct may
sound, there is now suggestive evidence that part of the brain does
behave like a zombie, such as was the case with blindsight. That is, in
some cases, a person uses the current visual input to produce a relevant
motor output, without being able to say what was seen.51 There is
anecdotal evidence from sports. It is often stated that a trained tennis
player reacting to a fast serve has no time to see the ball; the seeing
comes afterward.52 In a similar way, a sprinter is believed to start to run
before he or she consciously hears the starting pistol; the hearing comes
afterward.53 This zombie consciousness may in fact represent aspects of
a subcortical consciousness, that is, the way we process information
without having it on-line in consciousness (consider driving a car while
thinking about another topic). Again, this zombie consciousness seems as
an example of what Hameroff was describing—that consciousness, in its
most basic form, may be considered equivalent to minimal awareness.
’ The Possibility of Fetal Consciousness
This attempt to distinguish an off-line, and hence an on-line,
consciousness may be particularly fruitful for investigating the possibility
of fetal consciousness. Such off-line processing may be at play much
earlier in fetal development and provide greater contributions to
possible fetal (and neonatal) conscious states than we may think, and
further help to explain some of the unique phenomena discussed so far.
Conscious, or on-line, perception and awareness are associated with
generalized activation of diverse brain areas.54 The reticular activating
system, with numerous subcortical inputs including the basal forebrain,
locus coeruleus, substantia nigra, ventral tegmentum, and median
raphe, seems to mediate such activation. Notably, lesions in this system,
but not in the thalamus or cortex, lead to a loss of consciousness
awareness.55 This begs the question as to whether such a system as the
reticular activating system, by itself or in conjunction with other rhythms
such as the 40 Hz g oscillation (believed to be a significant contributor to
conscious integration56,57), serves as a bridge between the off-line and
on-line states of consciousness. Further, a question arises as to whether
disruption of the on-line consciousness necessarily disrupts off-line

10. 20 ’ Brusseau
consciousness—could it be that an anesthetized preterm neonate is in
fact off-line but not on-line? Is a fetus in utero similarly off-line but not
on-line?
Using pain again as a surrogate marker for consciousness, the
question remains as to whether the fetus is in any way aware of
nociceptive stimuli. Physiochemical and behavioral data suggest that the
fetus remains largely in a sleeplike state while in utero.58 This state
seems to be mediated by substances such as adenosine, steroids, and
prostaglandins, as well as a low PO2.59 Evidence for this actively
maintained fetal sleeplike state is based on EEG and other observations
indicating the inhibition of cortical activity. (Perhaps not surprisingly,
adult studies of non-rapid eye movement sleep demonstrate that such
sleep is, as was the case with anesthetics, characterized by a loss of
effective cortical connectivity60). Although mild noxious stimuli do not
seem to be perceived during such fetal sleep, major tissue injury
occurring as a result of fetal trauma or fetal surgical intervention
generates behavioral and physiologic arousal.61 Nevertheless, given the
evidence for a subcortical or off-line consciousness that may be necessary
and sufficient for pain processing (eg, hydrancephalic children) and the
lack of evidence suggesting subcortical electrical nonconnectivity during
this period (indeed, appropriate arousal from sleep seems to suggest
some degree of continuous subcortical connectivity and/or function), the
fetus in its latter developmental period may well be capable of pain
processing and thus have at least limited consciousness while in utero—
even when apparently asleep.
Perhaps the subcortex is necessary and sufficient for at least a
minimal, Hameroffian consciousness, one that (if the data regarding
anencephalic children are to be believed) may render an integrated
experience of nociception that we might call pain. Multiple lines of
evidence presented herein indicate that the necessary subcortical
structures are present and functional in the preterm fetus. As discussed
above, it is clear that functionally effective patterns of nociceptive and
sensory processing develop during the second trimester in the fetal
thalamus. Several lines of evidence indicate that integrative support for
consciousness depends on a subcortical system, whereas the contents of
higher order, phenomenal consciousness seem to be located in cortical
areas. Neither ablation nor stimulation of cortical areas block or cause
pain perception in adults, whereas thalamic ablation or stimulation does.
It would seem, then, that thalamic structures play a central role in
conscious pain perception, and therefore in the generation of at least
minimally conscious states. Fetal development of the thalamus occurs
much earlier than the sensory cortex, providing the necessary structural
and functional mechanisms for conscious pain perception during the
second trimester. If we are to suggest that the fetus can experience pain,
then, this would seem to mandate the presence of at least a minimal

11. Developmental Perspectives ’ 21
form of consciousness—a minimal awareness—born out of the integra-
tion and unification of diverse sensory, and perhaps other, inputs. As
noted earlier, although consciousness does not necessarily presuppose
pain, pain as currently understood does presuppose a consciousness of
sorts. If we are to attribute pain to an anencephalic child, a preterm
neonate, or a uterine fetus, then it seems we would be compelled to
grant these same individuals at least a limited form of consciousness.
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