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Brain-gut connections in functional GI disorders: Anatomic and physiologic relationships

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Understanding the neural regulation of gut function and sensation makes it easier to understand the interrelatedness of emotionality, symptom-attentive behavior or hypervigilance, gut function and pain. The gut and the brain are highly integrated and communicate in a bidirectional fashion largely through the ANS and HPA axis. Within the CNS, the locus of gut control is chiefly within the limbic system, a region of the mammalian brain responsible for both the internal and external homeostasis of the organism. The limbic system also plays a central role in emotionality, which is a nonverbal system that facilitates survival and threat avoidance, social interaction and learning. The generation of emotion and associated physiologic changes are the work of the limbic system and, from a neuroanatomic perspective, the 'mind-body interaction' may largely arise in this region. Finally, the limbic system is also involved in the 'top down' modulation of visceral pain transmission as well as visceral perception. A better understanding of the interactions of the CNS, ENS and enteric immune system will significantly improve our understanding of 'functional' disorders and allow for a more pathophysiologic definition of categories of patients currently lumped under the broad umbrella of FGID.
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REVIEW ARTICLE
Brain–gut connections in functional GI disorders:
anatomic and physiologic relationships
M. P. JONES,* J. B. DILLEY,D. DROSSMANà& M. D. CROWELL§
*Division of Gastroenterology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
Division of Psychology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
àUNC Center for Functional GI & Motility Disorders, Division of Gastroenterology and Hepatology, University of North Carolina,
Chapel Hill, NC, USA
§Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Scottsdale, AZ, USA
Abstract Understanding the neural regulation of
gut function and sensation makes it easier to under-
stand the interrelatedness of emotionality, symptom-
attentive behavior or hypervigilance, gut function and
pain. The gut and the brain are highly integrated and
communicate in a bidirectional fashion largely through
the ANS and HPA axis. Within the CNS, the locus of gut
control is chiefly within the limbic system, a region of
the mammalian brain responsible for both the internal
and external homeostasis of the organism. The limbic
system also plays a central role in emotionality, which
is a nonverbal system that facilitates survival and
threat avoidance, social interaction and learning. The
generation of emotion and associated physiologic
changes are the work of the limbic system and, from a
neuroanatomic perspective, the Ômind-body interac-
tionÕmay largely arise in this region. Finally, the limbic
system is also involved in the Ôtop downÕmodulation of
visceral pain transmission as well as visceral percep-
tion. A better understanding of the interactions of the
CNS, ENS and enteric immune system will sig-
nificantly improve our understanding of ÔfunctionalÕ
disorders and allow for a more pathophysiologic
definition of categories of patients currently lumped
under the broad umbrella of FGID.
Keywords brain-gut axis, functional gastrointestinal
disorders, irritable bowel syndrome, neuroimaging,
psychosocial stressors.
INTRODUCTION
Functional gastrointestinal disorder (FGID) comprises a
major portion of clinical practice for gastroenterologists
and primary care physicians. Psychosocial disturbances
are present in many patients with FGID and are
increasingly prevalent in referral populations. Psycho-
social factors can influence digestive function, symp-
tom perception, illness behaviour and outcome.
Conversely, visceral pain can affect central pain percep-
tion, mood and behaviour.
1,2
The combined functioning
of gastrointestinal intestinal motor, sensory and CNS
activity is termed the brain–gut axis and FGID can be
conceptualized as resulting at least in part from dysreg-
ulation of the brain–gut axis.
2
This review will explore
the relationship between the CNS and the gut to provide
the reader with an understanding of gut–brain neuro-
physiology, which forms the basis for understanding the
relevance of the biopsychosocial model of illness as it
relates to irritable bowel syndrome (IBS) and other FGID.
BRAIN–GUT AXIS: NEUROANATOMY
Communication between the central nervous system
(CNS) and enteric nervous system (ENS) involves
neural pathways as well as immune and endocrine
mechanisms.
3
Within the CNS, the hypothalamus, an
older midbrain structure, plays a central role in main-
taining physiological homeostasis of the organism and
Address for correspondence
Michael P. Jones MD,
251 East Huron St, Galter Pavilion 4-104,
Chicago, IL 60611-2908, USA
Tel.: 312-926-7719; fax: 312-926-6540;
e-mail: mpjones@nmh.org
Received: 23 March 2005
Accepted for publication: 9 September 2005
Neurogastroenterol Motil (2005) doi: 10.1111/j.1365-2982.2005.00730.x
2005 The Authors
Journal compilation 2005 Blackwell Publishing Ltd 1
regulating autonomic and neuroendocrine function.
4
The hypothalamus forms an integral part of the limbic
system, a region of the mammalian brain regarded as
the ÔvisceralÕor ÔemotionalÕbrain. In addition to its role
in regulating homeostasis of the organism, the limbic
system functions to mediate emotional responses.
5
An
overview of the relationship between the Ôemotional
nervous systemÕ, higher level cortical inputs and the
enteric nervous system is shown in Fig. 1.
Anatomically the limbic system consists of the
hypothalamus, amygdala, medial thalamus and anter-
ior cingulate cortex (ACC) (Fig. 2). The primary func-
tions and connections of these structures are outlined
in Table 1 and only major functions in humans will be
discussed here.
The amygdala plays a central role in processing
social signals of emotion (such as posture and facial
expression), in emotional conditioning (the association
of an emotions with a given stimulus) and in the
consolidation of emotional memories.
6
In humans,
damage to the amygdala results in loss of conditioned
fear responses.
7,8
A direct thalamo-amygdala pathway
processes crude sensory aspects of incoming stimuli
and allows an early conditioned fear response if any of
these crude sensory elements are signals of threat. A
thalamo-cortico-amygdala pathway that allows more
complex analysis of the incoming stimulus and deliv-
ers a slower, conditioned emotional response.
9–11
The ACC integrates visceral, attentional and emo-
tional information and regulates affect.
12,13
The ACC
also plays a role in the conscious representation of
emotional experience and autonomic arousal.
14–16
The
ACC monitors conflict between the functional state of
the organism and any new information that has poten-
tial affective or motivational consequences.
6
When such
conflicts are detected, the ACC projects information
about the conflict to areas of the prefrontal cortex (PFC)
where adjudications among response options can occur.
The ACC consists of a dorsal ÔcognitiveÕsubdivision and
a ventral ÔaffectiveÕsubdivision (also called the perige-
nual ACC or pACC
12
. The pACC is routinely activated
in functional imaging studies involving all types of
emotional stimuli.
6
Current thinking suggests that it
monitors conflict between the functional state of the
organism and any new information that has potential
affective or motivational consequences.
12
The PFC is a neocortical region involved in affective
processing.
17
Its central role is to maintain the repre-
sentation of goals and the means to achieve them.
18
Particularly in situations that are ambiguous, the PFC
signals other areas of the brain to facilitate the
expression of task-appropriate responses in the face of
Life events
Stress
exteroceptive
Stress
interoceptive
Autonomic
response
Sensory
modulation
GI pathophysiology
symptoms
Neuroendocrine
response
Cortisol
Epinephrine
Cytokines
+
EMS
Vigilance
attention
Emotional feelings
arousal
Figure 1 Inputs and outputs of the emotional motor system (EMS). Output pathways of the EMS are activated by psychosocial
(exteroceptive) and physical (interoceptive) stressors. Major outputs to the periphery are autonomic, pain modulatory and neuro-
endocrine responses. An important output to the forebrain occurs in terms of attentional and emotional modulation. Feedback from
the gut to the EMS occurs in form of neuroendocrine (epinephrine, cortisol) as well as visceral afferent mechanisms. From Mayer
et al.
96
2
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M. P. Jones et al. Neurogastroenterology and Motility
competition with potentially stronger alternatives.
Patients with lesions to certain zones of the PFC,
particularly the ventromedial PFC, have been shown to
exhibit profoundly impaired decision making.
19,20
Sev-
eral studies have demonstrated abnormalities of left
PFC function in persons with depression and depressed
individuals often experience difficulties responding
effectively in situations that are heavily laden with
competitive alternative responses.
17,21,22
PATHOPHYSIOLOGY OF
GASTROINTESTINAL PAIN
The discussion above highlights the central role of the
limbic system in monitoring and responding to the
internal and external environment in a manner that
preserves the organism. In this context, emotions can
be regarded as nonverbal language allowing us to
attend, prioritize and respond to stimuli in our envi-
ronment. Pain is also a potent nonverbal signal. The
central nervous system prioritizes pain transmission
amplifying or diminishing pain signals depending upon
relevant environmental and internal perceptions.
Ascending pain transmission
Pain perception is an active and plastic process that
incorporates sensory, emotional and cognitive experi-
ences. The principal afferent pathways responsible for
ascending pain transmission are shown in Fig. 3.
Visceral pain is transmitted to the spinal cord and on
to the brain by three primary pathways: the spinotha-
lamic, spinoreticular and spinomesencephalic tracts.
23
These divergent pathways process and modulate reflex-
ive, affective and motivational responses to pain.
Elegant studies using positron emission tomography
(PET) and hypnotic suggestion have helped to discrim-
inate the functioning of these pathways.
24
Hypnotic
suggestion does not influence activity of the somato-
sensory cortex (SSC). Subjects receiving suggestions
that a stimulus will be painful have greater activation
of the mid-cingulate portion of the ACC than subjects
receiving suggestions that the stimulus will be either
pleasant or not painful. The mid-cingulate portion of
the ACC is an area involved in negative cognitive
perceptions such as fear and unpleasantness.
Descending modulation of pain
According to the gate control theory, the brain
modulates afferent pain signals by dispersing inhib-
itory signals to the spinal cord (Fig. 3).
25
Specifically,
the pACC, because of its high opioid content and
possibly also due to its having been activated by
afferent pain signals, sends inhibitory efferent signals
directly and indirectly, via the amygdala, to ponto-
medullary networks.
26
These networks include the
periaqueductal grey (PAG), rostral ventral medulla
and the raphe nuclei. The inhibitory efferent signals
then travel by way of the opioidergic, serotoninergic
and noradrenergic systems to the dorsal horn of the
spinal cord where they presynaptically inhibit the
afferent pain signals. As the ACC and amygdala are
implicated in the processing of visceral, attentional
and emotional information, the dispersal of inhibi-
tory efferent messages by these structures may be
mediated by cognitive, emotional and behavioural
factors.
Parietal
association
cortex
Parietal
association
cortex
Prefrontal
cortex
Emotional coloring
Emotional experiences
Emotional expression
H
yp
othalamus
Cingulate cortex
Mammillary body
Prefrontal
cortex
Anterior n
Anterior n
Mammillary body
Amygdala
Amygdala
Hippocampus
Hippocampus
Hypothalamus
Cingulate cortex
Fornix
Figure 2 Schematic representation of limbic structures. The
top panel provides an anatomic representation while the bot-
tom panel provides dominant functional interrelationships.
2005 The Authors
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Brain–gut connections in functional GI disorders
AUTONOMIC FUNCTION IN FGID
The earliest suggestion that alterations in CNS func-
tion are associated with FGID came from studies
demonstrating alterations in autonomic nervous sys-
tem (ANS) activity in subsets of patients. Unfortu-
nately, data from these studies have been inconsistent.
Various studies have suggested that sympathetic activ-
ity may be increased or reduced
27–30
while others have
suggested diminished or enhanced parasympathetic
tone.
31,32
Some authors have suggested that patients
with IBS having constipation or diarrhoea-predominant
symptoms have specific patterns of autonomic altera-
tions.
33,34
Unfortunately, no consistent pattern has
emerged. Nevertheless, it is commonly observed that a
subset of patients with IBS and other FGID have altered
autonomic activity associated with flares of their
symptoms.
33,35,36
Central and psychological factors can also be
associated with altered ANS activity. Several studies
have reported an association between anxiety and
depression with altered ANS function in IBS.
32,37
Table 1 The primary connections and functions of human limbic structures
Limbic structure Primary connection(s) Functions Stimulation causes Lesion results
Hypothalamus Autonomic nervous
system (via hypothalamic
–pituitary–endocrine axis);
sensory structures in the
brain
Govern CNS autonomic
function; maintain
homeostasis; generate
coordinated and
sophisticated emotional
responses
Emotional responses,
incl. anger, fear,
curiosity, lethargy
Aberrant autonomic
activity; emotional
dysregulation
Amygdala Thalamus; cortex Process emotions; form
emotional memories
Changes in emotion
and autonomic
function
Impairment in memory
for emotionally
charged events
Anterior cingulate
cortex (ACC)
PFC Integrate visceral,
attentional, and emotional
information; regulate affect
Information processing;
dispersal of pain-
inhibition signals
Profoundly impaired
decision-making
Prefrontal cortex
(PFC)
ACC Represent goals; maintain
vigilance to goal-directed
behaviour; process effect
Increased vigilance;
affective processing
Tangential
(i.e. non-goal-directed)
behaviour
IBS - ascending visceral pain pathway
Primary
somatosensory cortex
Spinoreticular
Serotonergic
Noradrenergic
Opioidergic
Amygdala
Rostral ventral
medulla
Spinomesencephalic
Dorsal reticular
nucleus
Colon Colon
Descending visceral pain pathway
Figure 3 Neuroanatomic pathways mediating visceral pain sensation. The left panel illustrates ascending visceral pain pathways.
The spinothalamic tracts provide information that is largely directed to the primary somatosensory cortex and functions to localize
and discriminate visceral stimuli. Spinoreticular pathways do not function primarily to localize stimuli but are important in the
reflexive, affective and motivational aspects of sensation. Pathways involved in the descending inhibition of visceral pain trans-
mission are shown in the right panel. The anterior cingulate cortex (ACC) exerts influences on mid- and hind-brain structures that
project fibres to the dorsal horn of the spinal cord. These opiodergic, serotonergic and noradrenergic pathways regulate the degree to
which ascending afferent stimuli are allowed to project to the CNS. From Drossman.
23
4
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M. P. Jones et al. Neurogastroenterology and Motility
While other studies have not found such an associ-
ation, most of these were either methodologically
limited in the detection of psychiatric disorders or
too poorly powered to allow one to confidently reject
an association between psychiatric disorders and
autonomic activity.
27,33,38
It is also possible that
alterations in ANS function are more strongly linked
to acute stress or pain than with psychiatric ill-
ness.
28,39,40
THE HYPOTHALAMIC–PITUITARY–
ADRENAL AXIS IN FGID
Alterations in the hypothalamic–pituitary–adrenal
(HPA) axis are reported in FGID although the area is
understudied and observations conflicted. Corticotro-
phin releasing hormone (CRH) release is reported to be
increased in IBS and CRH affects motility and sensi-
tivity in the gut. Further investigation is required to
ascertain whether these changes in HPA axis represent
a primary event or occur in response to other stressors
including digestive symptoms.
41,42
A number of inves-
tigators have also reported increased levels of cortisol
either at baseline or in response to stress.
34,43,44
but
other investigators have not replicated these observa-
tions.
38,45
The HPA axis also affects immune responses and at
least one study has demonstrated altered cellular
immune function in response to a meal in women
with IBS.
45
In patients with postinfectious IBS (PI-IBS),
greater psychological distress also characterizes the
group of patients with ongoing pain and greater
concentration of mucosal inflammatory cells 3 months
after the initial enteritis
46
and this may be mediated
through altered HPA axis function.
NEUROIMMUNE INTERACTIONS AND
PLASTICITY OF THE ENS
The rich neural network of the digestive tract is a
unique extension of the ANS capable of generating
intrinsic activity independent of extrinsic neural
input.
47
The digestive tract also contains the largest
component of the immune system in the human body.
Complex interrelationships exist between gut associ-
ated immune tissue, CNS and ENS (Fig. 4).
48
Addi-
tionally, motility disturbances can occur at sites
remote from the inflammatory stimulus suggesting
that a local insult may actually generate a more diffuse
Ôfield effectÕ.
47
Low-grade inflammation or immune activation has
been postulated as a basis for alterations in intestinal
motility or sensation in at least a subset of patients
with IBS.
48,49
A small group of patients with IBS report
symptom onset at the time of gastroenteritis (PI-IBS).
Prospective studies report persistently abnormal bowel
Psychosocial
stressor
PVN CRF
AVP
Pituitary
ACTH
Cortisol
IL-1
LC-NE
CRF,NE,EPI
Immune system
response
MC
Humoral
Th 2
Th 1
Cellular
Ag
Pathogen
Allergen
Physical
Stressor
Epithelium
IL-6
LIF
TNF-α
EMS
Mucosal
immune system
Gut lumen
Figure 4 Putative bidirectional brain–gut interactions in-
volved in modulating responsiveness of organism to CNS- and
gut-directed stressors. Psychosocial stressors activate stress
circuits within the EMS, and the resulting peripheral output
in form of neuroendocrine (cortisol), corticotropin-releasing
factor (CRF), and autonomic [norepinephrine (NE), epineph-
rine] responses shifts the mucosal immune system towards a
Th2 response (increased mast cells, inducible nitric oxide
synthase expression). Autonomic responses can also directly
or indirectly modulate gut permeability, thereby changing the
access of luminal factors (antigens, bacteria) to the gut im-
mune system. Luminal factors (physical stressors) modulate
gut immune function, and immune products from the gut
such as cytokines and chemokines can modulate the respon-
siveness of the EMS. Temporal properties of the stressor and
age to the animal at stress exposure are important determi-
nants of type of neuroimmune interaction. ACTH, adreno-
corticotropin hormone; AVP, arginine vasopressin peptide;
EPI, epinephrine; IL, interleukin; MC, mast cell; LIF, leuke-
mia inhibitory factor; PVN, paraventricular nucleus; Th, T
helper; TNF, tumour necrosis factor. From Mayer and Col-
lins.
48
2005 The Authors
Journal compilation 2005 Blackwell Publishing Ltd 5
Brain–gut connections in functional GI disorders
patterns and symptoms in 9–31% of patients stud-
ied.
46,50–53
A case control study using Rome II criteria
for IBS reported a incidence of 16.7% 6 months after
infection compared with an IBS incidence of 1.9% in
healthy controls.
54
The risk of developing PI-IBS is
increased 11-fold by an initial diarrhoeal illness lasting
longer than 3 weeks or more toxigenic organisms.
52
The likelihood of developing PI-IBS is doubled by the
presence of adverse life events at the time of initial
illness or hypochondriasis.
46,50
Patients with PI-IBS have also been shown to have a
number of persistent neuroimmune abnormalities.
These include increased numbers of intraepithelial T
lymphocytes in rectal biopsy specimens, persistent
increases in interleukin 1bmRNA expression and
increased numbers of mast cells in proximity to
mucosal innervation.
55–59
Increased gut permeability
has also been reported in a subset of patients with PI-
IBS.
56
FUNCTIONAL NEUROIMAGING IN FGID
While heightened sensitivity to visceral stimuli is
postulated as an important pathophysiological mech-
anism in FGID, mechanisms of visceral hypersensi-
tivity are undetermined. Central modulation of
afferent visceral neural pathways attracts increasing
evidence and support.
60
Functional neuroimaging is
increasingly being used to evaluate central networks
involved in processing visceral stimuli in patients
with FGID. These studies are cumbersome, techni-
cally challenging and interpretation can be highly
operator dependent. While these studies call attention
to important relationships between CNS and ENS, the
findings have not always been consistent. Addition-
ally, it is unclear to what extent functional neuro-
imaging will advance our understanding of FGID. An
understanding of functional neuroimaging studies in
patients with FGID is best approached by also under-
standing functional neuroimaging in healthy subjects
in response to pain as well as patients with affective
and mood disorders.
Visceral pain and neuroimaging in healthy
subjects
In healthy subjects, a common network of cortical and
subcortical regions referred to as the Ôpain matrixÕis
consistently activated in response to both visceral and
somatic pain. The areas most commonly activated in
response to visceral or somatic pain include the mid/
anterior insula, subregions of the ACC, PFC, thalamus
and pontine regions such as the dorsal pons and PAG.
60
Several studies have examined brain activations in
response to visceral and somatic stimulation (Table 2).
Studies examining both somatic and visceral disten-
sion have shown fairly consistent patterns of activa-
tion although there are differences in representation in
the somatosensory cortices.
61–64
In comparing oeso-
phageal balloon distension with midline cutaneous
heat, Strigo et al.
61
found that heat applied to the
midline chest evoked higher activation bilaterally in
the anterior insular cortex. Further, cutaneous but not
oesophageal pain activated ventrolateral PFC, despite
higher affective scores for visceral pain.
61
In addition,
visceral pain activated a more anterior locus within
ACC. The differences in activation patterns may
account for the ability to distinguish visceral and
cutaneous pain as well as the differential emotional,
autonomic and motor responses associated with these
different sensations. Dunckley et al.
62
also assessed
healthy subject responses to rectal and cutaneous
stimuli. This study included visceral and cutaneous
stimuli matched for unpleasantness. In general, their
findings support the observations of Strigo and col-
leagues although they differ with respect to ACC
response to visceral stimulation.
Limited data exist with respect to regional brain
activity in response to gastric distension, but available
studies demonstrate activation of the Ôpain matrixÕ.
65–67
There is insufficient evidence to clarify differences
resulting from distension of the proximal or distal
stomach.
Two studies have evaluated non-painful rectal (vis-
ceral) and anal (somatic) distension in healthy sub-
jects.
63,64
Hobday et al.
63
found that both rectal and
anal distension resulted in similar regions of brain
activation although anal distension resulted in activa-
tion of the SSC at a greater level and there was no
increase in ACC activity. Lotze et al.
64
also noted that
rectal and anal distension resulted in similar regions of
brain activation but that anal stimulation resulted in
additional activation of primary sensory and motor
cortex, supplementary motor area and left cerebellum.
Neuroimaging abnormalities in affective and
mood disorders
Studies of functional neuroimaging in patients with
affective and mood disorders are helpful in furthering
our understanding of the brain–gut connection. Many
of the alterations reported in patients with affective
and mood disorders are similar to those seen in
patients with FGID. This highlights the close interre-
latedness of emotionality and psychosocial distress
with gut perception and function. Phan et al.
68
recently
6
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M. P. Jones et al. Neurogastroenterology and Motility
reviewed functional neuroimaging studies of human
emotions in healthy subjects. These studies vary in
task dimensions and type(s) of emotion studied, and are
limited by statistical power and sensitivity. Of 11
studies using fear-related stimuli and 15 studies using
aversive stimuli, the amygdala was activated in over
60% of studies. Amygdala activation can occur even
when the fearful expression is not consciously per-
ceived or even when subjects report a threatening
stimulus as non-fearful.
69,70
No specific brain region has been consistently
activated across the spectrum of human emotion
although the median PFC is activated in approximately
half of all studies using emotional stimuli.
68
Several
studies suggest that median PFC activity is particularly
increased when subjects are asked to make introspec-
tive judgments regarding experiences or feelings.
71–73
The ACC appears to be activated by tasks involving
recalled emotional experiences and with the emotion
of sadness. Of the studies reviewed by Phan et al.,
68
50% of studies requiring subjects to recall previous
emotional experiences reported ACC activation com-
pared with 31% and 0% of visual and auditory-based
emotion studies. Alterations in this region have been
found in studies of patients with depression during the
resting state,
74,75
and these alterations have been
reported to normalize with effective treatment of the
depression.
76
Several studies have assessed regional brain activa-
tion in response to placebo. Lieberman et al.
77
reported
that patients experiencing an effective placebo re-
sponse demonstrated increased activity in the region
of the right ventrolateral PFC and decreased activity in
the dorsal ACC. Previous studies have identified the
right ventrolateral PFC as an area associated with
inhibition in general as well as overcoming negative
affect.
78–80
In a study of depressed patients using PET after
receiving fluoxetine or placebo in blinded manner for
6 weeks, Mayberg et al.
81
found that responders to
either treatment had similar metabolic increases
involving the PFC, ACC, posterior cingulate cortex
(PCC), premotor, parietal, posterior insular cortices and
metabolic decreases involving the subgenual cingulate,
parahippocampus and thalamus. Fluoxetine response,
however, was also associated with additional subcor-
tical and limbic changes in the brainstem, striatum,
anterior insula and hippocampus. These regions are
Table 2 Changes in regional brain activation between patients with FGID and controls or patients with FGID before and after
treatment intervention
Study Modality Methods ACC PCC Insula Brainstem PFC Amyg Thalamus PPC SSC
Strigo et al.
61
7 healthy subjects
fMRI Oesophageal balloon
distension
L ACC nd na nd na ››
Midline cutaneous heat L ACC nd ›› na ›› na ››
Dunckley et al.
62
10 healthy subjects
fMRI Rectal balloon
distension
flfl na nd R
side
only
Cutaneous heat to
lower back or dorsum
of L foot
nd ›› ›na ››
Ladabaum et al.
65
15 healthy subjects
PET Balloon distension of
distal stomach
nd ›› nd na nd nd
Vandenbergh et al.
66
11 healthy subjects
PET Balloon distension of
proximal stomach
nr nr nd nd nr
Stephan et al.
67
18 healthy subjects
PET Balloon distension of
proximal stomach
nr ›› ›nr nr nr nr
Hobday et al.
63
18 healthy subjects
fMRI Balloon distension of
anal canal
nr nr nr nr nr
Balloon distension of
rectum
nd nr nr nr nr nr
Lotze et al.
64
8 healthy subjects
fMRI Balloon distension of
anal canal
nd nd nd nd nd ››
Balloon distension of
rectum
nd nd ›› ›› ›
Increased rCBF or BOLD signal; decreased rCBF or BOLD signal.
ACC, anterior cingulate cortex; PFC, prefrontal cortex; Amyg, amygdala; PCC, posterior cingulate cortex; SSC, somato-
sensory cortex; PPC, posterior parietal cortex; na, not assessed; nr, not reported; nd, no significant difference or change.
2005 The Authors
Journal compilation 2005 Blackwell Publishing Ltd 7
Brain–gut connections in functional GI disorders
sources of efferent input to the response-specific
regions identified with both agents.
Neuroimaging abnormalities in FGID
Most studies suggest that while patients with IBS may
have visceral hypersensitivity, they do not exhibit a
generalized hypersensitivity to somatic stimuli.
82–85
Recently, Verne et al.
86
demonstrated, however, that
compared with healthy subjects, patients with IBS had
both visceral and somatic hypersensitivity. Both rectal
distension and cutaneous heat activated regions
involved in the Ôpain matrixÕ(Table 3). IBS patients
showed greater degrees of activation in these regions
than controls. While IBS patients did not rate
visceral stimulation as more intense than somatic
stimulation, they did rate it as more unpleasant.
Increased PFC activity (a region associated with affect-
ive processing) occurred in the IBS patients and coin-
cided with higher ratings for fear and anxiety given by
these patients in response to rectal distension. For
controls, visceral stimulation was both more intense
and more unpleasant than somatic stimulation. These
observations support the hypothesis that visceral and
cutaneous hyperalgesia in IBS patients is related to
increased afferent processing in pathways ascending to
the brain rather than selectively increased activity at
higher cortical levels.
Table 3 Changes in regional brain activation between patients with FGID and controls or patients with FGID before and after
treatment intervention
Study Modality Methods ACC Insula Brainstem PFC Amyg Thalamus PCC SSC
Verne et al.
86
Ctrls ¼9
IBS ¼9
fMRI Rectal
distension
››na na ››
Cutaneous heat ››na na ››
Chang et al.
87
IBS ¼10
IBS + FM ¼10
PET Rectal distension mACC nd nd nd nd nd nd nd
Cutaneous
mechanical
pressure
mACC* nd nd nd nd nd nd nd
Mertz et al.
88
Ctrls ¼16
IBS ¼18
fMRI Rectal
distension
na na na na na na
Naliboff et al.
89
Ctrls ¼12
IBS ¼12
PET Anticipated and
delivered rectal
distension
pACC
rostral ACC
na flflna fl›na
Silverman et al.
95
Ctrls ¼6
IBS ¼6
PET Anticipated
rectal
distension
pACC na na na na na na
Berman
91
IBS ¼37
PET Anticipated and
delivered rectal
distension
pre-/post-alosetron
pACC ›flpons vmPFC
vlPFC
fl› na na
Morgan
92
IBS ¼19
fMRI Rectal
distension with
hi/lo acoustic
stress
pre-/postamitriptyline
pACC nd nd nd nd nd nd
Lackner
90
Ctrls ¼6
IBS ¼6
PET Rectal
distension
pre-/postcognitive
therapy
pACC nd nd flflnd nd
Increased rCBF or BOLD signal; decreased rCBF or BOLD signal
ACC, anterior cingulate cortex; PFC, prefrontal cortex; Amyg, amygdala; PCC, posterior cingulate cortex; SSC, somatosensory
cortex; pACC, perigenual anterior cingulate cortex; sgACC, subgenual anterior cingulate cortex; vmPFC, ventromedial prefrontal
cortex; vlPFC, ventrolateral prefrontal cortex; FM, fibromyalgia; na, not assessed or reported; nd, no difference reported between
groups.
*Response represents rCBF in IBS compared with IBS + FM groups. In response to cutaneous pressure, the IBS + FM group
demonstrated greater mACC activity as well as increased activity in the thalamus.
No differences in rCBF were seen between IBS and ctrl groups for painful and non-painful distensions. For brevity, this condition is
omitted from the table.
8
2005 The Authors
Journal compilation 2005 Blackwell Publishing Ltd8
M. P. Jones et al. Neurogastroenterology and Motility
Chang et al.
87
studied responses to visceral and
somatic pain in patients with either IBS or IBS and
fibromyalgia. IBS patients regarded visceral stimula-
tion as more unpleasant than somatic stimulation
while patients with IBS and fibromyalgia rated visceral
and somatic stimuli as equally unpleasant. This was
paralleled by activity changes in the middle subregion
of the ACC. There was a greater regional cerebral blood
flow (rCBF) increase in the ACC in response to visceral
stimuli in patients with IBS and to somatic stimuli in
patients with both IBS and fibromyalgia (Table 3). This
highlights the important observation that CNS re-
sponses to visceral and somatic stimuli do not appear
condition-specific but simply reflect central mecha-
nisms of afferent processing.
Mertz et al.
88
demonstrated that rectal distension in
both controls and patients with IBS activated similar
brain regions. While rectal distension led to greater
ACC activation in patients with IBS than in controls,
the degree of activation did not correlate with reported
pain severity. These data suggested a qualitatively
normal but quantitatively enhanced pattern of CNS
activation in patients with IBS.
Naliboff et al.
89
used PET to evaluate regional brain
activity in response to real vs simulated rectal disten-
sion in healthy subjects and patients with IBS.Figure 5
shows between-groups comparisons of PET scan ima-
ges from controls and patients with IBS in response to
both actual and anticipated rectal distension. Com-
pared with controls, patients with IBS had increased
rCBF in the right PFC, ACC and PCC and decreased
activity in the pACC, temporal lobe and brainstem.
These responses occurred even when rectal distension
was anticipated but not delivered suggesting that IBS
patients may have reduced activation of neural circuits
associated with antinocioceptive responses to aversive
stimuli (ACC) and preferential activation of regions
involved in processing negatively charged emotional
information (PFC).
Silverman et al. also found that patients with IBS
responded to actual or anticipated rectal distension
with significant activation of the PFC. While healthy
subjects displayed ACC activation in response to
administered or anticipated pain, no such pattern was
seen in the IBS patients. The authors concluded that
painful rectal distension in healthy subjects was
associated with ACC activity but patients with IBS
displayed an aberrant response in response to both
actual and anticipated visceral pain.
The above studies demonstrate that in patients with
IBS, CNS responses to unpleasant or painful visceral
stimuli produce patterns of CNS activity that are
qualitatively similar to controls. Differences exist
between patients and controls with respect to antici-
pated stimulation and the correlation between reported
experience and ACC activation. While more detailed
study is needed in this area, the reviewed studies
suggest that an important determinant pain behaviour
in patients with IBS may be attentional rather than an
abnormality of afferent transmission.
Influence of behavioural and pharmacological
therapies on neuroimaging in FGID
Lackner et al.
90
reported a series of six individuals with
IBS and six controls. Patients with IBS were treated
with a 10-week course of cognitive therapy. Treatment
was associated with a significant reduction in anxiety
and digestive symptoms. PET scans showed reduced
activity in the region of the left amygdala and right
ACC following therapy (Table 3 and Fig. 6).
Berman et al.
91
reported that patients with IBS
treated with alosetron compared with placebo-treated
controls had reduced rCBF as measured by PET in the
ventromedial PFC, infragenual cingulate, hypothala-
mus, ventral striatum and amygdala. Symptom
improvement correlated with decreased rCBF in the
amygdala, ventral striatum and dorsal pons. The
alosetron-associated reduction in rCBF was greatest at
rest and less pronounced during rectal or sigmoid
distension. The same group published a second study
of the effects of alosetron on regional brain activation
and symptom responses to rectal distension after a
3-week, placebo-controlled trial of alosetron in male
and female patients with non-constipation IBS.
91
Left Right
4
3
2
1
0Ctrl IBS
Figure 5 Summary of control (yellow scale) and IBS (pink
scale) responses along the medial surface of the anterior cin-
gulate cortex for the comparison of stimulation and antici-
pation with the baseline before and after conditioning. Two
slices are shown from the left and right hemisphere to a depth
of 2 mm (top) and 6 mm (bottom). From Naliboff et al.
89
2005 The Authors
Journal compilation 2005 Blackwell Publishing Ltd 9
Brain–gut connections in functional GI disorders
Treatment with alosetron but not placebo was associ-
ated with a decrease in symptom ratings and reductions
in emotional stimulus ratings. Alosetron treatment was
associated with reduced rCBF in bilateral frontotem-
poral and various limbic structures, including amygd-
ala. It is unclear whether or not the observed effects
were related to central or peripheral actions of the drug.
Finally, Morgan et al.
92
showed similar effects on
cingulate activation after treatment with the a tricyclic
antidepressant amitriptyline. Females with IBS were
randomized to amitriptyline 50 mg daily or placebo in
a crossover fashion. Rectal balloon distension was
performed under both stressful and non-stressful con-
ditions. Treatment with amitriptyline resulted in
decreased pain-related activations of the pACC and
left posterior parietal cortex, but only during stress.
Amitriptyline did not significantly reduce ratings of
pain intensity nor did it influence activity in the
insular cortex (where visceral sensation is represented).
These data suggest that low dose tricyclic antidepres-
sants (TCA) may improve symptoms in patients with
IBS by diminishing the inhibitory effects of stress on
ACC function.
These reports suggest that symptom improvement in
IBS with behavioural therapies, serotonergic agents and
antidepressants is associated with changes in brain
activations in areas associated with the affective and
cognitive processing of pain. Whether the observed
responses to treatment reflect primary effects or
epiphenomenon is undetermined.
Overview of neuroimaging in IBS
Studies discussed above that evaluated patients with
IBS either compared with controls or pre- and post-
therapeutic intervention are summarized in Table 3.
Overall, there are a small number of studies containing
small sample sizes. While discrepancies exist, most
studies demonstrate heightened activity in regions
previously noted to be involved with visceral or
somatic pain.
93
These areas include pACC, mACC,
PFC, insula, SSC and thalamus. The three studies
evaluating treatment interventions have all shown
decreased activity in the pACC after treatment but
effects on brain activity in other regions have not been
as consistently reported. Whether these interventions
specifically target brain regions identified is unknown
at present.
While it seems that difference do exist between
patients with IBS and healthy subjects with respect to
regional brain activation, functional neuroimaging is
not yet developed enough to provide more specific
information or to clarify these reported differences and
their relationship to stress, pain and emotion.
94
These
studies suffer from a variety of methodological limita-
tions that are summarized in Table 4. The true value of
functional neuroimaging will only become apparent
when these issues have been successfully addressed.
CONCLUDING COMMENTS
Understanding the neural regulation of gut function
and sensation makes it easier to understand the
interrelatedness of emotionality, symptom-attentive
behaviour or hypervigilance, gut function and pain.
The gut and the brain are highly integrated and
communicate in a bi-directional fashion largely
through the ANS and HPA axis. Within the CNS, the
locus of gut control is chiefly within the limbic
system, a region of the mammalian brain responsible
Figure 6 Brain regions showing reduced neural activity after cognitive therapy. The most pronounced reductions occurred in the
region of the left amygdala and right anterior cingulated cortex. From Lackner et al.
90
10
2005 The Authors
Journal compilation 2005 Blackwell Publishing Ltd10
M. P. Jones et al. Neurogastroenterology and Motility
for both the internal and external homeostasis of the
organism. The limbic system also plays a central role
in emotionality, which is a nonverbal system that
facilitates survival and threat avoidance, social inter-
action and learning. The generation of emotion and
associated physiological changes are the work of the
limbic system and, from a neuroanatomic perspective,
the Ômind–body interactionÕmay largely arise in this
region. Finally, the limbic system is also involved in
the Ôtop–downÕmodulation of visceral pain transmis-
sion as well as visceral perception.
A better understanding of the interactions of the
CNS, ENS and enteric immune system will signifi-
cantly improve our understanding of ÔfunctionalÕdis-
orders and allow for a more pathophysiological
definition of categories of patients currently lumped
under the broad umbrella of FGID.
REFERENCES
1 Drossman D, Creed F, Olden K, Svedlund J, Toner B,
Whitehead W. Psychosocial aspects of the functional gas-
trointestinal disorders. In: Drossman D, Corazziari E,
Talley N, Thompson W, Whitehead W, eds. Rome II. The
Functional Gastrointestinal Disorders: Diagnosis, Patho-
physiology and Treatment; A Multinational Consensus,
2nd edn. McLean, VA: Degnon and Associates, 2000: 157–
245.
2 Drossman DA, Camilleri M, Mayer EA, Whitehead WE.
AGA technical review on irritable bowel syndrome. Gas-
troenterology 2002; 123: 2108–31.
3 Tougas G. The autonomic nervous system in functional
bowel disorders. Gut 2000; 47(Suppl. 4): iv78–80; discus-
sion iv87.
4 Kolb B, Whishaw IQ. Fundamentals of Human Neuro-
psychology, 4th edn. New York: WH Freeman and Com-
pany, 1996.
5 Tucker DM, Luu P, Pribram KH. Social and emotional
self-regulation. Ann NY Acad Sci 1995; 769: 213–39.
6 Dalgleish T. The emotional brain. Nat Rev Neurosci 2004;
5: 583–9.
7 Bechara A, Tranel D, Damasio H, Adolphs R, Rockland C,
Damasio AR. Double dissociation of conditioning and
declarative knowledge relative to the amygdala and hip-
pocampus in humans. Science 1995; 269: 1115–8.
8 Angrilli A, Mauri A, Palomba D et al. Startle reflex and
emotion modulation impairment after a right amygdala
lesion. Brain 1996; 119(Pt 6): 1991–2000.
9 Armony JL, Servan-Schreiber D, Cohen JD, LeDoux JE. An
anatomically constrained neural network model of fear
conditioning. Behav Neurosci 1995; 109: 246–57.
10 LeDoux JE. Emotional memory systems in the brain. Be-
hav Brain Res 1993; 58: 69–79.
11 Romanski LM, LeDoux JE. Equipotentiality of thalamo-
amygdala and thalamo-cortico-amygdala circuits in
auditory fear conditioning. J Neurosci 1992; 12: 4501–9.
12 Bush G, Luu P, Posner MI. Cognitive and emotional
influences in anterior cingulate cortex. Trends Cogn Sci
2000; 4: 215–222.
13 Davidson RJ, Lewis DA, Alloy LB et al. Neural and be-
havioral substrates of mood and mood regulation. Biol
Psychiatry 2002; 52: 478–502.
14 Lane RD, Reiman EM, Axelrod B, Yun LS, Holmes A,
Schwartz GE. Neural correlates of levels of emotional
awareness. Evidence of an interaction between emotion
and attention in the anterior cingulate cortex. J Cogn
Neurosci 1998; 10: 525–35.
15 Critchley HD, Mathias CJ, Josephs O et al. Human cin-
gulate cortex and autonomic control: converging neuroi-
maging and clinical evidence. Brain 2003; 126(Pt 10):
2139–52.
16 Matthews SC, Paulus MP, Simmons AN, Nelesen RA,
Dimsdale JE. Functional subdivisions within anterior
cingulate cortex and their relationship to autonomic ner-
vous system function. Neuroimage 2004; 22: 1151–6.
17 Davidson RJ. Affective neuroscience and psychophysiolo-
gy: toward a synthesis. Psychophysiology 2003; 40: 655–
65.
18 Miller EK, Cohen JD. An integrative theory of prefrontal
cortex function. Annu Rev Neurosci 2001; 24: 167–202.
19 Bechara A, Damasio AR, Damasio H, Anderson SW.
Insensitivity to future consequences following damage to
human prefrontal cortex. Cognition 1994; 50: 7–15.
20 Damasio H, Grabowski T, Frank R, Galaburda AM,
Damasio AR. The return of Phineas Gage: clues about the
brain from the skull of a famous patient. Science 1994;
264: 1102–5.
21 Okada G, Okamoto Y, Morinobu S, Yamawaki S, Yokota
N. Attenuated left prefrontal activation during a verbal
fluency task in patients with depression. Neuropsychobi-
ology 2003; 47: 21–6.
22 Drevets WC. Functional anatomical abnormalities in
limbic and prefrontal cortical structures in major depres-
sion. Prog Brain Res 2000; 126: 413–31.
23 Drossman DA. Functional abdominal pain syndrome. Clin
Gastroenterol Hepatol 2004; 2: 353–65.
24 Rainville P, Duncan GH, Price DD, Carrier B, Bushnell
MC. Pain affect encoded in human anterior cingulate but
not somatosensory cortex. Science 1997; 277: 968–71.
25 Melzack R, Wall P. Gate-control and other mechanisms.
In: Melzack R, Wall P, eds. The Challenge of Pain, 2nd
edn. London: Pelican Books, 1988: 165–193.
Table 4 Methodological limitations of current functional
neuroimaging studies in patients with FGID. Adapted from
Drossman
94
Activations often involve neural circuitry of several
interacting regions which make it difficult to target
single sites
Potential imaging differences between PET and fMRI
Gender differences
Confounding effects on the registration of images to rectal
distension with anticipation of that event
Confounding central influences, such as placebo effects
Clinical heterogeneity among patients with regard to
diagnosis and severity of the disorders
Methodological issues in technique, lack of instrument and
protocol standardisation, low Ôsignal to noiseÕratios, and
limitations in measuring functionally heterogeneous
regions of the cingulate and other brain regions.
2005 The Authors
Journal compilation 2005 Blackwell Publishing Ltd 11
Brain–gut connections in functional GI disorders
26 Vogt BA, Watanabe H, Grootoonk S, Jones AKP. Topog-
raphy of diprenorphine binding in human cingulate gyrus
and adjacent cortex derived from coregistered PET and MR
images. Hum Brain Mapp 1995; 3: 1–12.
27 Waring WS, Chui M, Japp A, Nicol EF, Ford MJ. Auto-
nomic cardiovascular responses are impaired in women
with irritable bowel syndrome. J Clin Gastroenterol 2004;
38: 658–663.
28 Kellow JE, Langeluddecke PM, Eckersley GM, Jones MP,
Tennant CC. Effects of acute psychologic stress on small-
intestinal motility in health and the irritable bowel syn-
drome. Scand J Gastroenterol 1992; 27: 53–8.
29 Gupta V, Sheffield D, Verne GN. Evidence for autonomic
dysregulation in the irritable bowel syndrome. Dig Dis Sci
2002; 47: 1716–22.
30 Karling P, Nyhlin H, Wiklund U, Sjoberg M, Olofsson BO,
Bjerle P. Spectral analysis of heart rate variability in pa-
tients with irritable bowel syndrome. Scand J Gastroen-
terol 1998; 33: 572–6.
31 Lee CT, Chuang TY, Lu CL, Chen CY, Chang FY, Lee SD.
Abnormal vagal cholinergic function and psycho-
logical behaviors in irritable bowel syndrome patients:
a hospital-based Oriental study. Dig Dis Sci 1998; 43:
1794–9.
32 Jarrett ME, Burr RL, Cain KC, Hertig V, Weisman P,
Heitkemper MM. Anxiety and depression are related to
autonomic nervous system function in women with
irritable bowel syndrome. Dig Dis Sci 2003; 48: 386–94.
33 Aggarwal A, Cutts TF, Abell TL et al. Predominant
symptoms in irritable bowel syndrome correlate with
specific autonomic nervous system abnormalities. Gas-
troenterology 1994; 106: 945–50.
34 Elsenbruch S, Orr WC. Diarrhea- and constipation-pre-
dominant IBS patients differ in postprandial autonomic and
cortisol responses. Am J Gastroenterol 2001; 96: 460–6.
35 Camilleri M, Ford MJ. Functional gastrointestinal disease
and the autonomic nervous system: a way ahead? Gas-
troenterology 1994; 106: 1114–8.
36 Bharucha AE, Camilleri M, Low PA, Zinsmeister AR.
Autonomic dysfunction in gastrointestinal motility dis-
orders. Gut 1993; 34: 397–401.
37 Punyabati O, Deepak KK, Sharma MP, Dwivedi SN.
Autonomic nervous system reactivity in irritable bowel
syndrome. Indian J Gastroenterol 2000; 19: 122–5.
38 Elsenbruch S, Lovallo WR, Orr WC. Psychological and
physiological responses to postprandial mental stress in
women with the irritable bowel syndrome. Psychosom
Med 2001; 63: 805–13.
39 Burr RL, Heitkemper M, Jarrett M, Cain KC. Comparison
of autonomic nervous system indices based on abdominal
pain reports in women with irritable bowel syndrome. Biol
Res Nurs 2000; 2: 97–106.
40 Monnikes H, Tebbe JJ, Hildebrandt M et al. Role of stress
in functional gastrointestinal disorders. Evidence for
stress-induced alterations in gastrointestinal motility and
sensitivity. Dig Dis 2001; 19: 201–11.
41 Tache Y, Martinez V, Million M, Rivier J. Corticotropin-
releasing factor and the brain-gut motor response to stress.
Can J Gastroenterol 1999; 13(Suppl. A): 18A–25A.
42 Patacchioli FR, Angelucci L, Dellerba G, Monnazzi P, Leri
O. Actual stress, psychopathology and salivary cortisol
levels in the irritable bowel syndrome (IBS). J Endocrinol
Invest 2001; 24: 173–7.
43 Posserud I, Agerforz P, Ekman R, Bjornsson ES, Abra-
hamsson H, Simren M. Altered visceral perceptual and
neuroendocrine response in patients with irritable bowel
syndrome during mental stress. Gut 2004; 53: 1102–8.
44 Heitkemper M, Jarrett M, Cain K et al. Increased urine
catecholamines and cortisol in women with irritable bo-
wel syndrome. Am J Gastroenterol 1996; 91: 906–13.
45 Elsenbruch S, Holtmann G, Oezcan D et al. Are there
alterations of neuroendocrine and cellular immune re-
sponses to nutrients in women with irritable bowel syn-
drome? Am J Gastroenterol 2004; 99: 703–10.
46 Gwee KA, Leong YL, Graham C et al. The role of psy-
chological and biological factors in postinfective gut dys-
function. Gut 1999; 44: 400–6.
47 Lomax AE, Fernandez E, Sharkey KA. Plasticity of the
enteric nervous system during intestinal inflammation.
Neurogastroenterol Motil 2005; 17: 4–15.
48 Mayer EA, Collins SM. Evolving pathophysiologic models
of functional gastrointestinal disorders. Gastroenterology
2002; 122: 2032–48.
49 Bradesi S, McRoberts JA, Anton PA, Mayer EA. Inflam-
matory bowel disease and irritable bowel syndrome: sep-
arate or unified? Curr Opin Gastroenterol 2003; 19: 336–
42.
50 Gwee KA, Graham JC, McKendrick MW et al. Psycho-
metric scores and persistence of irritable bowel after
infectious diarrhoea. Lancet 1996; 347: 150–3.
51 McKendrick MW, Read NW. Irritable bowel syndrome –
post salmonella infection. J Infect 1994; 29: 1–3.
52 Neal KR, Hebden J, Spiller R. Prevalence of gastrointestinal
symptoms six months after bacterial gastroenteritis and
risk factors for development of the irritable bowel syn-
drome: postal survey of patients. BMJ 1997; 314: 779–82.
53 Thornley JP, Jenkins D, Neal K, Wright T, Brough J, Spiller
RC. Relationship of Campylobacter toxigenicity in vitro to
the development of postinfectious irritable bowel syn-
drome. J Infect Dis 2001; 184: 606–9.
54 Parry SD, Stansfield R, Jelley D et al. Does bacterial gas-
troenteritis predispose people to functional gastrointesti-
nal disorders? A prospective, community-based, case-
control study. Am J Gastroenterol 2003; 98: 1970–5.
55 Gwee KA, Collins SM, Read NW et al. Increased rectal
mucosal expression of interleukin 1beta in recently ac-
quired post-infectious irritable bowel syndrome. Gut 2003;
52: 523–6.
56 Spiller RC, Jenkins D, Thornley JP et al. Increased rectal
mucosal enteroendocrine cells, T lymphocytes, and in-
creased gut permeability following acute Campylobacter
enteritis and in post-dysenteric irritable bowel syndrome.
Gut 2000; 47: 804–11.
57 Barbara G, Stanghellini V, De Giorgio R et al. Activated
mast cells in proximity to colonic nerves correlate with
abdominal pain in irritable bowel syndrome. Gastroen-
terology 2004; 126: 693–702.
58 O’Sullivan M, Clayton N, Breslin NP et al. Increased mast
cells in the irritable bowel syndrome. Neurogastroenterol
Motil 2000; 12: 449–57.
59 Weston AP, Biddle WL, Bhatia PS, Miner Jr PB. Terminal
ileal mucosal mast cells in irritable bowel syndrome. Dig
Dis Sci 1993; 38: 1590–5.
60 Chang L. Brain responses to visceral and somatic stimuli
in irritable bowel syndrome: a central nervous system
disorder? Gastroenterol Clin North Am 2005; 34: 271–9.
12
2005 The Authors
Journal compilation 2005 Blackwell Publishing Ltd12
M. P. Jones et al. Neurogastroenterology and Motility
61 Strigo IA, Duncan GH, Boivin M, Bushnell MC. Differ-
entiation of visceral and cutaneous pain in the human
brain. J Neurophysiol 2003; 89: 3294–303.
62 Dunckley P, Wise RG, Aziz Q et al. Cortical processing of
visceral and somatic stimulation: Differentiating pain
intensity from unpleasantness. Neuroscience 2005; 133:
533–42.
63 Hobday DI, Aziz Q, Thacker N, Hollander I, Jackson A,
Thompson DG. A study of the cortical processing of ano-
rectal sensation using functional MRI. Brain 2001; 124(Pt
2): 361–8.
64 Lotze M, Wietek B, Birbaumer N, Ehrhardt J, Grodd W,
Enck P. Cerebral activation during anal and rectal stimu-
lation. Neuroimage 2001; 14: 1027–34.
65 Ladabaum U, Minoshima S, Hasler WL, Cross D, Chey
WD, Owyang C. Gastric distention correlates with acti-
vation of multiple cortical and subcortical regions. Gas-
troenterology 2001; 120: 369–76.
66 Vandenbergh J, Dupont P, Fischler B et al. Regional brain
activation during proximal stomach distention in humans:
a positron emission tomography study. Gastroenterology
2005; 128: 564–73.
67 Stephan E, Pardo JV, Faris PL et al. Functional neuro-
imaging of gastric distention. J Gastrointest Surg 2003; 7:
740–9.
68 Phan KL, Wager TD, Taylor SF, Liberzon I. Functional
neuroimaging studies of human emotions. CNS Spectr
2004; 9: 258–66.
69 Whalen PJ, Rauch SL, Etcoff NL, McInerney SC, Lee MB,
Jenike MA. Masked presentations of emotional facial
expressions modulate amygdala activity without explicit
knowledge. J Neurosci 1998; 18: 411–8.
70 Morris JS, Ohman A, Dolan RJ. Conscious and uncons-
cious emotional learning in the human amygdala. Nature
1998; 393: 467–70.
71 Gusnard DA, Akbudak E, Shulman GL, Raichle ME.
Medial prefrontal cortex and self-referential mental activ-
ity: relation to a default mode of brain function. Proc Natl
Acad Sci USA 2001; 98: 4259–64.
72 Johnson SC, Baxter LC, Wilder LS, Pipe JG, Heiserman JE,
Prigatano GP. Neural correlates of self-reflection. Brain
2002; 125(Pt 8): 1808–14.
73 Zysset S, Huber O, Ferstl E, von Cramon DY. The anterior
frontomedian cortex and evaluative judgment: an fMRI
study. Neuroimage 2002; 15: 983–91.
74 Mayberg HS, Liotti M, Brannan SK et al. Reciprocal lim-
bic-cortical function and negative mood: converging PET
findings in depression and normal sadness. Am J Psychi-
atry 1999; 156: 675–82.
75 Drevets WC, Price JL, Simpson Jr JR et al. Subgenual
prefrontal cortex abnormalities in mood disorders. Nature
1997; 386: 824–7.
76 Mayberg HS, Brannan SK, Mahurin RK et al. Cingulate
function in depression: a potential predictor of treatment
response. Neuroreport 1997; 8: 1057–61.
77 Lieberman MD, Jarcho JM, Berman S et al. The neural
correlates of placebo effects: a disruption account. Neuro-
image 2004; 22: 447–55.
78 Aron AR, Fletcher PC, Bullmore ET, Sahakian BJ, Robbins
TW. Stop-signal inhibition disrupted by damage to right
inferior frontal gyrus in humans. Nat Neurosci 2003; 6:
115–6.
79 Eisenberger NI, Lieberman MD, Williams KD. Does
rejection hurt? An FMRI study of social exclusion. Science
2003; 302: 290–2.
80 Hariri AR, Bookheimer SY, Mazziotta JC. Modulating
emotional responses: effects of a neocortical network on
the limbic system. Neuroreport 2000; 11: 43–8.
81 Mayberg HS, Silva JA, Brannan SK et al. The functional
neuroanatomy of the placebo effect. Am J Psychiatry 2002;
159: 728–37.
82 Accarino AM, Azpiroz F, Malagelada JR. Selective dys-
function of mechanosensitive intestinal afferents in irrit-
able bowel syndrome. Gastroenterology 1995; 108: 636–43.
83 Whitehead WE, Holtkotter B, Enck P et al. Tolerance for
rectosigmoid distention in irritable bowel syndrome.
Gastroenterology 1990; 98(Pt 1): 1187–92.
84 Cook IJ, van Eeden A, Collins SM. Patients with irritable
bowel syndrome have greater pain tolerance than normal
subjects. Gastroenterology 1987; 93: 727–33.
85 Chang L, Mayer EA, Johnson T, FitzGerald LZ, Naliboff B.
Differences in somatic perception in female patients with
irritable bowel syndrome with and without fibromyalgia.
Pain 2000; 84: 297–307.
86 Verne GN, Himes NC, Robinson ME et al. Central rep-
resentation of visceral and cutaneous hypersensitivity in
the irritable bowel syndrome. Pain 2003; 103: 99–110.
87 Chang L, Berman S, Mayer EA et al. Brain responses to
visceral and somatic stimuli in patients with irritable bo-
wel syndrome with and without fibromyalgia. Am J
Gastroenterol 2003; 98: 1354–61.
88 Mertz H, Morgan V, Tanner G et al. Regional cerebral
activation in irritable bowel syndrome and control sub-
jects with painful and nonpainful rectal distention. Gas-
troenterology 2000; 118: 842–8.
89 Naliboff BD, Derbyshire SW, Munakata J et al. Cerebral
activation in patients with irritable bowel syndrome and
control subjects during rectosigmoid stimulation. Psy-
chosom Med 2001; 63: 365–75.
90 Lackner JM, Lockwood A, Coad ML et al. Alterations in
GI symptoms, psychological status, and brain functioning
following participation in cognitive therapy for IBS. Gas-
troenterology 2004; 126: A-477.
91 Berman SM, Chang L, Suyenobu B et al. Condition-specific
deactivation of brain regions by 5-HT3 receptor antagonist
Alosetron. Gastroenterology 2002; 123: 969–77.
92 Morgan V, Pickens D, Gautam S, Kessler R, Mertz H.
Amitriptyline reduces rectal pain related activation of the
anterior cingulate cortex in patients with irritable bowel
syndrome. Gut 2005; 54: 601–7.
93 Derbyshire SW. A systematic review of neuroimaging data
during visceral stimulation. Am J Gastroenterol 2003; 98:
12–20.
94 Drossman DA. Brain imaging and its implications for
studying centrally targeted treatments in irritable bowel
syndrome: a primer for gastroenterologists. Gut 2005; 54:
569–73.
95 Silverman DH, Munakata JA, Ennes H, Mandelkern MA,
Hoh CK, Mayer EA. Regional cerebral activity in normal
and pathological perception of visceral pain. Gastroenter-
ology 1997; 112: 64–72.
96 Mayer EA, Naliboff BD, Chang L, Coutinho SV. V. Stress
and irritable bowel syndrome. Am J Physiol Gastrointest
Liver Physiol 2001; 280: G519–24.
2005 The Authors
Journal compilation 2005 Blackwell Publishing Ltd 13
Brain–gut connections in functional GI disorders
... Fatigue is mediated via the integration of the CNS and peripheral musculoskeletal systems (Giulio et al., 2006), whereby physiological perturbations occurring in the brain and spinal cord (central fatigue) or at the neuromuscular junction and the skeletal muscle (peripheral fatigue) result in acute and transient decrements in performance. Pro-inflammatory cytokines are involved in symptom generation of central fatigue (Borren et al., 2019), possibly via increasing bloodbrain barrier (BBB) permeability, propagating inflammatory signals within the brain via activation of endothelial, glial cells and macrophage, resulting in neuronal cell death (Jones et al., 2006). Systemic inflammation may be linked with demyelinating complications reflected in morphometric changes in the brain of CD patients (Zikou et al., 2014). ...
... Systemic inflammation may be linked with demyelinating complications reflected in morphometric changes in the brain of CD patients (Zikou et al., 2014). Intestinal inflammation and abdominal pain may activate central sensitization pathways that convey visceral nociceptive afferent signals from the gut to the brain (Jones et al., 2006;Hubbard et al., 2016), affecting symptom perception and gut function (Jones et al., 2006), with high levels of somatization strongly associated with fatigue severity and impact in inflammatory bowel disease (IBD) patients (Ratnakumaran et al., 2018). ...
... Systemic inflammation may be linked with demyelinating complications reflected in morphometric changes in the brain of CD patients (Zikou et al., 2014). Intestinal inflammation and abdominal pain may activate central sensitization pathways that convey visceral nociceptive afferent signals from the gut to the brain (Jones et al., 2006;Hubbard et al., 2016), affecting symptom perception and gut function (Jones et al., 2006), with high levels of somatization strongly associated with fatigue severity and impact in inflammatory bowel disease (IBD) patients (Ratnakumaran et al., 2018). ...
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Alterations in grey matter volume (GMV) and cortical thickness (CT) in Crohn’s disease (CD) patients has been previously documented. However, the findings are inconsistent, and not a true representation of CD burden, as only CD patients in remission have been studied thus far. We investigate alterations in brain morphometry in patients with active CD and those in remission, and study relationships between brain structure and key symptoms of fatigue, abdominal pain, and extraintestinal manifestations (EIM). Magnetic Resonance Imaging brain scans were collected in 89 participants; 34 CD participants with active disease, 13 CD participants in remission and 42 healthy controls (HCs); Voxel based morphometry (VBM) assessed GMV and white matter volume (WMV), and surface-based analysis assessed cortical thickness (CT). We show a significant reduction in global cerebrospinal fluid (CSF) volume in CD participants compared with HCs, as well as, a reduction in regional GMV, WMV and CT in the left precentral gyrus (motor cortex), and an increase in GMV in the frontal brain regions in CD compared with HCs. Atrophy of the supplementary motor area (SMA) was associated with greater fatigue in CD. We also show alterations in brain structure in multiple regions in CD associated with abdominal pain and extraintestinal inflammations (EIMs). These brain structural alterations likely reflect neuroplasticity to a chronic systemic inflammatory response, abdominal pain, EIMs and fatigue. These findings will aid our understanding of the cross-linking between chronic inflammation, brain structural changes and key unexplained CD symptomatology like fatigue.
... For example, the stress hormone CRF has central stress modulatory and peripheral gut physiologic effects. It produces gastric stasis and an increase in the colonic transit rate in response to psychologically aversive stimuli 78 and can increase visceral hypersensitivity 79 and alter immune functioning. 64 Thus, CRF appears to be active in stress-induced exacerbations of IBS 80 and in cyclic vomiting syndrome (see Chapters 14 and 118 ). ...
... Conversely, mucosal pallor and decreased secretion and motor activity accompanied fear or depression, states of withdrawal (i.e., giving-up behavior), or disengagement from others. Complicated cognitive tasks produce high-amplitude, high-velocity esophageal contractions, 78 a reduction in phase II intestinal motor activity, 79 and prolongation of phase III activity of the migrating myoelectric complex (MMC) 80 in the small intestine (see Chapter 99 ). Experimentally induced anger increases motor and spike potential activity in the colon and is greater in patients with FGIDs (see Chapter 100 ). ...
... It is a bidirectional system in which thoughts, feelings, and memories lead to neurotransmitter release (the software) that affects sensory, motor, endocrine, autonomic, immune, and inflammatory function. 78,79 Gut microbiota also engage in bidirectional communication with the brain via neural, endocrine, and immune pathways with significant consequences for behavioral disorders including anxiety, depression, and cognitive disorders as well as chronic visceral pain. 80 Dysregulation of this system explains motility disturbances, pain and other GI symptoms, and FGIDs. ...
... For Parkinson's disease, it is hypothesized whether this pathology may have its origin in the intestinal system rather than the brain [6]. In order to understand such pathologic pathways, it may be important to understand the bilateral connection of the intestinal system and the brain [5,7]. The enteric nervous system (ENS) is part of the autonomic nervous system [8] with associated pacemakers in the plexus [9] and a closed circuit which is not dependent on inputs from the CNS. ...
... The filter was designed with the function butter (n = 3rd order). We calculated the normalized cutoff frequency (Wn) for EEG bands delta [0-4 Hz], theta[4][5][6][7][8], alpha[8][9][10][11][12][13], beta[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30], low gamma, and high gamma [80-120 Hz]. Wn is a number between 0 and 1, where 1 corresponds to the Nyquist frequency which is half the sampling rate (here: 500 Hz). ...
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Many diseases affect the autonomous nervous system and the central nervous system simultaneously, for example Parkinson’s disease or irritable bowel syndrome. To study neurophysiologic interactions between the intestinal electrical activity and the electroencephalography (EEG) pattern of the brain, we combined intestinal electrical stimulation (IES) and non-invasive telemetric full-band DC EEG recordings in an acute pig-model. Intestinal motility was monitored with accelerometers. Brain activity was analyzed with regard to network driven phenomena like phase amplitude coupling (PAC) within two time-windows: 1 min after IES (early response) and 3 min after stimulation (late response). Here we present the results for two stimulation sites (small intestine, colon) and two parietal scalp-EEG channels (right and left somatosensory cortex region). Electrical stimulation consisted of a 30 or 130 Hz pulse. In summary, the PAC modulation index at a parietal EEG recording position is decreased after IES. This effect is in line with an inhibitory effect of our IES protocol regarding peristalsis. The surprisingly strong effects of IES on network driven EEG patterns may be translated into new therapeutic techniques and/or diagnostic tools in the future. Furthermore, analytic tools, operating on sparse datasets, may be ideally suited for the integration in implantable intestinal pacemakers as feedback system.
... For Parkinson's disease, it is hypothesized whether this pathology may have its origin in the intestinal system rather than the brain [6]. In order to understand such pathologic pathways, it may be important to understand the bilateral connection of the intestinal system and the brain [5,7]. The enteric nervous system (ENS) is part of the autonomic nervous system [8] with associated pacemakers in the plexus [9] and a closed circuit which is not dependent on inputs from the CNS. ...
... The filter was designed with the function butter (n = 3rd order). We calculated the normalized cutoff frequency (Wn) for EEG bands delta [0-4 Hz], theta[4][5][6][7][8], alpha[8][9][10][11][12][13], beta[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30], low gamma, and high gamma [80-120 Hz]. Wn is a number between 0 and 1, where 1 corresponds to the Nyquist frequency which is half the sampling rate (here: 500 Hz). ...
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Full-text available
Many diseases affect the autonomous nervous system and the central nervous system simultaneously, for example Parkinson’s disease or irritable bowel syndrome. To study neurophysiologic interactions between the intestinal electrical activity and the electroencephalography (EEG) pattern of the brain, we combined intestinal electrical stimulation (IES) and non-invasive telemetric full-band DC EEG recordings in an acute pig-model. Intestinal motility was monitored with accelerometers. Brain activity was analyzed with regard to network driven phenomena like phase amplitude coupling (PAC) within two time-windows: 1 min after IES (early response) and 3 min after stimulation (late response). Here we present the results for two stimulation sites (small intestine, colon) and two parietal scalp-EEG channels (right and left somatosensory cortex region). Electrical stimulation consisted of a 30 or 130 Hz pulse. In summary, the PAC modulation index at a parietal EEG recording position is decreased after IES. This effect is in line with an inhibitory effect of our IES protocol regarding peristalsis. The surprisingly strong effects of IES on network driven EEG patterns may be translated into new therapeutic techniques and/or diagnostic tools in the future. Furthermore, analytic tools, operating on sparse datasets, may be ideally suited for the integration in implantable intestinal pacemakers as feedback system.
... [4,5] The pathogenesis of CAPS is not fully understood, and studies have suggested that [6,7] may be related to increased visceral sensitivity, abnormal brain-gut interactions, intestinal flora disturbances, and psychosomatic factors. Recent studies have found that the central nervous system plays an important role in the pathogenesis of CAPS, possibly related to the limbic system and pain downregulation mechanisms, [8] and the renaming of FAPs to CAPS in the 2016 book Rome IV: Functional Gastrointestinal Disorders [9] reinforces the role of the central nervous system in the pathogenesis of CAPS. Since the pathogenesis of CAPS is unclear, it is considered a clinically difficult disease. ...
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Full-text available
Background: This study aimed to evaluate the clinical efficacy of Chinese medicine for the treatment of centrally mediated abdominal pain syndrome (CAPS) using a meta-analysis system. Methods: Six databases, including China National Knowledge Infrastructure, Vendor Information Pages, Chinese Biomedical Database, Wanfang, PubMed, and Embase were searched for randomized controlled trials related to the treatment of CAPS with traditional Chinese medicine. The bias risk assessment tool and RevMan5.3 software (Copenhagen, The Nordic Cochrane Centre, The Cochrane Collaboration) were used to conduct quality assessment and meta-analysis, and the GRADE grading system was used to evaluate the quality of evidence for outcome indicators. Results: Fifteen articles were included in this study. Meta-analysis results showed that the treatment group was more effective in terms of the total effective rate (relative risk = 1.27; 95% confidence interval [CI], 1.19-1.34; P < .00001), Behavioral Rating Scale-6 pain score (mean difference [MD] = -0.79; 95% CI, -0.99 to -0.59; P < .00001), and traditional Chinese medicine (TCM) symptom score (MD = -1.74; 95% CI, -2.23 to -1.26; P < .00001) than the control group (P < .05). However, in terms of numerical rating scale pain score (MD = 0.79; 95% CI, -1.70 to 0.12; P = .09), the efficacy was comparable between the 2 groups, and the difference was not statistically significant (P > .05). In terms of verbal rating scale pain, depression, and anxiety scores, the data could not be combined due to inconsistent scoring criteria, and only descriptive analysis was performed. The results showed that the treatment group was slightly better than the control group in terms of relieving verbal rating scale pain and improving anxiety and depression (P < .05). Conclusion: Chinese medicine can effectively improve the pain and TCM clinical symptoms of patients with CAPS and relieve patients' anxiety and depression with fewer adverse effects, which has certain therapeutic advantages. However, because of the low methodological quality assessment of the included literature, the quality of GRADE evidence for outcome indicators is of mostly low and very low quality, the strength of recommendation is weak, and the credibility of the conclusion is average. More rigorous, larger sample, and higher-quality clinical trials are required to provide a higher level of evidence-based medicine for the development of TCM treatment standards for CAPS.
Chapter
The relationship between the brain and the gut, termed the “gut-brain axis,” links emotional and cognitive centers of the brain with intestinal function. The complex pathophysiology underlying disorders of gut-brain interaction (DGBI) can involve motility disturbances, visceral hypersensitivity, altered mucosal and immune function, changes in gut microbiota, and abnormal central nervous system processing. Additionally, gastrointestinal and psychological symptoms commonly coexist with DGBI. Targeting the gut-brain axis using neuromodulators for the treatment of DGBI has garnered significant attention in recent years. This chapter aims to review the pharmacologic agents that play a role in modulating the gut-brain axis and literature that supports their use in children. We include a discussion of cyproheptadine, aprepitant, azapirones, clonidine, benzodiazepines, atypical antipsychotics, anticonvulsants, melatonin, cannabis, tricyclic antidepressants, selective serotonin receptor inhibitors, serotonin and norepinephrine reuptake inhibitors, tetracyclics and serotonin antagonist and reuptake inhibitors, opiates, and placebo effect. While there is limited evidence in pediatrics, the use of neuromodulators in children for the treatment of DGBI is often supported by data extrapolated from adult research. There remains significant need for further research on the use of these drugs in pediatric patients with DGBI.
Article
Behavioral digital therapeutics represents a diverse range of health technology tools that can offer beneficial options for patients with gastrointestinal disorders, particularly with the shortage of mental health providers. Challenges to the uptake of behavioral digital interventions exist and can be addressed with mobile device applications, improved interoperability of technology platforms, and flexible integration into clinical practice.
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The brain and the gut are linked together with a complex, bi-path link known as the gut-brain axis through the central and enteric nervous systems. So, the brain directly affects and controls the gut through various neurocrine and endocrine processes, and the gut impacts the brain via different mechanisms. Epilepsy is a central nervous system (CNS) disorder with abnormal brain activity, causing repeated seizures due to a transient excessive or synchronous alteration in the brain's electrical activity. Due to the strong relationship between the enteric and the CNS, gastrointestinal dysfunction may increase the risk of epilepsy. Meanwhile, about 2.5% of patients with epilepsy were misdiagnosed as having gastrointestinal disorders, especially in children below the age of one year. Gut dysbiosis also has a significant role in epileptogenesis. Epilepsy, in turn, affects the gastrointestinal tract in different forms, such as abdominal aura, epilepsy with abdominal pain, and the adverse effects of medications on the gut and the gut microbiota. Epilepsy with abdominal pain, a type of temporal lobe epilepsy, is an uncommon cause of abdominal pain. Epilepsy also can present with postictal states with gastrointestinal manifestations such as postictal hypersalivation, hyperphagia, or compulsive water drinking. At the same time, antiseizure medications have many gastrointestinal side effects. On the other hand, some antiseizure medications may improve some gastrointestinal diseases. Many gut manipulations were used successfully to manage epilepsy. Prebiotics, probiotics, synbiotics, postbiotics, a ketogenic diet, fecal microbiota transplantation, and vagus nerve stimulation were used successfully to treat some patients with epilepsy. Other manipulations, such as omental transposition, still need more studies. This narrative review will discuss the different ways the gut and epilepsy affect each other.
Article
Anterior cingulate cortex (ACC) is a part of the brain's limbic system. Classically, this region has been related to affect, on the basis of lesion studies in humans and in animals. In the late 1980s, neuroimaging research indicated that ACC was active in many studies of cognition. The findings from EEG studies of a focal area of negativity in scalp electrodes following an error response led to the idea that ACC might be the brain's error detection and correction device. In this article, these various findings are reviewed in relation to the idea that ACC is a part of a circuit involved in a form of attention that serves to regulate both cognitive and emotional processing. Neuroimaging studies showing that separate areas of ACC are involved in cognition and emotion are discussed and related to results showing that the error negativity is influenced by affect and motivation. In addition, the development of the emotional and cognitive roles of ACC are discussed, and how the success of this regulation in controlling responses might be correlated with cingulate size. Finally, some theories are considered about how the different subdivisions of ACC might interact with other cortical structures as a part of the circuits involved in the regulation of mental and emotional activity.
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Different types of stress play important roles in the onset and modulation of irritable bowel syndrome (IBS) symptoms. The physiological effects of psychological and physical stressors on gut function and brain-gut interactions are mediated by outputs of the emotional motor system in terms of autonomic, neuroendocrine, attentional, and pain modulatory responses. IBS patients show an enhanced responsiveness of this system manifesting in altered modulation of gastrointestinal motility and secretion and in alterations in the perception of visceral events. Functional brain imaging techniques are beginning to identify brain circuits involved in the perceptual alterations. Animal models have recently been proposed that mimic key features of the human syndrome.
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Investigation of human ano-rectal physiology has concentrated largely on understanding the motor control of defecation and continence mechanisms. However, little is known of the physiology of ano-rectal sensation. There are important differences in the afferent innervation and sensory perception between the rectum and anal canal. This suggests that there could also be differences in the brain's processing of sensation from these two areas; however, this possibility remains unexplored. The aim of our study was to identify the cerebral areas processing anal (somatic) and rectal (visceral) sensation in healthy adults, using functional MRI. Eight male subjects with an age range of 21–39 years were studied on two separate occasions, one for rectal and the other for anal stimulation studies. Single shot gradient echo planar imaging was performed using a 1.5 tesla Phillips MRI scanner. For each subject, a series of 40 image sets containing 24 slices of the brain was obtained during periods of rapid phasic non-painful distension of the rectum or anal canal, alternating with rest periods, without stimulation. After motion correction, the images were analysed using cross correlation to identify the cerebral areas activated by the stimulus. Rectal stimulation resulted in bilateral activation of the inferior primary somatosensory, secondary somatosensory, sensory association, insular, peri-orbital, anterior cingulate and prefrontal cortices. Anal canal stimulation resulted in activation of areas similar to rectal stimulation, but the primary somatosensory cortex was activated at a more superior level, and there was no anterior cingulate activation. In conclusion, anal and rectal sensation resulted in a similar pattern of cortical activation, including areas involved with spatial discrimination, attention and affect. The differences in sensory perception from these two regions can be explained by their different representation in the primary somatosensory cortex. The anterior cingulate cortex was only activated by rectal stimulation, suggesting that the viscera have a greater representation on the limbic cortex than somatic structures, and this explains the greater autonomic responses evoked by visceral sensation in comparison with somatic sensation.
Article
Psychological stress is widely believed to play a major role in functional gastrointestinal (GI) disorders, especially irritable bowel syndrome (IBS), by precipitating exacerbation of symptoms. The available data clearly demonstrate that inhibition of gastric emptying and stimulation of colonic transit is the most consistent pattern in the motility response of the GI tract to acute or short-term stress. Thus, one might propose that these alterations might play a pathophysiological role in dyspeptic symptoms and alterations in stool frequency and consistency in patients with stress-related functional GI disorders. Taken together, the above-mentioned studies suggest that the colonic motor response to stress is exaggerated in IBS. There is evidence that an increased emotional response is associated with this difference in colonic, and perhaps also gastric motor responses to certain stressors. However, almost no valid data are available so far from human studies addressing the question if differences in motility responses to stress between patients with functional GI disorders and healthy subjects are due to an altered stress response associated with an imbalance of the autonomic nervous system or increased stress susceptibility. We can summarize that in experimental animals the most consistent pattern of GI motor alterations induced by various psychological and physical stressors is that of delaying gastric emptying and accelerating colonic transit. Endogenous corticotropin-releasing factor (CRF) in the brain plays a significant role in the central nervous system mediation of stress-induced inhibition of upper GI and stimulation of lower GI motor function through activation of brain CRF receptors. The inhibition of gastric emptying by CRF may be mediated by interaction with the CRF-2 receptor, while CRF-1 receptors are involved in the colonic and anxiogenic responses to stress. Endogenous serotonin, peripherally released in response to stress, seems to be involved in stress- and central CRF-induced stimulation of colonic motility by acting on 5HT-3 receptors. Taken together, the limited data available from investigations in healthy subjects and patients with functional GI disorders provide some evidence that stress affects visceral sensitivity in humans. Acute psychological stress seems to facilitate increased sensitivity to experimental visceral stimuli, if the stressor induces a significant emotional change. In summary, studies in experimental animals suggest that stress-induced visceral hypersensitivity is centrally mediated by endogenous CRF and involvement of structures of the emotional motor system, e.g. the amygdala. Stress-induced activation or sensitization of mucosal mast cells in the GI tract seem to be involved in stress-associated alterations of visceral sensitivity.
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The capacity to reflect on one’s sense of self is an important component of self‐awareness. In this paper, we investigate some of the neurocognitive processes underlying reflection on the self using functional MRI. Eleven healthy volunteers were scanned with echoplanar imaging using the blood oxygen level‐dependent contrast method. The task consisted of aurally delivered statements requiring a yes–no decision. In the experimental condition, participants responded to a variety of statements requiring knowledge of and reflection on their own abilities, traits and attitudes (e.g. ‘I forget important things’, ‘I’m a good friend’, ‘I have a quick temper’). In the control condition, participants responded to statements requiring a basic level of semantic knowledge (e.g. ‘Ten seconds is more than a minute’, ‘You need water to live’). The latter condition was intended to control for auditory comprehension, attentional demands, decision‐making, the motoric response, and any common retrieval processes. Individual analyses revealed consistent anterior medial prefrontal and posterior cingulate activation for all participants. The overall activity for the group, using a random‐effects model, occurred in anterior medial prefrontal cortex ( t = 13.0, corrected P = 0.05; x , y , z , 0, 54, 8, respectively) and the posterior cingulate ( t = 14.7, P = 0.02; x , y , z , –2, –62, 32, respectively; 967 voxel extent). These data are consistent with lesion studies of impaired awareness, and suggest that the medial prefrontal and posterior cingulate cortex are part of a neural system subserving self‐reflective thought.
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THE relationship between pretreatment regional cerebral glucose metabolism and eventual antidepressant drug response was measured using positron emission tomography (PET) in hospitalized patients with unipolar depression. Rostral anterior cingulate metabolism uniquely differentiated eventual treatment responders from non-responders. Hypometabolism characterized non-responders when compared with controls, in contrast to responders who were hypermetabolic. Metabolism in no other region discriminated the two groups, nor did associated demographic, clinical or behavioral measures, including motor speed, cognitive performance, depression severity or illness chronicity. Cingulate hypermetabolism may represent an important adaptive response to depression and failure of this response may underlie poor outcome. A critical role for rostral cingulate area 24a/b in the limbic-cortical network involved in abnormal mood states is proposed.