doi: 10.1111/1346-8138.

12956 Journal of Dermatology 2015; 42: 761–767

REVIEW ARTICLE
Itch and brain
Hideki MOCHIZUKI,1 Ryusuke KAKIGI2
1
Department of Dermatology, Temple University School of Medicine, Temple Itch Center, Philadelphia, Pennsylvania, USA,
2
Department of Integrative Physiology, National Institute for Physiological Sciences, Okazaki, Japan

ABSTRACT
Itch is an unpleasant somatic sensation that evokes the urge to scratch. Chronic itch is a severe problem that
diminishes quality of life. There are many patients suffering from chronic itch across the world. The brain is the
final terminal to receive itch-related signals from the body and plays an important role in perceiving the itch sen-
sation. Thus, to understand the cerebral mechanism of itch perception and how this mechanism differs between
healthy subjects and chronic itch patients is important for advancing our understanding on the pathophysiology
of chronic itch. Itch is suppressed by scratching or applying painful stimuli. The pleasurable sensation evoked by
scratching an itch increases the urge to scratch. Viewing others in itch or imagining the itch sensation may evoke
real itch sensations and the scratching response. To understand the mechanisms responsible for these phenom-
ena may provide useful information for the development of treatment of itch and advance our understanding of
the cerebral mechanism of itch and scratch. Several functional brain imaging studies have addressed these
issues and reported interesting findings. In this review article, the authors discussed the findings of previous
studies and how they have advanced our understanding of the central mechanisms of itch, scratch and chronic
itch.

Key words: cerebral response to itch, contagious itch, functional brain imaging, itch suppression,
pleasurability derived from scratching.

INTRODUCTION including positron emission tomography (PET), functional mag-

Itch is defined as an unpleasant sensation that provokes the
desire to scratch.1 Chronic itch caused by diseases severely
diminishes the quality of life of these patients and affects mil-
lions of people worldwide, and is, thus, considered a global
health problem. A deeper understanding of the mechanism of
itch is very important. The brain is the final terminal to receive
itch-related signals from the body and process these signals.
However, this processing may be modulated by several physi-
cal and psychological factors. For example, scratching or
applying painful stimuli has been shown to suppress the itch
sensation. The pleasurable sensation evoked by scratching an
itch can reinforce and motivate scratching behavior. Stress,
relaxation, and distraction of attention may modulate itch.
Viewing others in itching and imagery of the itch sensation may
also evoke a real itch sensation and scratching response. A
deeper understanding of the cerebral mechanism of itch per-
ception, how this mechanism differs between healthy and
chronic itch patients, and how itch-related processing in the
brain is modulated by physical and psychological factors will
provide useful information for the treatment of itch and
advance our understanding of the cerebral mechanisms
responsible for itch perception and scratching and the patho-
physiology of chronic itch. Previous studies investigated some
of those issues using functional brain imaging techniques
netic resonance imaging (fMRI), electroencephalography (EEG)
and magnetoencephalography (MEG). These studies are dis-
cussed in this review.
CEREBRAL RESPONSE TO ACUTE ITCH IN
HEALTHY SUBJECTS
The itch sensation is mainly associated with the excitation of
C-fibers.2–4 The neural signal associated with itch is transmit-
ted to the brain via the spinothalamic tract (STT).5 Ascending
neural signals in the STT reach the thalamus, and are then
transmitted to the primary somatosensory cortex (SI) and the
secondary somatosensory cortex (SII). The SI and SII on one
side receive somatosensory input from the contralateral side of
the body (Fig. 1). Accordingly, previous studies have reported
the activation of the contralateral SI during itch stimuli.6–8 The
SII also responds to itch. This region responds to itch stimuli
bilaterally.7,9,10 A previous study using high temporal resolution
such as MEG demonstrated that the response of the contralat-
eral SII to itch stimuli was significantly earlier than that of the
ipsilateral SII, suggesting that this difference in responses
reflected the transmission of neural signals from the contralat-
eral to ipsilateral SII (Fig. 1).
In pain studies, the SI and SII play important roles in pain
perception and pain intensity; however, their roles appear to

Correspondence: Hideki Mochizuki, Ph.D., Department of Dermatology, Temple University School of Medicine, Temple Itch Center, 3322 North
Broad Street, Suite 212, Philadelphia, PA 19140, USA. Email: hideki.mochizuki@tuhs.temple.edu
Received 14 April 2015; accepted 16 April 2015.

© 2015 Japanese Dermatological Association 761

H. Mochizuki and R. Kakigi
SI
SII SII
Th
Figure 1. Ascending pathway from the periphery to the brain.
Itch-related signals from the periphery reach the thalamus (Th).
Then, they are transmitted to the primary somatosensory cor-
tex (SI) and secondary somatosensory cortex (SII). Template
brain: the brain template implemented in the MRIcron software
(http://www.mccauslandcenter.sc.edu/mricro/).
differ. Animal and human studies have demonstrated that the
SI activity bears a linear relationship with stimulus intensity and
subjective pain sensation, while the SII activity exhibited an S-
shaped function with a sharp increase in amplitude only at a
stimulus intensity well above the pain threshold.11–15 Based on
this finding, the SI is considered to play a more important role
for perception of pain intensity and SII may subserve the rec-
ognition of the noxious nature and attention toward painful
stimuli. In itch studies, Drzezga et al.6 investigated cerebral
responses to different intensities of itch stimuli and reported
that activity in the SI, but not in the SII, significantly and posi-
tively correlated with the intensities of the itch stimuli and sub-
jective itch sensation. Similar to pain, the SI plays a more
important role in itch perception and itch intensity than the SII.
Activation of the cingulate cortex has frequently been
reported in previous itch studies. The peak locations of signifi-
cant activation in the cingulate cortex in previous itch studies
were mainly located in the dorsal part of the anterior cingulate
cortex (dACC), which also corresponds to the anterior part of
the midcingulate cortex (aMCC) (Fig. 2). Electrical stimulation
of the MCC evoked motivation to act, whereas the pregenual
ACC (pACC), more anterior to aMCC, evoked emotion such as
fear in a previous study.16 Another role of the dACC/aMCC is
in cognition.17 The dACC/aMCC activated by itch stimuli may
play a role in the cognition of itch stimuli and desire to scratch.
The insular cortex (IC) is also activated by itch stimuli. The
anterior and posterior parts of the IC have different roles
(Fig. 3). The anterior part is more engaged in emotion and sub-
jective feeling, while the posterior part is mainly associated
with the perception of affective bodily feeling (e.g. pain, cold,
thirst).18 This concept is partly supported by clinical studies in
762
which lesions in the anterior part of the IC (aIC) caused a defi-
cit in emotional awareness (e.g. alexithymia), while those in the
posterior part of the IC (pIC) induced loss of bodily feeling (e.g.
anosognosia).19,20 Several previous itch studies reported acti-
vation in both parts of the IC,7,9,10,21–23 suggesting that it may
be associated with awareness of the emotional state and bod-
ily feeling in itch perception.
In previous brain imaging studies, subjects were instructed
not to scratch the skin at the site where the itch sensation was
evoked while measuring brain activity. Many brain regions
associated with movement such as the supplementary motor
area (SMA), premotor cortex (PM), primary motor cortex (MI),
striatum and cerebellum were found to be active during itch
stimuli.6,7,9,10,21,22,24–28 This activation may reflect motor prepa-
ration for scratching and the desire to scratch.
A MEG study previously reported that the precuneus was
sensitive to itch stimuli (Fig. 2). This region has also been
observed in other brain imaging studies on itch.7,10,29 On the
other hand, previous pain or tactile studies using MEG and
EEG did not report responses in the precuneus.30–39 A large
number of PET and fMRI studies have investigated the cerebral
mechanism of pain, with few of them observing activation of
the precuneus during pain stimuli.40–43 Some differences may
exist in parietal processing between itch and pain. However,
the precise role of the precuneus in somatosensory processing
currently remains unclear. Some neuroimaging studies on pain
previously reported that the precuneus was associated with
empathy for pain, pain hallucination and the modulation of pain
by hypnosis, implying that the precuneus may partly be associ-
ated with the subjective sensation of pain and itch.44–48 The
precuneus was shown to be activated when attention shifted in
a certain direction and during a motor imagery task that
included spatial information such as moving eyes, hands, arms
Prec
PAG
Figure 2. The anatomical location of the cingulate cortex, pre-
cuneus (Prec), periaqueductal gray matter (PAG). The rostral
part of the anterior cingulate cortex (rACC)/anterior part of the
midcingulate cortex (aMCC), Prec and PAG are shown in the
sagittal view of the brain template implemented in the MRIcron
software (http://www.mccauslandcenter.sc.edu/mricro/).
© 2015 Japanese Dermatological Association

aIC aIC
BG BG
pIC pIC
Figure 3. The anatomical location of the insular cortex and
basal ganglia. The anterior part of the insular cortex (aIC), pos-
terior part of the insular cortex (pIC) and basal ganglia (BG) are
shown in the transverse view of the brain template imple-
mented in the MRIcron software (http://www.mccauslandcen-
ter.sc.edu/mricro/).
and legs in certain directions.49–53 The itch sensation may
induce similar mental processes such as directing attention to
the itchy skin caused by the desire to scratch. This mental
component may be associated with activation of the precu-
neus during itch stimuli. Further studies are needed in order to
elucidate the role of this region in itch perception.
CEREBRAL RESPONSE TO ACUTE ITCH IN
CHRONIC ITCH PATIENTS
Chronic itch is associated with several medical conditions
including dermatological, systemic, neurological and psycho-
genic diseases, and is idiopathic in many cases.54 It affects
millions of people worldwide, and is considered a global health
problem.55–58 Severe itch and pathological scratching behavior
represent significant problems for chronic itch patients, dimin-
ishing their quality of life. However, only a few functional brain
imaging studies have been conducted on these patients. Two
studies previously investigated similarities and differences in
brain activation patterns associated with itch between patients
with atopic dermatitis and healthy subjects.8,28 These studies
reported an abnormality in the basal ganglia of chronic itch
patients (Fig. 3). One study reported significantly higher activity
in the basal ganglia for patients with atopic dermatitis, while
© 2015 Japanese Dermatological Association
Itch and brain
the other also observed significant activation of this area in
patients with atopic dermatitis, but not in healthy controls. A
voxel-based morphometry study previously reported that the
density of gray matter in the basal ganglia was higher in
patients with end-stage renal disease pruritus.59 The basal
ganglia are associated with motor control and motivation.
Excessive scratching and habitual scratching are common in
chronic itch patients. These behaviors may be partly associ-
ated with enhanced activity and an increase in the density of
gray matter in the basal ganglia. An fMRI study investigated
how different brain regions functionally interacted in patients
with atopic eczema,60 and demonstrated that functional con-
nectivity in several brain regions was significantly lower during
itch stimuli than during the resting condition. Because this
study selected limited brain regions to investigate functional
connectivity, other brain regions may show increased func-
tional connectivity. A difference may exist in functional connec-
tivity between healthy subjects and chronic itch patients, which
may provide useful information to better understand the patho-
physiology of chronic itch.
CONTAGIOUS ITCH
The itch sensation may be evoked simply by discussing a topic
associated with itch or viewing others in itch. Niemeier et al.61
investigated whether scratching behavior was evoked in those
situations. Two different conditions were used: an itch-inducing
lecture including pictures of insects, scratch marks and allergic
reactions, while the other condition focused on relaxation. They
found that scratching behavior was more robust during the
itch-inducing lecture than during the relaxation lecture. Other
studies reported similar findings.62,63 Two previous studies
investigated the cerebral mechanism underlying contagious
itch using fMRI,64,65 and demonstrated that several brain
regions including the IC, SMA, PM and prefrontal cortex were
activated while viewing others experiencing the itch sensation.
Moreover, it was reported that functional connectivity between
the IC and basal ganglia significantly increased during imagery
of itch.65 The IC is associated with emotional processing, while
the basal ganglia is associated with the motivation to act. This
functional coupling may play an important role in triggering
scratching response or urge to scratch by viewing others in
itching and the imagery of itch.
ITCH SUPPRESSION AT THE SPINAL AND
SUPRASPINAL LEVEL
The itch sensation is suppressed by applying counter stimuli
including painful and scratching stimuli. A previous study
reported that itch suppression was observed even though
these counter stimuli were applied far from the itchy site.66
This finding suggested that the central nervous system may
also be associated with itch suppression, and was subse-
quently investigated by animal studies.67,68 These animal stud-
ies recorded neural activity from the spinal cord when animals
perceived the itch sensation and observed that the neural
activity associated with itch was suppressed during and after
763
H. Mochizuki and R. Kakigi

scratching. Akiyama et al.68 reported that scratching was 50%
less effective in reducing neuronal firing after transection of the
upper cervical spinal cord, and that scratching still reduced
neuronal firing (by 24%), but to a lesser degree than before
transection. This finding demonstrated that top-down modula-
tion from the supraspinal level played a major role in itch sup-
pression. A human PET study speculated that an activation of
descending pathway from the periaqueductal gray matter
(PAG) may induce itch relief in humans.26 Carstens69 reported
that excitation of the PAG inhibited the neural firing associated
with itch at the spinal level. The descending inhibitory pathway
from the PAG70 may be associated with the itch suppression
(Fig. 2). By contrast, an fMRI study reported deactivation of
the PAG during scratching.71 Based on this finding, this study
suggested that an opposite effect operates in itch modulation
during scratching. That is, deactivation of the PAG may be a
key factor in itch modulation by scratching. A more detailed
investigation is needed in order to clarify whether the PAG is
associated with itch modulation. Acupuncture may also reduce
the itch sensation. An fMRI study indicated that acupuncture-
induced itch relief was associated with the modulation of itch-
related neural activity, in particular in the putamen.72
PLEASURE OF SCRATCHING AND THE
REWARD SYSTEM
Scratching suppresses the itch sensation. At the same time, it
evokes a pleasurable sensation. Pleasure is one of the factors
to reinforce and motivate this behavior. Thus, this pleasurable
sensation may induce excessive scratching. However, it cur-
rently remains unclear why scratching an itch is pleasurable
and can induce excessive scratching. Two fMRI studies inves-
tigated these issues.23,71 One study reported that activity in the
reward system including the striatum and midbrain was signifi-
cantly higher when the pleasurable sensation was evoked by
scratching than when the pleasurable sensation was not
evoked by scratching (Fig. 4c). The other study demonstrated
that activity in the reward system while scratching an itch posi-

z = –29 z = –13 z = –8 z=0 z = 10 z = 36 z = 52

(a) Pleasant R

(b) Control

IC IFG/PM
Striatum MCC
PM SMA

(c) P>C

Midbrain Thalamus S1
Cb

Figure 4. Brain activity during scratching. (a) Brain activity during scratching itchy skin (pleasant condition). (b) Brain activity during
scratching far from itchy skin (control condition). (c) Brain regions that showed significantly higher activity in the pleasant condition
compared with the control condition (P > C). Cb, cerebellum; IC, insular cortex; IFG, inferior frontal gyrus; MCC, midcingulate cor-
tex; PM, premotor cortex; S1, primary somatosensory cortex; SMA, supplementary motor area.23

764 © 2015 Japanese Dermatological Association


tively correlated with the perceived pleasurable sensation.71
The reward system is the key structure of hedonic experi-
ences,73–78 suggesting that this system also plays an important
role in scratching-induced pleasurability. The midbrain is rich in
dopaminergic neurons,79 which send projections to several
areas including the striatum and regulate dopamine levels in
the innervated areas.79,80 Dopaminergic neurons are activated
by pleasurable stimuli.73,75,77,81–89 Dopamine may be associ-
ated with scratching-induced pleasurability. Previous studies
have observed that motor-related regions such as the SMA,
PM and cerebellum were activated during scratching.10,23
However, subjects did not perform any movement including
scratching during fMRI measurements in these studies. Thus,
the significant activation of motor-related regions were inde-
pendent of movement. Animal and human studies have dem-
onstrated that activity in motor-related regions positively
correlates with motivation and craving.90–93 One possible inter-
pretation of the activations in the motor-related regions
observed in previous studies is that scratching itchy skin
unconsciously or consciously induces a different type of desire
such as the desire to scratch to achieve further pleasantness,
which may be associated with the excessive scratching
induced by pleasurable sensations.
FUTURE PROSPECTS
Brain imaging studies previously demonstrated that many brain
regions were activated by itch stimuli including key regions for
processing perception, emotions and motivation to act. How-
ever, these regions are not specific to itch. The same brain
regions are also activated by painful stimuli.94,95 How are itch
and pain perceived as different sensations? Unfortunately,
there is no clear answer. There may be itch-specific neurons.
Spatial resolution of MRI is not sufficient to measure neural
activity in a single neuron. An animal study may be more
appropriate for exploring this possibility. A previous study
reported that a functional network may be important for under-
standing differences in perceptions between itch and pain.96
Detailed investigations with different approaches are needed to
answer these questions. Itch-specific neural factors (e.g. neu-
rons, brain regions or networks) may be potential targets that
can selectively reduce the itch sensation, which will ultimately
lead to the development of novel therapies for itch. The patho-
physiology of chronic itch largely remains unclear. Previous
brain imaging studies have observed abnormal activities and
anatomical changes in itch-related brain regions in chronic itch
patients. It is unclear whether these abnormalities are causes
of severe itch and pathological scratching behavior in chronic
itch patients. To address this issue will provide useful informa-
tion to advance our understanding of the pathophysiology of
chronic itch.
Physical and psychological factors can modulate itch. Previ-
ous brain imaging studies have investigated some of them. How-
ever, some other important factors have not been investigated
as yet. For example, stress is a significant factor that exacer-
bates or leads to development of chronic itch. Stress affects the
autonomic nervous and immune systems. The control center of
© 2015 Japanese Dermatological Association
Itch and brain
these systems in the brain such as the hypothalamus may be
associated with stress-induced exacerbation or development of
chronic itch. Distraction of attention can reduce the itch sensa-
tion. An fMRI study have suggested that analgesic effect caused
by distraction of attention is associated with descending inhibi-
tory system.97 The same system may be associated with itch
reduction by distraction of attention. Psychological interventions
(e.g. relaxation training) is effective for treatment of chronic itch
recently.98–101 This important theme should also be addressed in
future brain imaging studies.
CONFLICT OF INTEREST: There is no conflict of interest.
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