THE JOURNAL OF COMPARATIVE NEUROLOGY 493:154 –166 (2005)

Neural Mechanisms of Autonomic,

Affective, and Cognitive Integration
HUGO D. CRITCHLEY*
Wellcome Department of Imaging Neuroscience, Institute of Neurology, University College
London (UCL) Autonomic Unit, National Hospital for Neurology and Neurosurgery,
University College London Hospitals, Institute of Cognitive Neuroscience, UCL, Queen
Square, London WC1N 3BG, United Kingdom

ABSTRACT
Influential theoretical models propose a central role for afferent information from the
body in the expression of emotional feeling states. Feedback representations of changing
states of bodily arousal influence learning and facilitate concurrent and prospective decision-
making. Functional neuroimaging studies have increased understanding of brain mecha-
nisms that generate changes in autonomic arousal during behavior and those which respond
to internal feedback signals to influence subjective feeling states. In particular, anterior
cingulate cortex is implicated in generating autonomic changes, while insula and orbitofron-
tal cortices may be specialized in mapping visceral responses. Independently, ventromedial
prefrontal cortex is recognized to support processes of internal (self-) reference that predom-
inate in states of rest and disengagement and which putatively serve as a benchmark for
dynamic interactions with the environment. Lesion data further highlight the integrated role
of these cortical regions in autonomic and motivational control. In computational models of
control, forward (efference copies) and inverse models are proposed to enable prediction and
correction of action and, by extension, the interpretation of the behavior of others. It is
hypothesized that the neural substrate for these processes during motivational and affective
behavior lies within the interactions of anterior cingulate, insula, and orbitofrontal cortices.
Generation of visceral autonomic correlates of control reinforce experiential engagement in
simulatory models and underpin concepts such as somatic markers to bridge the dualistic
divide. J. Comp. Neurol. 493:154 –166, 2005. © 2005 Wiley-Liss, Inc.

Indexing terms: autonomic; arousal; cognition; emotion; neuroimaging

States of bodily excitement distinguish “passion” from
“cold reason.” Shivering with fear, flushing with anger or
embarrassment, and quickening of heart during anxiety
or love represent the peripheral bodily expression of sub-
jective emotional experience. Nevertheless, some pretty
dry cognitive processes can also evoke changes in periph-
eral arousal that reveal changes in attention, expectation,
and effort to the psychophysiologist. Functional neuroim-
aging, initially with positron emission tomography (PET),
has revolutionized human cognitive neuroscience. More
recently, functional magnetic resonance imaging (fMRI)
enables neural activity to be measured (albeit indirectly)
across whole brain simultaneously; at the temporal reso-
lution of many thought processes; and with a spatial res-
olution approximating the size of functional neuronal
modules (suggested by electrophysiology and cytoarchitec-
tonics) (Frackowiak et al., 2003). Importantly, these tech-
niques enable psychologists to probe workings of the hu-
man mind in search of correlates of human phenomena
such as language, conscious reasoning, and subjective
feeling. Human physiologists have also applied functional
neuroimaging to whole-brain, systems-level examination
of processes such as motor control, and the encoding and
representation of visual, auditory, and somatosensory (in-
cluding pain) sensations. Such neuroimaging studies com-
plement animal investigations by allowing mechanistic
processes to be explored in relation to motivational chal-
lenges, with an additional parallel subjective account.
Grant sponsor: Wellcome Trust.
*Correspondence to: Hugo D. Critchley, Wellcome Department of Imag-
ing Neuroscience, Institute of Neurology, UCL Autonomic Unit, National
Hospital for Neurology and Neurosurgery, UCLH, Institute of Cognitive
Neuroscience, UCL, Queen Square, London WC1N 3BG, UK. E-mail:
h.critchley@fil.ion.ucl.ac.uk
Received 29 March 2005; Revised 17 June 2005; Accepted 20 June 2005
DOI 10.1002/cne.20749
Published online in Wiley InterScience (www.interscience.wiley.com).

© 2005 WILEY-LISS, INC.

NEURAL MECHANISMS OF INTEGRATION
This article presents an overview of autonomic mecha-
nisms and an interpretation of neuroimaging studies that
link generation and feedback of autonomic nervous re-
sponses to central processing, particularly in relation to
emotion.
EFFERENT AND AFFERENT
MECHANISMS
A hierarchy of homeostatic mechanisms is responsible
for regulating functions within and across bodily systems.
At the organ level, coordinated control is mediated pri-
marily by neural and humoral pathways. At the top of the
hierarchy is the adaptive control of behavior within the
environment. Internal bodily changes serve to motivate
behavior, signaling physical needs such as hunger. Prepa-
ratory bodily responses, for example, states of readiness
evoked by threat, are shaped by experience and when
evoked serve to guide future behaviors.
The autonomic nervous system represents the principal
regulatory route of internal bodily functions. Sympathetic
and parasympathetic autonomic axes provide neural in-
put into every major bodily system (Brading, 1999). Their
interaction enables continuous control of “vegetative” pro-
cesses and the dynamic modification of bodily state in
response to environmental challenges. Sympathetic activ-
ity facilitates motor action, increasing cardiac output, by
dilating vessels of the musculature and reducing blood
supply to the gut. In contrast, parasympathetic activity
promotes recuperative functions effecting heart rate re-
duction, lowering of blood pressure, and slowing of gut
motility. Bodily states of arousal associated with survival
(e.g., fight and flight responses) are typically character-
ized by increased sympathetic activity and, usually, de-
creased parasympathetic activity (Cannon, 1929; see also
Porges, 1995; Morrison, 2001). A subset of autonomic
arousal responses have developed into potent social cues
that can betray an individual’s motivational state (Dar-
win, 1898; Ekman et al., 1983).
Peripheral sympathetic drive originates in brainstem
nuclei whose neurons project ipsilaterally down interme-
diolateral columns of thoracolumbar spinal cord to syn-
apse at preganglionic sympathetic neurons in spinal seg-
ments T1–L2. (These neurons relay cholinergically at
ganglia located in bilateral paravertebral chains with (un-
myelinated) postganglionic nerves terminating at the ef-
fector organ.) Sympathetic terminal synapses are typi-
cally noradrenergic and may respond to circulating (tonic)
levels of adrenaline and noradrenaline. However, sympa-
thetic endings at eccrine sweat glands and arterioles
within the skeletomusculature are largely cholinergic.
Parasympathetic efferents originate in brainstem in the
motor nuclei of cranial nerves III, VII, IX, and X (vagus)
and also from sacral spinal segments. Preganglionic fibers
travel to ganglia at the effector organ, where short post-
ganglionic fibers innervate target tissues. Acetylcholine is
the neurotransmitter at both parasympathetic ganglionic
and effector synapses. Most peripheral bodily organs re-
ceive their parasympathetic innervation via the vagus
nerve. Parasympathetic fibers within oculomotor (III), fa-
cial (VII), and glossopharyngeal (IX) cranial nerves medi-
ate pupil and salivary gland responses, and sacral para-
sympathetic fibers innervate distal gastrointestinal and
urogenital systems (Langley, 1898; Brading, 1999).
155
Homoeostatic autonomic control is supported by a func-
tional organization of sympathetic and parasympathetic
nuclei within hypothalamus, pons, and medulla. Sympa-
thetic nuclei hypothalamus interact with homeostatic
(e.g., thermoregulatory centers) and in dorsal pons regions
lie in close proximity to ascending neuromodulator path-
ways (dopamine, 5HT, acetylcholine, and noradrenaline)
implicated in cortical arousal and motivational signaling.
Interactions between medullary, pontine, and hypotha-
lamic centers may support the generation of autonomic
response patterns evoked differentially across physiologi-
cal or behavioral challenges (Saper, 2002). Noradrenergic
projections to thalamus and cortex of locus coeruleus nor-
adrenergic cell group of (A6 and A4) are further implicated
in mediating central arousal and alertness, enhancing
attention, and the sensory processing of environmental
challenges including novel stimuli (Aston-Jones et al.,
1991). The locus coeruleus and caudal noradrenergic cell
groups in the lateral tegmentum influence efferent sym-
pathetic drive via brainstem and descending spinal pro-
jections (Svensson, 1987). Similarly, within the brainstem
efferent parasympathetic centers (nucleus ambiguus and
dorsal motor nucleus of the vagus, Edinger-Westphal nu-
cleus and salivatory nucleus) interconnect with nucleus of
the solitary tract in which afferent visceral information
relayed is represented (e.g., Davidson and Koss, 1975;
Willette et al., 1984; Blessing, 1997; Bennarroch, 1997;
Collins, 1999; Spyer, 1999). Animal and human experi-
ments have demonstrated descending influences from pre-
frontal and limbic cortices (cingulate, medial temporal,
and insula) and amygdala on autonomic control mediated
by hypothalamic and brainstem centers (Pool and Ranso-
hoff, 1949; Kaada, 1951; Gelsema et al., 1989; Neafsey,
1990; Fish et al., 1993; Oppenheimer et al., 1992; Mangina
and Buezeron-Mangina, 1996; Asahina et al., 2003).
Afferent information from the body is essential for co-
ordinated regulation of functions. Brainstem autonomic
centers require feedback from the periphery to maintain
homeostasis and monitor the general integrity of the body.
This afferent interoceptive information also provides cor-
poreal drive for motivational behaviors. It conveys basic
states such as hunger and thirst and sensations of comfort
and discomfort. Moreover, where autonomic arousal oc-
curs in anticipation of behavioral responses, feedback of
bodily changes reinforces stimulus processing to influence
behavioral judgments, implicitly or explicitly (Damasio et
al., 1991; Damasio, 1994; Bechara et al., 1997). Central
representation of these internal motivational signals is
hypothesized as the origin of emotional feeling states
(Lange, 1885; James, 1894; Damasio, 1994, 1999).
Interoceptive information from bodily organs is con-
veyed centrally by humoral, spinal, and vagal pathways.
Central chemoreceptors, including those in the hypothal-
amus, directly monitor the internal milieu. Studies of
afferent neural pathways have highlighted the role of thin
fibers conveying information from many sensory receptor
subtypes to the spinal cord and along the vagus. It is
argued on the basis of neuroanatomical studies (Craig,
2003, 2003) that the Lamina 1 spinothalamocortical path-
way is especially dedicated to conveying interoceptive in-
formation, converging within the diencephalon with affer-
ent information carried by cranial nerves, including the
vagus nerve. This stream of interoceptive information
then projects to viscerosensory cortex in mid-insula
(Cechetto and Saper, 1987) and onto right anterior insula
156
Fig. 1. Schematic representation of neuroanatomical pathways in
interoception and afferent visceral control. From Craig (2003). Affer-
ent thin fibers traveling in Lamina 1 of the spinal cord and the vagus
nerve convey interoceptive and motivationally salient information to
the brain. In primates, a pontine relay is bypassed via an evolution-
arily specialized thalamocortical pathway to interoceptive cortices
that terminates in right anterior insula (which projects further into
orbitofrontal cortex). There is an accessory branch to anterior cingu-
and orbitofrontal cortices. This neuroanatomical arrange-
ment has been proposed to be evolutionarily specialized in
primates, bypassing an obligatory pontine (parabrachial)
relay to enable cortical representation of motivationally
important visceral and somatosensory information (Fig.
1). This representation maps visceral sensations of auto-
nomic responses and is further enriched by other salient
sensations including metaboreception, pain, itch, temper-
ature, and sensual touch (Craig, 2003). Differences thus
exist between primate and nonprimate species in finer
organization of afferent streams for visceral and motiva-
tionally salient information such as pain. However, both
cranial nerves and spinal cord (via collaterals) synapse in
parabrachial nucleus in the dorsal pons and are relayed
topographically via ventroposterior medial parvicellular
(VPpc) thalamic nucleus to insula cortex, the putative site
of viscerosensory awareness (Saper, 2002).
THEORIES OF EMOTION
Changes in internal bodily arousal are considered ob-
jective indicators of emotional processing. Darwin (1898)
drew attention to evolutionary homology of bodily reac-
tions to specific emotional challenges across species, de-
tailing somatic and visceral components of affective ex-
pressions. At the same time, peripheral theories of
emotion developed that emphasized an obligatory associ-
ation of emotions with bodily responses. The James-Lange
theory, in particular, argued that changes in bodily re-
sponses are necessary for emotional experience; without
H.D. CRITCHLEY
late cortex. This specialized route is highlighted using a thicker line.
NTS, nucleus of solitary tract; A1, catecholaminergic cell group of
ventrolateral medulla; PB, parabrachial nucleus. Thalamic nuclei:
MD, mediodorsal; VMb, basal ventromedial; VMpo, parvocellular ven-
troposterormedial; ACC, anterior cingulate cortex; PAG, periaqueduc-
tal gray; RVLM, ventrolateral medulla; VMM, ventromedial medulla;
ANS, peripheral autonomic nervous system.
the bodily response processing of stimuli would be devoid
of emotional color. Thus, sadness arises from crying, fear
from running away. Lange emphasized internal arousal
responses, particularly those mediated autonomically as
the basis of emotional feeling (Lange, 1885; James, 1894).
The James-Lange theory of emotion generates a number
of predictions: First, emotive stimuli generate bodily re-
sponses automatically, even without awareness. Second,
different emotions are associated with different bodily
responses. Third, sensitivity to internal bodily changes is
important in determining the intensity of, and individual
differences in, emotional experience. It is the second point
that has generated perhaps the most controversy, since it
was central to Walter Cannon’s (1927) argument against a
peripheral theory of emotion: Bodily arousal responses
(particularly sympathetic) are too stereotyped and undif-
ferentiated to account for the wealth of different emotional
experiences; emotions arise from appraisal of emotional
stimuli, not from bodily feedback. Psychologists have ad-
hered to the “Cannon-ical” heuristic that autonomic
arousal is a unitary phenomenon of sympathetic activa-
tion (and parasympathetic withdrawal). Evidence mounts
for the presence of discrete autonomic response patterns
even within the sympathetic and parasympathetic axes
(Porges, 1995; Morrison, 2001) where sympathetic re-
sponses accompanying defensive behavior, thermal, met-
abolic, and sensory challenges can be distinguished and
differentially elicited (Saper, 2002). Emotion-specific
bodily reactions, such as facial reddening with rage, have
long been noted and periodically detailed (Darwin, 1898;
NEURAL MECHANISMS OF INTEGRATION
Ekman et al., 1983). Yet there is still controversy regard-
ing the usefulness to psychophysiology of emotion-specific
bodily arousal states. Human psychologists tend to em-
brace a two-stage empirical view of Schachter and Singer
(1962) that changes in peripheral arousal can engender
“emotionality” and determines its intensity, but the actual
quality of the emotion (e.g., anger or elation) is ultimately
determined by cognitive context. Moreover, the general
validity of the James-Lange theory needs to be qualified in
the face of subjective phenomenological accounts from pa-
tients with, for example, pathological laughter and (Par-
vizi et al., 2001) who provide instances where emotional
feelings uncouple from peripheral physiological expres-
sion. Similarly, the debate continues whether people with
acquired or constitutional insensitivity to bodily response
(e.g., patients with high spinal cord transection) show
emotional blunting (Cobos et al., 2002). In parallel, a
motor/mimicry argument (e.g., Dimberg et al., 2000) sug-
gests that the automatic induction by emotive stimuli of
somatomotor responses, such as emotional facial expres-
sions, generates feedback information (from facial mus-
cles) to enhance subjective emotion feelings and even to
permit interpretation of how other people feel emotionally.
Peripheral models of emotion, incorporating both auto-
nomic and somatomotor components, have gained renewed
exposure through the empirical findings and theoretical
propositions of Antonio Damasio and co-workers in Iowa.
This research group examined why people with ventral or
orbital prefrontal damage (like Phineas Gage [Harlow,
1891]) may exhibit profound impairments of social and emo-
tional behavior, while overtly retaining an ability to reason
rationally. It was observed that these patients made unwise
decisions (in a gambling task) and failed to curb risk-taking
behavior despite repeated experience of negative outcomes.
Parallel observations in frontal lobe patients suggested a
deficit in curbing ongoing behavior and activate intentional
markers (Shallice and Burgess, 1991). A concurrent finding
of the Iowa group was that orbitofrontal lesion patients had
blunted autonomic arousal responses when taking risks. The
somatic marker hypothesis was formulated, which empha-
sized bodily feedback as a guiding influence on motivational
decision-making (colloquially expressed as “gut-feelings”)
and underpinning emotional and social behavior (Damasio
et al., 1991; Bechara et al., 1996, 1997; Damasio, 1994).
Damasio (1999) extended these concepts to propose a theory
of consciousness in which dynamic representations of self
arise hierarchically from a core representation of bodily state
to be ordered within environmental and prospective con-
texts.
NEUROIMAGING INVESTIGATIONS
Theoretical associations between autonomic response
and social/emotional behavior has driven a program of
collaborative research between the Wellcome Department
of Imaging Neuroscience and the Autonomic Unit, Insti-
tute of Neurology, UCL, London, UK. This work combined
functional neuroimaging and psychophysiological subject
monitoring with studies on neurological patients to pro-
vide functional neuroanatomical insights into interactions
between cognition, emotion, and autonomic responses.
Much of the focus has been to disentangle and dissect the
components of Jamesian emotion, i.e., the central gener-
ation and feedback representation of autonomic bodily
responses.
157
Generation of autonomic arousal during
volitional behaviors
One way of mapping autonomic control centers using
functional imaging is to test where changes in signal cor-
relate with fluctuations in an autonomic measure. One
such imaging study examined brain correlates of changes
in sympathetic skin response (electrodermal arousal)
evoked during performance of a gambling task (Critchley
et al., 2000a). The use of a gambling task was predicated
on the work of Damasio and colleagues on “somatic mark-
ers.” The task elicited dynamic changes in skin conduc-
tance as a consequence of decision-making, winning and
losing (Damasio et al., 1991; Bechara et al., 1996, 1997).
Unknown to the subject in the scanner, the pattern of wins
and losses was predetermined, allowing for these motiva-
tional aspects of the task, and much of the associated
cognitive processing, to be accounted for in the analyses
(and partialed out). The electrodermal measure of sympa-
thetic arousal correlated with activity enhancement in
cortical regions, including bilateral ventromedial prefron-
tal cortices and right anterior insula (Fig. 2). Time-related
analyses of discrete sympathetic skin responses impli-
cated these brain regions in both generation and feedback
representation of transient autonomic arousal.
Other groups report similar findings, associating changes
in electrodermal arousal with activity enhancement in ven-
tral and medial prefrontal cortices and adjacent subgenual
anterior cingulate cortex (e.g., Williams et al., 2000; Patter-
son et al., 2002), consistent with the observed effects of
lesions (Tranel, 2000) and with neuroanatomical predictions
(Price, 2005). In addition, electrodermal-related enhance-
ment of activity within dorsal anterior cingulate cortex were
reported in an early PET study (Fredrikson et al., 1998) in a
region proposed by others (Paus et al., 1998) to represent a
nonspecific response to task demand. In our gambling task
study (Critchley et al., 2000), stimulus-driven activity was
masked from the analysis to deconfound pure “autonomic-
related” activity from direct task-induced effects. As a con-
sequence, we did not report an association between dorsal
supragenual anterior cingulate activity and electrodermal
arousal.
It should be noted that dorsal anterior cingulate cortex,
above the corpus callosum, has gained a special signifi-
cance among cognitive neuropsychologists, particularly
neuroimagers. Almost every task that contrasts an atten-
tional or cognitively demanding condition with a less de-
manding “control” condition elicits activity enhancement
within dorsal anterior cingulate cortex and, equally nota-
bly, deactivation of subgenual anterior cingulate regions
(Paus et al., 1998; Raichle et al., 2001; Gusnard and
Raichle, 2001). As a consequence, dorsal “cognitive” ante-
rior cingulate has been variously proposed to be a center of
(external) attentional processes, the seat of consciousness,
or a critical center of executive control (e.g., Posner and
Peterson 1990; Frith, 2001; Cohen and Huston, 1994).
More pragmatically, and perhaps more consistent with
lesion data, Paus et al. (1998) highlighted an association
between dorsal anterior cingulate activity (in 107 PET
studies) and task difficulty. A feature of cognitive effort is
that it evokes autonomic arousal: Mental stress is a potent
challenge for enhancing peripheral sympathetic activity
and as a “pressor task” is used in diagnostic evaluation of
autonomic integrity (along with cold pressor challenge,
isometric exercise, hyperventilation) (Mathias, 2000).
158
Fig. 2. Activity covarying with skin conductance during a gam-
bling task. From Critchley et al. (2000a). A: On repeated trials sub-
jects were selected between pairs of playing cards, resulting in imme-
diate feedback of consequent financial gain or loss and the change in
cumulative winnings. The visual display on typical trial before re-
sponse selection is illustrated. B: Unaware to the subjects, wins and
losses were predetermined by a random binomial walk function (il-
lustrated which enabled activity relating to positive and negative
feedback and cumulative gains to be partialed out of the analyses).
C: Electrodermal activity (EDA, sympathetic skin conductance) was
One way of deconfounding brain activity associated with
autonomic arousal from activity merely associated with
task performance is to test for activity shared across dif-
ferent autonomic pressor tasks. This experiment was con-
ducted using isometric exercise and mental arithmetic in
a PET study of men (mean age 35 years). Task selection
was motivated by the prediction that activity cognitive/
speech regions can be dissociated neuroanatomically from
motor regions and the remaining shared activity would be
observed in regions representing effort and autonomic
control (Critchley et al., 2000b). Activity in dorsal anterior
cingulate cortex and brainstem (dorsal pons) showed
effort-related activity independently of task modality.
Moreover, the magnitude of evoked responses was used as
a regressor of interest to increase sensitivity in identifying
autonomic control centers. Most strikingly, right dorsal
anterior cingulate activity correlated in both tasks with
H.D. CRITCHLEY
continuously recorded in each subject during the study. The continu-
ous trace (black line was used as a covariate of interest to determine
regional brain correlates of electrodermal activity). Subsequent anal-
yses also examined activity relating to the timing and amplitude of
individual peaks in skin conductance. D: Activity correlating signifi-
cantly across the group of subjects with changes in peripheral elec-
trodermal activity was observed in right anterior insula, extending
into orbitofrontal cortex, bilateral ventromedial prefrontal cortices,
and “attentional” areas of right parietal and extrastriate visual
cortices.
evoked changes in mean arterial blood pressure, a mea-
sure of sympathetic cardiovascular arousal. These find-
ings were replicated in a PET study of healthy older (mean
age 65 years) control subjects (Critchley et al., 2001a), and
also extended in an fMRI study: Subjects performed rep-
etitions of two different sequences of an isometric hand-
grip exercise and a cognitive task (n-back) at two levels of
difficulty. ECG was recorded simultaneously with the
fMRI data acquisition. An electrocardiographic (ECG)-
derived measure of sympathetic influence on heart rate
(power in the 0.04 – 0.15 Hz “low-frequency” range) corre-
lated significantly with dorsal anterior cingulate activity
(Critchley et al., 2003).
These studies argue for a direct involvement of dorsal
anterior cingulate cortex in the control of autonomic
arousal during volitional behaviors, including effortful
cognitive processing. Work in our own laboratory and else-
NEURAL MECHANISMS OF INTEGRATION
where further highlighted a role for anterior cingulate
cortex in the integration of cognitive processes (including
anticipation and appraisal) with autonomic arousal, in-
dexed by electrodermal, cardiovascular, or pupillary mea-
sures (Critchley et al., 2001b, 2005a,b) (Fig. 3). Further
evidence of a dynamic integration of autonomic and cog-
nitive processes comes from biofeedback studies (Critchley
et al., 2001c) in which the subject volitionally changes
their state of autonomic arousal, facilitated by a visual
display. Unfortunately, these neuroimaging studies do not
address causality, i.e., whether the activity in anterior
cingulate and related regions is involved, generates and/or
represents the peripheral autonomic response, or even,
indeed, whether observed activity contributes to cognitive
or autonomic functioning.
Patient studies
Autonomic control was studied in three patients who
had acquired lesions involving dorsal anterior cingulate
cortex. On tests of low-level autonomic control, the pa-
tients performed within the normal range. However, each
demonstrated blunted autonomic response to effortful cog-
nitive work (mental arithmetic stress task). The patients
also showed abnormalities in cardiovascular responses
generated during physical effort, although in one case this
was hyperreactive. These observations were consistent
with other evidence suggesting that normal “cognitively
driven” autonomic responsivity requires the integrity of
dorsal anterior cingulate cortex (Tranel, 2000). A parsi-
monious interpretation is that dorsal anterior cingulate
region contributes to efferent generation of peripheral au-
tonomic response (Critchley et al., 2004). Notably, it was
shown that the patients did not demonstrate significant
deficits on attentional executive or general neuropsycho-
logical tasks (including arithmetic). The cognitive conse-
quences of anterior cingulate lesions remain rather equiv-
ocal, with a number of case reports of intact general
neuropsychological and executive function in the presence
of large anterior dorsal cingulate lesions (Cohen et al.,
1999; Swick and Turken, 2002; Stemmer et al., 2004;
Fellows and Farah 2005).
Further insight into central autonomic control centers has
been achieved by examining consequences of peripheral dis-
ruption of autonomic response. Patients with pure auto-
nomic failure (PAF) are unable to generate autonomic
arousal as a consequence of circumscribed peripheral dener-
vation of the autonomic nervous system (Mathias, 2000).
PAF is not associated with central degeneration or cognitive
impairment, and therefore represents a powerful lesion def-
icit model to examine the consequences of a failure in inte-
grated feedback of autonomic arousal (the word integrated
acknowledges the fact that changes in bodily state, including
labile blood pressure, do occur in PAF patients, but these are
not the consequence of central autonomic drive). PAF pa-
tients participated in a PET study of effortful isometric ex-
ercise and mental arithmetic (as above, Critchley et al.,
2001a). Consistent with diagnosis, the PAF patients did not
increase heart rate or blood pressure with the effortful men-
tal arithmetic or exercise tasks. Compared to matched con-
trols, PAF patients nevertheless showed a general (across
pressor and control tasks) hyperactivity within dorsal pons.
This was interpreted as a correlate of perturbation within
homeostatic, first-order representations of autonomic con-
trol. Importantly, compared to controls, the PAF patients
demonstrated hyperactivity of dorsal anterior cingulate cor-
159
tex when they performed the effortful pressor tasks. Dorsal
anterior cingulate is active when healthy subjects generate
autonomic arousal with volitional behavior (Critchley et al.,
2000b). We therefore observed even greater activity within
the same region when no autonomic activity was generated
in PAF, suggesting that the system to generate autonomic
arousal works harder in the absence of negative feedback
from the periphery. Evidence from the cingulate lesion and
PAF patient studies converge with neuroimaging evidence to
suggest that dorsal anterior cingulate cortex is involved in
generating integrated states of autonomic arousal during
effortful volitional behavior.
It should be fully acknowledged that anterior cingulate
is not alone in generating behaviorally integrated bodily
responses. A wealth of animal data supports a fundamen-
tal role for the amygdala, particularly the central nucleus,
in the production of autonomic arousal in response to
emotive stimuli, particularly threat stimuli (LeDoux,
1992, 1996). This observation is corroborated by human
lesion data (Bechara et al., 1995; Tranel, 2000; Asahina et
al., 2003). Interestingly, enhanced dorsal anterior cingu-
late and amygdala activity often cohere in situations
where autonomic arousal is generated by emotional stim-
uli (e.g., Büchel et al., 1998; Critchley et al., 2005a).
This account of (dorsal) anterior cingulate as a genera-
tor of behaviorally integrated autonomic responses is a
simplification. Patterns of autonomic response within and
across sympathetic, parasympathetic and humoral axes
are differentially generated in different behavioral con-
texts (Ekman et al., 1983; Porges, 1985; Morrison, 2001;
Saper, 2002). Variation in the loci of anterior cingulate
activity across studies possibly point to organ or pattern
specificity across subregions (Critchley, 2004) and may be
observed in even different control phases of the same
process, e.g., micturition (Blok et al., 1997). Pairing of
dorsal anterior cingulate with transient sympathetic
arousal responses (Fig. 3) contrasts with a suggestion that
subgenual cingulate preferentially relates to parasympa-
thetic efferent responses, consistent with a putative tonic
antisympathetic role (Nagai et al., 2004). Moreover, en-
gagement of anterior cingulate (and amygdala) during
largely volitional behaviors may provide top-down inte-
grative control over first-order centers regulating efferent
autonomic response, including hypothalamus, periaque-
ductal gray, rostral medullary raphe, and ventrolateral
medulla (Saper, 2002).
Afferent representations of autonomic
response
As described above, afferent feedback from the body is
central to influential peripheral theories of emotion and
their extension into accounts of motivational behavior and
even self-awareness (Lange, 1885; James, 1894; Damasio,
1994, 1999). Identifying the brain substrates for represen-
tations of internal visceral signals is therefore an inter-
esting neuroscientific goal. A number of neuroimaging
studies have examined the effects of visceral stimulation
or challenge on central brain activity. One early example
is the study of Rosen et al. (1996) who demonstrated
subcortical activation associated with ECG indicators of
silent cardiac ischemia and recruitment of cortical brain
centers when the patient was aware of their angina. Other
groups have focused on central correlates of direct visceral
stimulation (e.g., Aziz et al., 2000; Athwal et al., 2001;
Hobday et al., 2001). These studies have been comple-
160
Fig. 3. Anterior cingulate activity associated with autonomic
arousal. Significant correlations between activity in supragenual an-
terior cingulate cortex and measures of autonomic arousal observed in
different neuroimaging experiments. A: Regional cerebral blood flow
(PET study) covarying with mean blood pressure evoked during ef-
fortful and effortless isometric exercise and mental arithmetic tasks
in a group of healthy volunteers; mean age 35 years (Critchley et al.,
2000b). Activity is illustrated on a sagittal section of a template brain
scan. B: Regional cerebral blood flow (PET study covarying with mean
blood pressure evoked during effortful and effortless isometric exer-
cise and mental arithmetic tasks in a group of healthy control sub-
jects, mean age 65 years) (Critchley et al., 2001a). Patients with pure
autonomic failure, who did not generate a hypertensive response,
showed greater enhancement of anterior cingulate than controls dur-
ing effortful tasks. C: BOLD activity (fMRI) covarying with power of
sympathetic influence on beat-to-beat heart rate evoked during effort-
ful and effortless isometric exercise and mental arithmetic tasks
(Critchley et al., 2003). Activity is illustrated on mean normalized,
smoothed EPI brain scan. This study with A and B above implicated
anterior cingulate in integrated generation of sympathetic cardiovas-
H.D. CRITCHLEY
cular responses during volitional cognitive and motor behavior.
D: BOLD activity (fMRI) covarying with anticipatory skin conduc-
tance (electrodermal activity in expectation of outcome, and also with
the risk associated with earlier choice. Subjects performed a gambling
task and waited for the outcome to determine if the choice won or lost
(Critchley et al., 2002). E: BOLD activity (fMRI) predicting the heart
rate response differentially evoked during processing of facial expres-
sions. Dorsal anterior cingulate and amygdala activity predicted the
magnitude of orienting heart rate change within and between differ-
ent emotion categories (Critchley et al., 2005a). F: BOLD activity
evoked during Stroop task performance that covaried with trial-by-
trial changes in pupil response (recovery from light reflex). Much of
the variability in pupil response was accounted for by errors. The
anterior extent of the highlighted clusters (centroid marked with
continuous line cross, yellow on color figure) localizes activity attrib-
utable to pupil response, but not to error processing. Overlapping and
more posterior (centroid marked with cross from dotted lines, green
on color figure) localizes activity attributable to both the pupil re-
sponse and enhanced during error trials (Critchley et al., 2005b).
NEURAL MECHANISMS OF INTEGRATION
Fig. 4. Insula activity dependent on evoked autonomic response:
Fear conditioning in patients with pure autonomic failure. Healthy
controls and patients with pure autonomic failure (PAF) were scanned
during a fear conditioning experiment (Critchley et al., 2002). A: Pre-
sentation of one angry face was paired with an aversive burst of white
noise on 50% of trials. Through conditioning, this face became a threat
(CS⫹), and evoked in the healthy controls an autonomic response,
even when unpaired. In contrast, another angry face, which was never
paired with an aversive noise (CS–) did not evoke an autonomic
response in healthy controls. Both PAF and control subjects showed
reaction time differences between CS⫹ and CS– stimuli, indexing
learning of the conditioned association. In controls, activity in right
insula was enhanced to unpaired CS⫹ compared to CS– stimuli. PAF
subject, who did not generate an autonomic response to the CS⫹
mented closely by investigations with pain (e.g., Rainville,
2002). Together, these studies tend to reach a consensus
in describing enhanced activity of bilateral anterior cin-
gulate and (anterior and mid) insula cortices, often with
thalamus, associated with both visceral and painful stim-
ulation. It is noteworthy that the challenges themselves
probably provoke efferent autonomic arousal.
The study of PAF patients described above makes use of
the rare occurrence of an autonomic lesion-deficit model to
address peripheral feedback-dependency of brain areas. It
highlighted the sensitivity of brainstem (dorsal pons) and
anterior cingulate cortex activity to an absence of afferent
information concerning centrally generated autonomic re-
sponse. Nevertheless, simplistically the brain regions that
map changes in bodily state might be expected to show
diminished activity when afferent information is absent.
Interestingly, the same study reported reduced right mid-
insula activity in PAF patients (Critchley et al., 2001a).
161
stimuli, did not show this difference in right insula activity. Our
interpretation is that right insula activity is sensitive to feedback of
autonomic arousal, absent in PAF patients. B: A second factor in the
experiment was modulation of the subjects’ level of awareness of
threat CS⫹ stimulus. Backward masking enables subliminal presen-
tation of stimuli. Flashing the CS⫹ for 35 msec, then replacing it with
a neutral face (mask) for 45 msec activates amygdala (and autonomic
responses to threat), without the subject having seen (consciously) the
CS⫹. However, if a neutral face is presented before the CS⫹, the
subject is aware of the threat stimulus. In this experiment it was
shown that activity within the same region of right insula (illustrated
on sections of template brain) was sensitive both to awareness of the
CS⫹ stimulus and to feedback of autonomic arousal.
Fear conditioning has proven a useful experimental il-
lustration of some of the predictions of the James-Lange
theory of emotion. In Pavlovian fear conditioning, a pre-
viously neutral stimulus gains emotional salience, i.e.,
becomes threatening, through associative paring with an
aversive unconditioned stimulus (US). The conditioned
threat stimulus predicts the bodily consequences of aver-
sive US and produces a similar behavioral/autonomic
arousal response, whether or not it is paired with the US.
In an fMRI study of PAF patients, we tested the effect of
the uncoupling of peripheral autonomic response from the
emotional brain response during fear conditioning (Critch-
ley et al., 2002). PAF and control subjects viewed one face
(CS⫹) which was paired with an aversive white noise on
half of the trials. As a consequence, it became a threat
stimulus, in contrast to a face (CS–) that had never been
associated with the noise. While both patients and con-
trols showed reaction-time evidence of fear conditioning,
162
only controls produced corresponding autonomic re-
sponses to threat stimuli. Comparison of conditioning-
related brain activity showed reduced activity of right
mid-insula and right amygdala in PAF patients to threat
stimuli that typically evoke autonomic responses in con-
trols. This indicates sensitivity of both mid-insula cortex
and amygdala, particularly on the right side, to afferent
visceral representations of autonomic arousal engendered
by emotion. Given the role of insula as viscerosensory
cortex (Saper, 2002; Craig, 2002, 2003), these observations
further suggest a role for right insula in emotional repre-
sentations, wherein “feelings” arising from representation
of bodily responses (Lange, 1885; James, 1894; Damasio,
1994) (Fig. 4a).
A further level was incorporated into this experiment:
the automatic processing of emotional stimuli without
conscious awareness. The James-Lange theory of emotion
predicts an automatic processing of emotive stimuli to
produce bodily responses which are subsequently inter-
preted as emotions. The automaticity of emotional pro-
cessing has been demonstrated in behavioral (Öhman and
Soares, 1993) and neuroimaging experiments (Morris et
al., 1998; Vuilleumier et al., 2002). Autonomic fear re-
sponses and neural activity in the amygdala showing fear-
processing can be elicited by stimuli rendered “unseen” by
subliminal presentation by backward-masking (Öhman
and Soares, 1993). Using this technique in our fear-
conditioning study of PAF patients, we observed activity
within right mid-insula that reflected both the mapping of
internal arousal and conscious awareness of the emotional
stimuli in contrast to amygdala. This observation extends
the proposal that right insula maps bodily arousal states
(Craig, 2002) to suggest that it does so contextually. A
brain region supporting conscious integration of internal
arousal with appraisal of external emotional stimuli actu-
ally fulfils predictions of the two-stage model of emotion
proposed by Schachter and Singer (1962) (Fig. 4b).
A problem with experimental studies of neural sub-
strates for interoceptive processing is that they are to
some extent confounded by the stimulus. While awareness
of an emotive stimulus may be modified by backward
masking, the stimulus is nevertheless processed and tem-
porally related to the generated internal response. Conse-
quently, activity changes related to afferent autonomic
response are difficult to dissociate using neuroimaging
from stimulus-induced changes. In an fMRI study, the
widespread observation that attention enhances activity
within relevant sensory cortices (e.g., Chawla et al., 1999)
provided an alternative means of probing interoceptive
representations, without confounding induced changes in
bodily response. The study represented collaboration with
A. Öhman and S. Wiens in Stockholm and adapted a
biofeedback task (Wiens et al., 2000). The task itself in-
volved playing back to the subject a series of tones, gen-
erated by the subject’s own heartbeat. A trial consisted of
a cue for the subject to attend introspectively to the timing
of his/her heartbeat. Ten tones were then played, after
which the subject had to judge if the tones were synchro-
nous with their heartbeat or played back with a half-
second delay (which occurred randomly on 50% of trials).
In our neuroimaging study (Critchley et al., 2004), we also
included an “exteroceptive” condition to control for non-
specific performance effects in the scanner, in which the
subjects were prompted at the start of each trial to attend
to the note quality and respond at the end if one of the
H.D. CRITCHLEY
sequences of notes subtly changed in pitch. Attending
interoceptively enhanced activity in a number of brain
regions, including anterior cingulate, somatomotor, and
anterior and mid-insula cortices. Individual differences in
interoceptive sensitivity, predicted by feedback theories of
emotion to influence subjective emotional experience,
were used to examine brain regions supporting conscious
awareness of internal state. Notably, only activity in the
right anterior insula cortex correlated with interoceptive
awareness (performance accuracy on the task). Further-
more, the activity with the right anterior insula (and in a
parallel structural study, its gray matter volume) pre-
dicted general visceral sensitivity and subjective day-to-
day emotional experience, at least of anxiety symptoms.
These observations highlight the contribution of right
anterior insula to emotional feeling states originating in
representations of visceral arousal (Fig. 5). Similar neu-
roimaging findings are reported in a heartbeat counting
task (Pollatos et al., 2004) and the magnitude of a right
frontal heartbeat-evoked electroencephalographic poten-
tial has been shown to be dependent on interoceptive
sensitivity (Pollatos and Schandry, 2004). Nevertheless,
the link with emotion may preferentially be expressed in
anxiety symptoms and may not be generalizable across all
emotions. Thus, Saper (2002), reappraising the findings of
Penfield and others, agues against insula cortex as a (gen-
eral) emotional integrator, attributing this function to me-
dial temporal lobe structures, such as amygdala. It is
noteworthy that in the context of threat processing both
amygdala and insula were observed to be sensitive to
interoceptive responses (Critchley et al., 2002b) and that
anterior insula cortex projects into the medial system of
ventromedial prefrontal cortex that also receives efferent
inputs from medial temporal lobe regions (Ongur et al.,
2003; Price, 2005).
Preliminary neuroimaging evidence from patients with
spinal cord damage and patients with implanted vagal
nerve stimulators for treatment of depression suggest par-
tial segregation in cortical representations of visceral in-
formation, with differential sensitivity in the right ante-
rior insula and orbitofrontal cortex (independent of insula)
to afferent inputs conveyed by spinal and vagus nerve
pathways. Current and future work will validate these
early observations and determine the differential impact
on emotional behavior of spinal and vagal sensory
streams.
CONTROL MODELS, ANTERIOR
CINGULATE CORTEX AND
ANTERIOR INSULA
The argument presented suggests that integrated gen-
eration of peripheral autonomic responses may originate
in anterior cingulate cortex during a variety of volitional,
cognitive, and noncognitive behaviors. Similarly, evidence
from a variety of sources converges to suggest a represen-
tation of autonomic and visceral responses within anterior
insula cortex, where, particularly on the right side, this
information is accessible to conscious awareness, influenc-
ing emotional feelings. The coactivation of dorsal “sympa-
thetic” cingulate with anterior and mid-insula cortices
(bilaterally) is characteristic both of states of visceral
arousal induced by pain, emotive stimuli (such as threat),
and of states of behavioral and attentional engagement.
Correspondingly, enhanced activity of dorsal anterior cin-
NEURAL MECHANISMS OF INTEGRATION
Fig. 5. Neural activity during interoceptive awareness. Healthy
subjects were scanned while they performed a heartbeat detection
task (adapted from that used in Wiens et al., 2001) in which they
judged the timing of their own heartbeats to auditory tones (triggered
by their heartbeats). A: Subjects were cued to attend to their heart,
then a series of 10 tones would be played that were either synchro-
nous with their finger pulse or delayed by 500 msec. They made the
judgment at the end of each trial of 10 beats. In a control condition
(“note”), subjects attended only to quality of the notes, identifying the
presence of a subtle change in note pitch in the sequence. B: Activity
gulate cortex predicts the occurrence of sympathetic
arousal responses, during both low-level visceral or motor
challenges (Hobday et al., 1998; Williamson et al., 2002)
and in many cognitive scenarios. The latter include mon-
itoring tasks such as error processing (Hajcak et al., 2005;
Critchley et al., 2005b) or processing outcomes (Corricelli
et al., 2005), but also predictive, prospective, and simula-
tory situations, for example, anticipating the outcome of
decisions (Critchley et al., 2002), during imagery of phys-
ical effort (old exercise hypnosis), and in empathetic re-
sponses (to another’s expected pain) (Singer et al., 2004)
(Fig. 6a).
Alternative accounts of activity in anterior cingulate
emphasize its role in cognitive control, i.e., processes
where behavior is interrupted or adjusted to orientate to
salient occurrences and optimize performance. In this
role, regions of anterior cingulate cortex are implicated in
163
when attending to heartbeat timing was enhanced (relative to the
exteroceptive “note” task) in bilateral insula, bilateral somatomotor,
and anterior cingulate cortices. C: Only activity in right anterior
insula correlated with conscious awareness of the timing of heart-
beats, i.e., interoceptive sensitivity (performance accuracy on the
task, relative to the control condition). Across subjects there were
significant correlations between activity of right anterior cortex, in-
teroceptive sensitivity, and day-to-day experience of anxiety symp-
toms, consistent with a proposal that right anterior insula is a sub-
strate for feeling states generated from afferent visceral responses.
monitoring actions and their consequences, notably, the
occurrence of performance errors (Carter et al., 1999; Ull-
sperger et al., 2004). Similar to ideas regarding cognitive
control are models of motor control and computational
learning. In these processes, internal models within the
brain are proposed to predict of consequences of actions
(Wolpert et al., 2003). In the motor system, forward mod-
els describe a direct influence of a motor command (effer-
ence copy) on central sensory representations; this copy of
efferent signal enables the sensory system to anticipate
the pattern of musculoskeletal feedback that should result
from the intended action. Mismatch between the simu-
lated (predicted) and actual sensory feedback (prediction
error) drives a dynamic adjustment of subsequent motor
commands.
More generally the notion of a prediction error represents
a core concept within computational models of learning.
164
Fig. 6. Activity in regions including anterior insula and anterior
cingulate in empathetic anticipation of pain of another and in aversive
prediction error. From Singer et al. (2004) and Seymour et al. (2004).
A: Subjects watched a video screen which displayed cues that indi-
cated either that they would receive a painful shock, or that another
person (their partner) would experience a shock of the same pain
intensity. Activity common to both conditions (i.e., anticipation and
Many neuroscience studies have empirically demonstrated
the instantiation of prediction error processes [for example
description of functional neuroanatomical correlates of the
Rescorla-Wagner proposal in which operant reinforcement
learning represents an experience-dependent shift from low
to high predictive power (Rescorla and Wagner, 1972;
O’Doherty et al., 2003)]. Neuromodulatory systems are im-
plicated in mediating prediction error signals, most notably
ascending mesolimbic dopaminergic projections are impli-
cated in reward (appetitive) learning (Schultz et al., 2000;
O’Doherty et al., 2003). In aversive learning, where stimuli
represent threats to body state, activity in right anterior
insula activity tracks the phasic occurrence of prediction
error (Seymour et al., 2004) (Fig. 6b). It is noteworthy that
the same insula region, perhaps with adjacent orbitofrontal
cortex is implicated in subjective feelings arising from inter-
nal bodily responses (Craig, 2003 Critchley, 2004) and pro-
spective, empathetic, external, counterfactual simulations of
feelings.
Simulatory “virtual” models of self represent mind-stuff
and are unconstrained by physical reality. Such a system
plausibly arises from action control systems including for-
ward and inverse models (an inverse model enables the
intended behavioral command to be inferred from conse-
quences at outcome) (Wolpert et al., 2003). Moreover, it is
proposed that the same processes characterize social cog-
nition and control communicative social interactions (Wol-
pert et al., 2003; Gallese et al., 2003). The Gallese “mirror
H.D. CRITCHLEY
experience of pain and empathetic emulation of pain experience) was
observed in insula and anterior cingulate cortices (Singer et al., 2004).
B: Activity tracking learning associated with the anticipation of an
aversive event. Insula and cingulate activity is correlated with the
temporal difference value generated by computational models of pre-
dicting the occurrence of an aversive event (Seymour et al., 2004).
neuron” model of social cognition (Gallese et al., 2003) in
fact proposes visceromotor activation in empathetic un-
derstanding of social emotions, drawing on impressive
neuroimaging and human single unit investigations of
disgust perception and experience (Phillips et al., 1997;
Phillips et al., 2000; Krolak-Salmon et al., 2003).
While theoretically, there may be no obvious obligation
for forward and inverse control processes to be physically
embodied in autonomic responses, the observed expres-
sion of cognitive “mind” processes in peripheral reactions
is fundamental to psychophysiological science. As with
emotional challenges, it is likely that the intensity of
bodily response represents an important metric, reflecting
the salience of cognition, degree of empathetic or environ-
mental engagement, and so on. Moreover, the neural sub-
strates (including dorsal anterior cingulate, amygdala,
and right anterior insula) that generate and map dynamic
changes in bodily response (in coherence with concurrent
or anticipated behavioral responses to environmental
challenges) are functionally interconnected with sub-
genual cingulate and orbitomedial regions that have been
implicated in default resting states of brain activity (Gus-
nard and Raichle, 2001). The self-referential default state,
related psychophysiologically to tonic reduction in sympa-
thetic activity (Nagai et al., 2004), may support the bench-
mark feeling state. Both systems are yoked to ascending
modulation from brainstem. Damasio (1999) proposed a
hierarchical structure in consciousness in which afferent
NEURAL MECHANISMS OF INTEGRATION
bodily information represents the core substrate. Internal
cognitions and prospective judgments may be closely cou-
pled with changes in bodily arousal that reinforce,
through feeling states, a sense of presence and “a feeling of
what happens” (Damasio, 1999). The emotional embodi-
ment of “mind-stuff” represents a plausible account of the
soul in which central efference and inverse models cohere
with feeling states arising from peripheral autonomic ex-
pression. Visceral correlates of “forward models” underpin
concepts such as somatic markers and bridge the dualistic
divide (Damasio, 1994).
ACKNOWLEDGMENTS
I thank Professors R.J. Dolan (Wellcome Department of
Imaging Neuroscience, Institute of Neurology, University
College London) and C.J. Mathias (Autonomic Unit, Na-
tional Hospital for Neurology and Neurosurgery, Univer-
sity College London Hospitals) for support.
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