premonitory urges and sensorimotor processing in tourette syndrome
TRANSCRIPT
Behavioural Neurology 27 (2013) 65–73 65DOI 10.3233/BEN-120308IOS Press
Premonitory urges and sensorimotorprocessing in Tourette syndrome
Sangeerthana Rajagopala, Stefano Serib and Andrea Eugenio Cavannaa,c,∗aThe Michael Trimble Neuropsychiatry Research Group, Department of Neuropsychiatry, BSMHFT and Universityof Birmingham, Birmingham, UKbSchool of Life and Health Sciences, Aston Brain Centre, Aston University, Birmingham, UKcSobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology and UniversityCollege London, London, UK
Abstract. Most patients with Tourette syndrome report characteristic sensory experiences (premonitory urges) associated withthe expression of tic symptoms. Despite the central role of these experiences to the clinical phenomenology of Tourette syndrome,little is known about their underlying brain processes. In the present article we present the results of a systematic literature reviewof the published studies addressing the pathophysiological mechanisms of premonitory urges. We identified some preliminaryevidence for specific alterations in sensorimotor processing at both cortical and subcortical levels. A better insight into the braincorrelates of premonitory urges could lead to the identification of new targets to treat the sensory initiators of tics in patients withTourette syndrome.
Keywords: Tourette syndrome, tics, premonitory urges, sensori-motor processing, pathophysiology
1. Introduction
Tourette syndrome (TS) is a highly prevalent neu-ropsychiatric disorder, estimated around 1% in school-age children [1]. According to DSM-IV criteria, theonset of tics is before 18 years of age, typically 3–8 years for motor tics and 11 years for phonic tics [2,3], lasting at least a year. Multiple motor and vocaltics vary in localisation over time and peak in sever-ity at around 10–12 years [4–6]. Interestingly, althoughfirst described and popularised by Georges Gilles de laTourette, an earlier publication by Armand Trousseauseems to offer a description which is more represen-tative of our modern day TS construct with minimalsampling bias [7]. In clinical practice the distinctionbetween tics and habits or repetitive behaviours can bechallenging, as all are characterised by various levelsof awareness and volitional control [8].
∗Corresponding author: Prof. Andrea Eugenio Cavanna, MDPhD, Department of Neuropsychiatry, The Barberry National Cen-tre for Mental Health, Birmingham B15 2FG, UK. Tel.: +44 1213012317; Fax: +44 121 3012291; E-mail: [email protected].
Premonitory urges (PUs) are not part of the DSM-IVcriteria for TS despite the vast majority of patients(77% of patients over 13 years) experience these symp-toms [9–12]. PUs, also called sensory tics, are de-scribed as focal or generalised intrusive feelings or sen-sations driving the individual to seek relief throughperformance of movements (motor tics) or vocali-sations (vocal tics) [13–16]. A study by Leckmanet al. [17] found 10 years to be the mean age ofPUs awareness, averaging 3 years after tic onset. Theawareness latency is suggested to reflect a transitionof the processing of sensory information to consciousawareness [18,19]. Studies with the Premonitory Urgefor Tics Scale (PUTS), a psychometric tool specificallydeveloped to measure the severity of PUs [20,21], havehighlighted that awareness of PUs can be a matura-tional process, independent of tic onset. The most fre-quently reported localisations of PUs are the palms,shoulders and throat, although 40% of patients localisethem exclusively in the muscle, and the remainders intheir joints or skin. The percentage of patients with TSor other chronic tic disorders experiencing PUs variesdepending on how the urge is defined [21–23].
ISSN 0953-4180/13/$27.50 c© 2013 – IOS Press and the authors. All rights reserved
66 S. Rajagopal et al. / Premonitory urges and sensorimotor processing in Tourette syndrome
It has been proposed to categorise PUs as sensory(SUs), cognitive (CUs) or autonomic urges (AUs) [24].SUs are focal or generalised muscular-skeletal orvisceral-sensations, whereas CUs are feelings of in-completeness or ‘just-right’ perceptions and AUs over-lap with symptoms of autonomic dysfunction, such assweating, palpitations and nausea. Interestingly, urgescan also be bound to external stimuli e.g. in auto-mutilatory tics where specific angulation of objects cantrigger tics, which are characteristically suggestibleby both audio and visual cues [3]. The exact roleand significance of PUs is at present unknown. It hasbeen postulated that they could reflect subjective ex-periences of neural dysfunction below tic-productionthreshold or heightened attention to physical sensa-tions [8]. PUs may be an illumination of fragments ofinnate behaviour, closely involved in the orchestrationof behavioural programmes. Central to this idea is thebinding role of the basal ganglia to allow movementexecution in sight of convergent information from thefunctionally distinct cortico-subcortical circuits, whichcan account for the heterogeneity of TS symptoms [25,26].
Importantly, about 90% of patients with TS can alsopresent with co-morbid behavioural problems, mainlyattention-deficit and hyperactivity disorder (ADHD),obsessive-compulsive disorder (OCD), affective dis-orders and impulse control disorders [27–29]. Withthis in mind, clinical subdivisions may be appropriate,from ‘pure TS’ (simply motor and vocal tics) to ‘full-blown TS’ (tics plus coprophenomena, echopenomenaand/or paliphenomena) and ‘TS-plus’ (with psychi-atric co-morbidities) [30]. PUs have been reported tocause more distress to patients with TS than tics, whichappear semi-voluntary in response to inner urges [4,31–33]. Self-awareness of these subjective symptomscould improve the ability to suppress tics, as shownby the effectiveness of behavioural strategies for ticcontrol such as exposure and response prevention andhabit reversal therapy [17,34,35].
Due to their intrinsic subjectivity the neural corre-lates of PUs are difficult to investigate. However a bet-ter understanding of their pathophysiology might havesignificant clinical implications. In the present articlewe present the results of a systematic literature reviewof the published studies addressing the pathophysio-logical mechanisms of PUs.
2. Methods
We conducted a systematic literature review accord-ing to the Prisma guidelines [36] using the search terms
‘tic∗’, ‘tourett∗’, ‘anxiety’, ‘mechanism’, ‘urge∗’, ‘sen-sor∗’ across the scientific databases EMBASE, HMIC,Medline and PsycINFO. We excluded from the re-view studies that did not focus on human subjects andall non-English literature. Additional relevant publica-tions were identified by snowballing reviewed papers;“grey” literature was retrieved from Google searchesusing the above-mentioned search terms.
3. Results
Our systematic literature review identified five stu-dies specifically focussing on the pathophysiology ofPUs in patients with TS and these are summarised inTable 1. Two articles were neurophysiological studies(focussing on the Bereitschaftspotential and Somato-sensory Evoked Potentials respectively), two were neu-roimaging studies (structural and functional magneticresonance imaging) and one was a recent review paper.
4. Discussion
4.1. The pathophysiology of premonitory urges
Despite their central role in subjective tic phe-nomenology, PUs have received little attention and fewstudies have focused on this intriguing phenomenonin patients with TS. The reviewed literature high-lights several hypotheses on the pathophysiologicalbases of PUs. Converging evidence supports the pres-ence of sensory gating dysfunction. Specifically, gat-ing dysfunction in TS may cause excessive inflowof somatosensory information, possibly generatingPUs by acting on particular cortico-striatal synapsesthrough LTP and increasing SMA activation. Abnor-mal dopamine function seems also to be implicated.Dopamine transporter hyperactivity can play a cen-tral role, as dopamine can have relevant effects onparticular cortico-striatal synaptic strengths. Moreover,the striosomal compartment of the striatum is inter-connected with limbic structures and can modulatematrix activity via dopaminergic neurons from thesubstantia nigra-pars compacta (SNpc), influencingmotivation-based behaviour. Of note, there is consider-able overlap with the neurobiological bases of rewardexperiences, which involve the mesolimbic dopamin-ergic system and prefrontal cortical regions interlinkedwith the ventral striatum. Anatomically, convergenceand topographical organisation of functionally related
S. Rajagopal et al. / Premonitory urges and sensorimotor processing in Tourette syndrome 67Ta
ble
1
Stud
ies
onth
epa
thop
hysi
olog
yof
prem
onito
ryur
ges
inpa
tient
sw
ithTo
uret
tesy
ndro
me
Stud
yA
imH
ypot
hese
sge
nera
ted
from
stud
yPa
rtic
ipan
tsM
ain
findi
ngs
Lim
itatio
ns
Dug
gale
tal
.,20
02[3
1]
Toin
vest
igat
eB
Ps(a
sses
sed
usin
gE
MG
and
EE
Gre
cord
ings
)as
am
easu
reof
PUs
BPs
may
beaf
fect
edby
dopa
min
ergi
cdy
sfun
ctio
nw
ithin
cort
ico-
stria
tal
circ
uitr
ies
2T
S+O
CD
,1
CT
DTi
csar
em
ore
sim
ilar
toin
tent
iona
lra
ther
than
re-
spon
sive
mov
emen
ts,b
utst
illno
tpur
ely
volu
ntar
yas
BPs
onse
tla
tenc
yw
assh
orte
ned
inal
lpa
tient
s.B
Psca
nbe
used
asa
mar
kero
fPU
s
–N
oco
ntro
lgro
up–
Smal
lsam
ple
size
–Po
ssib
leco
nfou
ndin
gro
leof
co-
mor
bid
OC
D(P
Us
mor
epr
eva-
lent
inpa
tient
sw
ithT
S+O
CD
)–
Did
not
com
pare
findi
ngs
with
BPs
asse
ssed
invo
lunt
ary
mov
e-m
ent
Sow
elle
tal.,
2008
[63]
Toas
sess
corti
cal
thin
ning
inre
latio
n-sh
ipw
ithtic
seve
rity
usin
gT
1-w
eigh
ted
MR
I
Spec
ific
cort
ical
chan
ges
may
beas
soci
ated
with
TS
25T
S(9
TS+
AD
HD
/OC
D),
25ag
ean
dse
xm
atch
edco
ntro
ls
Patie
nts
with
TS
have
sign
ifica
ntco
rtic
alth
inni
ngin
bila
tera
lve
ntra
lfr
onta
lco
rtex
e.g.
vent
ral
pre
and
post
cent
ralg
yri.
Thi
nnin
gof
infe
riorl
eftp
rimar
yse
n-so
ryco
rtex,
tem
pora
lan
dpa
rieta
lco
rtice
sno
tfou
ndin
youn
ger
child
ren
butp
rese
ntin
olde
rch
ildre
nan
dad
oles
cent
s.C
orre
latio
nsbe
twee
nw
orst
ticse
veri
ty(a
spe
rY
GT
SS)
and
cort
ical
thic
knes
sw
ere
sign
ifi-
cant
inth
edo
rsal
fron
talc
orte
xbi
late
rally
,lef
tdor
sal
parie
tal
lobe
s,pr
e-an
dpo
st-c
entr
algy
ri,
right
ven-
tral
fron
tal
corte
xan
dri
ght
tem
pora
lco
rtex.
Gre
ym
atte
rth
inni
ngw
ithin
sens
ory
area
sof
the
fron
to-
subc
ortic
alci
rcui
try,
with
exte
nsio
nto
fron
tal
and
parie
talc
ortic
es,m
aybe
rela
ted
toPU
sge
nera
tion
–C
orre
latio
nsw
ithtic
seve
rity
(YG
TSS
scor
es)
rath
erth
anPU
sse
verit
y
Boh
lhal
tere
tal
.,20
06[4
2]
Toas
sess
patte
rns
ofbr
ain
activ
itybe
fore
and
durin
gtic
expr
es-
sion
and
imita
tion
usin
gev
ent-
rela
ted
fMR
I
SMA
,AC
C,p
oste
rior
puta
men
activ
atio
npr
ior
totic
sm
ayin
part
bere
spon
sibl
efo
rPU
sge
nera
tion
10T
S,4
TS+
OC
D,
2T
S+A
DH
D
Bef
ore
ticon
set,
prem
otor
and
SMA
show
edm
ost
sign
ifica
ntac
tivity
,alo
ngw
ithan
terio
rcin
gula
ted
cor-
tex
(AC
C),
insu
lar
regi
on,
post
erio
rpu
tam
en,
pari-
etal
oper
culu
man
dve
ntro
late
ral
thal
amus
.The
irac
-tiv
ityre
cede
don
initi
atio
nof
ticm
ovem
ent.
Att
icon
-se
t,m
osts
igna
lcam
efr
omse
nsor
imot
or,c
ereb
ellu
man
dD
LPF
C.
The
SMA
,A
CC
insu
lar
and
thal
amus
seem
tobe
invo
lved
inur
gege
nera
tion.
The
pari
etal
oper
culu
mm
ayal
low
inte
grat
ion
ofvi
scer
alan
dso
-m
atos
enso
ryin
form
atio
nth
roug
hits
conn
ectio
nsw
ithth
eA
CC
and
mot
orre
gion
s
–A
stic
sar
ehi
ghly
sugg
estib
le,
tics
perf
orm
edin
the
scan
ner
may
bedi
ffer
ent
from
thos
eex
-pr
esse
din
the
ever
yday
envi
ron-
men
t
68 S. Rajagopal et al. / Premonitory urges and sensorimotor processing in Tourette syndrome
Tabl
e1,
cont
inue
d
Stud
yA
imH
ypot
hese
sge
nera
ted
from
stud
yPa
rtic
ipan
tsM
ain
findi
ngs
Lim
itatio
ns
Miy
azak
i,20
07[6
2]To
inve
stig
ate
SEP
usin
gm
edia
nne
rve
stim
ulat
ion
inch
il-dr
enw
ithA
DH
Dan
dtic
diso
rder
s
AD
HD
and
ticdi
sord
ers,
both
bein
ghy
perk
inet
icdi
sord
ers,
may
have
com
mon
som
atos
enso
rypa
thol
ogy
18A
DH
D,
18tic
diso
rder
s(1
0T
S),
10he
alth
yco
n-tr
ols
7/18
child
ren
with
AD
HD
and
9/18
child
ren
with
ticdi
sord
ers
had
SEP
abno
rmal
ities
,e.
g.la
tenc
yor
ampl
itude
devi
atio
ns.
Peak
-to-p
eak
late
ncie
sw
ere
mos
tlyre
duce
dan
dpe
akam
plitu
des
wer
egr
eate
rth
anco
ntro
ls.T
hese
findi
ngs
sugg
esth
yper
activ
ese
n-so
rim
otor
fron
to-s
ubco
rtic
alci
rcui
tlo
ops,
cons
iste
ntw
ithPU
sym
ptom
olog
y.T
hehi
ghSE
Pam
plitu
des
seem
tobe
asso
ciat
edw
ithsh
orte
dco
rtic
alsi
lent
pe-
riod,
sugg
estiv
eof
mot
orin
hibi
tion
dysf
unct
ion
–In
clud
edal
ltic
diso
rder
s,no
tjus
tT
S
Jack
son
etal
.,20
11[6
5]
Toin
vest
igat
eco
m-
paris
ons
betw
een
path
olog
ical
urge
s(e
.g.i
nT
S)an
dev
ery-
day
urge
sle
adin
gto
phys
iolo
gica
lsp
onta
-ne
ous
mov
emen
t(e.
g.ya
wni
ng,s
wal
low
ing)
Urg
esto
perf
orm
mov
e-m
entm
aybe
rela
ted
toth
est
reng
thof
affe
rent
sth
atle
adto
awar
enes
sof
urge
s
Syst
emat
iclit
era-
ture
revi
ewon
the
urge
-for
-act
ion
Con
verg
ing
evid
ence
sugg
ests
that
the
insu
lar
corte
xan
dci
ngul
ate
corte
xm
aybe
invo
lved
inPU
gene
ra-
tion.
The
insu
lar
corte
xre
gist
ers
whe
ther
the
urge
for
anac
tion
issa
tisfie
dw
here
asth
ein
sula
rco
rtex,
basa
lga
nglia
and
cing
ulat
eco
rtex
are
invo
lved
inre
war
dex
perie
nce
follo
win
gur
gesa
tisfa
ctio
n
–fM
RIs
resu
ltsar
edi
fficu
ltto
com
pare
betw
een
diff
eren
tst
ud-
ies
Abb
revi
atio
ns.
BPs
=B
erei
tsch
afts
pote
ntia
ls,
EM
G=
Ele
ctro
myo
grap
hy,
EE
G=
Ele
ctro
ence
phal
ogra
phy,
PUs=
Prem
onito
ryU
rges
,T
S=
Tour
ette
Synd
rom
e,O
CD
=O
bses
sive
-C
ompu
lsiv
eD
isor
der,
CT
D=
Chr
onic
Tic
Dis
orde
r,M
RI=
Mag
netic
Res
onan
ceIm
agin
g,A
DH
D=A
ttent
ion-
Defi
cit
Hyp
erac
tive
Dis
orde
r,Y
GT
SS=
Yal
eG
loba
lTi
cSe
veri
tySc
ale,
fMR
I,=
Func
tiona
lMR
I,SM
A=S
uppl
emen
tary
Mot
orA
rea,
AC
C=
Ant
erio
rC
ingu
late
Cor
tex,
DL
PF=D
orso
-Lat
eral
Pref
ront
alC
orte
s,SE
P=
Som
atos
enso
ryE
voke
dPo
tent
ials
.
S. Rajagopal et al. / Premonitory urges and sensorimotor processing in Tourette syndrome 69
cortico-striatal projections entertain particular striatalregions while impressing functional subdivision of thestriatum. The dorsolateral striatum is predominantly‘somatosensory’-related , the intermediate portion ‘as-sociative’ and the ventromedial ‘limbic’, which allowsthese areas to be implicated in different aspects ofmovement and complex behaviour [37,38].
4.2. Sensorimotor gating
The most accredited pathophysiological theory em-erging from this review, suggests that PUs are the ex-pression of a ‘sensorimotor gating’ dysfunction. Sen-sorimotor gating is responsible for the modulation inthe allocation of neural resources in the presence ofcompeting sensory and cognitive information from themultitude present in the environment [39]. When pre-motor and prefrontal cortices initiate a motor pattern,the striatum may allow initiation if agreeable with ac-tivity of other convergent corticostriatal inputs, whilesuppressing competing motor programmes. Therefore,basal ganglia may be involved in selection of mo-tor and behavioural patterns within appropriate con-text [40] via this gating mechanism. One study [37]found that externally paced movement created in-creased activity in the anterior caudate-putamen, a pos-sible pivotal site for this ‘gate’ mechanism. Addition-ally, electrical stimulation of the SMA in non-TS in-dividuals produced an urge to move (n = 13) or un-usual sensations (n = 9) [41]. This suggests SMA’sinvolvement in movement intentions, especially as theSMA and the anterior cingulate cortex (ACC) havedense dopaminergic projections from midbrain struc-tures such as the substantia nigra (SN) and its acti-vation prior to tic onset can potentially generate PUsvia limbic-motor connections [42]. In relation to thesepathways, other results show low metabolic activity ofthe ventral striatum and limbic regions and increasedactivity in SMA and sensory association regions [5].
4.3. Structured event complexes
The orbitofrontal-cortex (OFC) is typically associ-ated with social behaviour, emotion and reward, andhas been proposed to interact with BG in reward learn-ing. Via sensorimotor gating, the BG can favour initi-ation of particular ‘cognitive pattern generators’ in thecortex [43]. Through reinforcement by dopamine influ-encing long-term-potentiation (LTP) [44] of particularsynapses, gating can activate rewarding behaviour. Theamygdala, coding for stimulus intensity, also appears
to be involved. The prefrontal cortex (PFC) appears tohave ‘structured event complexes’ (SECs)/behaviouralpatterns that are hierarchical in nature. In OCD mod-els, the ACC seems to play an important role for mo-tivation and error processing in calculation of dispari-ties between expected and gained reward [43]. There-fore, motivation to complete a SEC could be processedthrough communication between reward regions suchas the OFC, activation threshold assigned by the BG,error calculation by ACC and emotional importanceby limbic areas. However, prevention from perform-ing SECs is punishing and this punishment is only re-moved once the behaviour is completed. In OCD mod-els, little relief is experienced because of ACC sig-nalling incomplete behaviour, OFC punishment, anxi-ety generated in limbic structures and the BG reducingthresholds for compensating SECs. This ‘feeling of in-completion’ of SECs causes an obsession to gain relieffrom anxiety. However, in OCD, only a small propor-tion of the full reward is experienced. A similar pro-cess may occur to generate PUs in TS: tics may oc-cur because of the reduced inhibitory BG output be-cause of its reduced threshold possibly due to fewerinhibitory-interneurons [45] and low metabolic activ-ity [5]. The cognitive-psychophysiological model ofTS [8] suggests that patients with TS have particularcognitive styles governing ‘correct’ manners to under-take and organise activities - a perfectionist style. Thismechanism, together with physiologically heightenedsensory awareness, creates tendencies to attempt toomuch and reduced relaxation, paralleling ADHD [46].This in turn creates conflicts between what should beundertaken and what is being done, diminishing feel-ings of achievement [8].
Interestingly, it seems that PUs may not be the onlymanifestation of fronto-striatal dysfunction in TS. Aninvestigation undertaken by Eddy et al. [47] into exec-utive function and Theory of Mind in TS revealed alter-ations in these functions generated by the frontal cor-tex. Patients and controls were assessed for reticenceand verbal fluency in various tasks such as evaluat-ing mental states by looking at images of faces, un-derstanding types of humour and other decision pro-cesses. On comparison with controls and even with ex-clusion of co-morbid OCD, performance in TS was re-duced, suggesting dissociation between ventromedialprefrontal cortex and the striatum. The results of differ-ent studies corroborate these findings [48,49]. More-over, an MRI study by Draganski et al. [50] foundadults with TS to have anterior cingulate, ventrolat-eral prefrontal and orbitofrontal grey matter volume re-
70 S. Rajagopal et al. / Premonitory urges and sensorimotor processing in Tourette syndrome
duction. Reduced grey matter in orbitofrontal region isthought to be related to reduced impulse control andbehavioural inhibition, which are known features ofTS [30]. Draganski et al. also found increased dorso-lateral putamen volume bilaterally, especially in thesubgroup of patients with TS+ADHD, and increasedthickness in the left primary somatosensory cortex,with a significant correlation to PU severity as mea-sured by the PUTS scores. PU sensory informationtriggering motor tics could potentially result in in-creased volume evidenced in the dorsolateral putamenvia plastic remodelling through dorsolateral putamenconnections to sensorimotor areas allowing ‘sensory-guided’ movement. Additionally, neuroleptic exposurecould also result in striatal volume increases, and in-creased thickness of somatosensory cortex can be re-lated to increased myelin thickness [51]. This sug-gests that PUs may impose greater functional demandsfor integration into motor responses (tics), allowingplasticity-mediated volume change. Alternatively, re-duced parietal operculum (a secondary somatosensoryregion) thickness may cause ‘rerouting’ of its demandsto the somatosensory cortex as a compensatory mech-anism.
4.4. Prepulse inhibition
Weak stimuli preceding startle stimuli can causereduction in sensitivity to sensory stimuli, resultingin reduced startle reflex magnitudes . This is termedprepulse inhibition (PPI) and is thought to be linkedwith basal ganglia’s role in sensorimotor gating pro-cesses, shaped by genetic, developmental and hor-monal factors [39]. Reduced PPI in TS appears to cor-relate with the presence of interfering cognitive, mo-tor and sensory information [52]. Interestingly, thisis not specific to TS, but is also found in other neu-ropsychiatric conditions, e.g. Huntington’s disease andschizophrenia [22]. On prepulse+pulse experiments,mixed D1/D2 agonist apomorphine increased the star-tle magnitude and reduced PPI, possibly reflectinggenetic differences in D1 and D2 receptor sensitiv-ity [39]. Converging evidence suggests that brain struc-tures involved in PPI may incorporate parallel connec-tions involving limbic areas, ventral striatum and pal-lidum, with the cortical-subcortical projections over-lapping the startle circuit at the level of the reticularispontis caudalis [53]. Lesions of the dorsal striatum (so-matosensory component) have also been shown to re-sult in PPI reduction [54]. The PPI model suggests par-allels between tics and adapted startle reflexes [55], in
line with the learning model of TS [47], where distress-ing events may create a reflex which later develops intoa reinforced tic [56].
4.5. The dopamine transporter system
Overactivity of the dopamine transporter system ap-pears to be consistently implicated in PUs genera-tion [57]. A study using amphetamine challenge in 7patients with TS found that mean putamen intrasy-naptic dopamine levels were increased by 21% [58].However, PET scans revealed no significant differ-ences between D2-receptors density between TS andcontrol brains. This may be explained by low tonic(basal) DA-levels, presynaptically regulated by D2 andD3-receptors (autoreceptors). Findings of low extras-triatal D2 receptors could also point to tonic/phasicdopamine dysfunction [59]. These findings are consis-tent with the clinical observations of tic exacerbationstriggered by environmental stimuli (e.g. stress and anx-iety), leading to increased phasic dopamine releaseand orbitofrontal and mesolimbocortical dopaminerg-ergic dysfunction. From a developmental perspective,aberrant habits can result from imbalances betweendorsolateral-somatosensory, intermediate-associativeand ventromedial-limbic striatum. These abnormalitiesin the prefrontal-ventral-striatal circuitry can in turncause inappropriate behavioural or motor sequence ex-pression, subjectively experienced as PUs.
4.6. Striatal tonically active neurons
Striatal tonically active neurons (TANs) are thoughtto play a key role in the application of motivationalcontexts to conditioned sensory-instigated behaviour,executed on anticipation of reward [57,66]. These neu-rons are cholinergic interneurons which are activatedby expectation of reward. Interestingly, TANs in thecaudate and putamen appear to differ in their encod-ing of motivational outcomes: they can influence mo-tivation for behaviour, ‘go-response’ for actions withexpected motivational contexts, or both, thus allowinganticipation of rewarding or undesirable circumstanceswith initiation of ‘goal-directed behaviour.’ Addition-ally, TANs are responsive to dopaminergic SNpc in-puts, which is a likely participant in reward calcula-tions with inputs from the thalamus [60,64]. Withinthe context of sensorimotor gating dysfunction in TS,TANs may facilitate formation of abnormal motiva-tional contexts for reward anticipation leading to PUs.Fast-spiking-GABA-interneurons (FSNs) can also be
S. Rajagopal et al. / Premonitory urges and sensorimotor processing in Tourette syndrome 71
implicated, as they receive somatosensory cortex pro-jections. Synchronised oscillatory TAN and FSN fir-ing in conditioned behaviour can modify the activ-ity of their respective striatal projections and favourdopaminergic plasticity of particular striatal synapsespossibly involved in PUs generation. According to onehypothesis on the pathophysiology of TS, specific ma-trix interneurons may dissociate from normal oscil-latory rhythm and ‘besiege’ individuals with sensoryexperiences [36,46]. Both abnormal activity of stri-atal interneurons [45,60] and hyperpolarisation of par-ticular thalamocortical neurons coupled with irregularGPi firing, may interfere with normal cortical activ-ity and result in PUs as experienced by patients withTS [61]. However, the abnormal cortico-subcorticalloop activation may also be of cortical origin, con-sistent with shortened cortical silent period [60], ab-normal sensory-evoked potentials [62] and thinning ofpremotor and sensorimotor cortical areas [3,38,63].
4.7. Future perspectives
Further research is needed to better characterise andunderstand PUs in patients with TS. Little is knownabout specific PUs mechanisms underlying differenttic subtypes, e.g. whether PUs associated with com-plex or simple tics or tics in particular anatomical lo-cations have different pathophysiological substrates. Itis possible that different neural pathways are identifiedbetween different tic subtypes, beyond shared sensori-motor processes. Moreover, studies comparing mecha-nisms of PUs generation in TS to other disorders suchas OCD and schizophrenia may reveal more detailsabout pathophysiological differences, which could alsohave clinical implications in terms of effectiveness ofantipsychotic treatment. Investigations into asymmetryof basal ganglia structural changes in neurodevelop-mental disorders such as TS could reveal indications ofbrain maturation dysfunction. This could in turn haveimplications for structures involved in PUs generation.Likewise, investigation into whether dysfunctional de-velopment of selective cognitive abilities leads to PUawareness may be important. Finally, the possible re-lationship between PU severity and Bereitschaftspo-tential also deserves further research, in order to useneurophysiological evidence to better characterise theclinical distinction between voluntary and involuntaryactions in response to PUs.
References
[1] Robertson MM. The prevalence and epidemiology of Gillesde la Tourette syndrome: Part 1: The epidemiological andprevalence studies. J Psychosom Res. 2008: 65; 461-472.
[2] American Psychiatric Association. Diagnostic and StatisticalManual of Mental Disorders – Fourth Edition, Text Revision(DSM-IV-TR). American Psychiatric Press, 2000.
[3] Leckman JF. Phenomenology of tics and natural history of ticdisorders. Brain Dev. 2004: 25 Suppl; S24-S28.
[4] Albin RL, Mink JW. Recent advances in Tourette syndromeresearch. Trends Neurosci. 2006; 29: 175-182.
[5] Braun AR, Stoetter B, Randolph C, Hsiao JK, Vladar K, Gern-ert J, Carson RE, Herscovitch P, Chase TN. The functionalneuroanatomy of Tourette’s syndrome: An FDG-PET study. I.Regional changes in cerebral glucose metabolism differenti-ating patients and controls. Neuropsychopharmacol. 1993: 9;277-291.
[6] Tourette Syndrome Classification Study Group. Definitionsand classification of tic disorders. Arch Neurol. 1993; 50:1013-1016.
[7] Rickards H, Woolf I, Cavanna AE. Trousseau’s disease: A de-scription of Gilles de la Tourette syndrome 12 years before1885. Mov Disord. 2010; 25: 2285-2289.
[8] O’Connor K. A cognitive-behavioural/psychophysiologicalmodel of tic disorders. Behav Res Ther. 2002:40; 113-1142.
[9] Chee KY, Sachdev P. A controlled study of sensory tics inGilles de la Tourette syndrome and obsessive-compulsive dis-order using a structured interview. J Neurol Neurosurg Psy-chiatry. 1997; 62: 188-192.
[10] Cohen AJ, Leckman JF. Sensory phenomena associated withGilles de la Tourette’s Syndrome. J Clin Psychiatry. 1992; 53:319-323.
[11] Kwak C, Dat Vuong K, Jankovic J. Premonitory sensoryphenomenon in Tourette’s syndrome. Mov Disord. 2003; 18:1530-1533.
[12] Steinberg T, King R, Apter A. Tourette’s Syndrome: A Re-view from a Developmental Perspective. Isr J Psych Relat Sci.2010; 47: 105-109
[13] Bliss J, Cohen DJ, Freedman DX. Sensory experiences ofGilles de la Tourette syndrome. Arch Gen Psychiatry. 1980;37: 1343-1347.
[14] Bullen JG, Hemsley DR. Sensory experiences as a trigger inGilles de la Tourette’s syndrome. J Behav Ther Exp Psychia-try. 1983; 14: 197-201.
[15] Kurlan R, Lichter D, Hewitt D. Sensory tics in Tourette’s syn-drome. Neurology. 1989; 39: 731-734.
[16] Scahill LD, Leckman JF, Marek KL. Sensory phenomena inTourette’s syndrome. Adv Neurol 1995; 65: 273-280.
[17] Leckman JF, Walker DE, Cohen DJ. Premonitory urges inTourette’s syndrome. Am J Psychiatry. 1993: 150; 98-102.
[18] Banaschewski T, Woerner W, Rothenberger A. Premonitorysensory phenomena and suppressibility of tics in Tourette syn-drome: Developmental aspects in youth and adolescents. DevMed Child Neurology. 2003; 45: 700-703.
[19] Kane MJ. Premonitory urges as “attentional tics” in Tourette’ssyndrome. J Am Acad Child Adolesc Psychiatry. 1994; 33:805-808.
[20] Steinberg T, Schmuel Baruch S, Harush A, Dar R, Woods D,Piacentini J, Apter A. Tic disorders and the premonitory urge.J Neural Transm. 2010; 117: 277-284.
[21] Woods DW, Piacentini J, Himle MB, Chang S. PremonitoryUrge for Tics Scale (PUTS): Initial psychometric results and
72 S. Rajagopal et al. / Premonitory urges and sensorimotor processing in Tourette syndrome
examination of the premonitory urge phenomenon in youthswith tic disorders. J Dev Behav Pediatr. 2005: 26; 397-403.
[22] Sutherland Owens AN, Miguel EC, Swerdlow NR. Sensorygating scales and premonitory urges in Tourette syndrome. SciWorld J. 2011: 11; 736-741.
[23] Prado HS, Rosário MC, Lee J, Hounie AG, Shavitt RG,Miguel EC. Sensory phenomena in obsessive-compulsive dis-order and tic disorders: A review of the literature. CNS Spec-trums. 2008; 13: 425-432.
[24] Miguel EC, do Rosario-Campos M, Prado H, do Valle R,Rauch SL, Coffey BJ, Baer L, Savage CR, O’Sullivan RL,Jenike MA, Leckman JF. Sensory phenomena in obsessive-compulsive disorder and Tourette’s disorder. J Clin Psychia-try. 2000: 61; 150-156.
[25] Peterson BS, Skudlarski P, Anderson AW, Ahang H, Gat-nenby JC, Lacadie CM, Leckman JF, Gore JC. A func-tional magnetic resonance imaging study of tic suppression inTourette syndrome. Arch Gen Psychiatry. 1998; 55: 326-333.
[26] Tekin S, Cummings J. Frontal-subcortical neuronal circuitsand clinical neuropsychiatry: An update. J Psychosom Res.2002; 25: 647-654.
[27] Freeman RD, Fast DK, Burd L et al. An international perspec-tive on Tourette’s syndrome L selected findings from 3,500individuals in 22 countries. Dev Med Child Neurol. 2000; 42:436-447.
[28] Robertson MM. Tourette syndrome, associated conditions andthe complexities of treatment. Brain. 2000: 123; 425-462.
[29] Rosário MC, Prado HS, Borcato S, Diniz JB, Shavitt RG,Hounie AG, Mathis ME, Mastrorosa RS, Velloso P, Perin EA,Fossaluza V, Pereira CA, Geller D, Leckman J, Miguel E. Val-idation of the University of São Paulo Sensory PhenomenaScale: initial psychometric properties. CNS Spectrums. 2009;14: 315-323.
[30] Cavanna AE, Servo S, Monaco F, Robertson MM. The Be-havioural Spectrum of Gilles de la Tourette Syndrome. J Neu-ropsychiatry Clin Neurosci. 2009: 21; 13-23.
[31] Duggal HS, Nizamie SH. Bereitschaftspotential in tic disor-ders: A preliminary observation. Neurol India. 2002: 50; 487-489.
[32] Lang AE. Patient perception of tics and other movement dis-orders. Neurology. 1991; 41: 223-228.
[33] Moretto G, Schwingenschuh P, Katschnig P, Bhatia KP, Hag-gard P. Delayed experience of volition in Gilles de la Tourettesyndrome. J Neurol Neurosurg Psychiatry. 2011; 82: 1324-1327.
[34] Himle MB, Woods DW, Conelea CA, Bauer CC, Rice KA. In-vestigating the effects of tic suppression on premonitory urgeratings in children and adolescents with Tourette’s syndrome.Behav Res Ther. 2007; 45: 2964-2976.
[35] Verdellen CWJ, Hoogduin CAL, Kato BS, Keijsers GPJ, CathDC, Hoijtink HB. Habituation of premonitory sensations dur-ing exposure and response prevention treatment in Tourette’ssyndrome. Behav Modif. 2008; 32: 2215-2227.
[36] Moher D, Liberati A, Tetzlaff J, Altman D, The PRISMAGroup. Preferred reporting items for systematic reviews andmeta-analyses: The PRISMA Statement. PLoS One. 2009; 6:1-6.
[37] Menon V, Glover GH, Pfefferbaum A. Differential activa-tion of dorsal basal ganglia during externally and self pacedsequences of arm movements. Neuroreport. 1998: 11;1567-1573.
[38] Worbe Y, Gerardin E, Hartmann A, Valabréue R, Chupin M,Tremblay L, Vidailhet M, Colliot O, Lehéicy S. Distinct struc-
tural changes underpin clinical phenotypes in patients withGilles de la Tourette syndrome. Brain. 2010: 133; 3649-3660.
[39] Swerdlow, NR, Braff, DL, Geyer, MA. Animal models of de-ficient sensorimotor gating: What we know, what we think weknow, and what we hope to know soon. Behav Pharmacol.2000: 11; 185-204.
[40] Groenewegen HJ, van den Heuvel, OA, Cath DC, Voorn P,Veltman DJ. Does an imbalance between the dorsal and ven-tral striatopallidal systems play a role in Tourette’s syndrome?A neuronal circuit approach. Brain Dev. 2003: 25 Suppl; S3-S14.
[41] Fried I, Katz A, McCarthy G, Sass KJ, Williamson P, SpencerSS, Spencer DD. Functional organisation of the human sup-plementary motor cortex studied by electrical stimulation. JNeurosci. 1991: 11; 3656-3566.
[42] Bohlhalter S, Goldfine A, Matteson S, Garraux G, HanakawaT, Kansaku K, Wurzman R, Hallett M. Neural correlates of ticgeneration in Tourette syndrome: An event-related functionalMRI study. Brain. 2006: 129; 2029-2037.
[43] Huey ED, Zahn R, Krueger F, Moll J, Kapogiannis D, Wasser-mann EM, Grafman J. A psychological and neuroanatomicalmodel of obsessive-compulsive disorder. J NeuropsychiatryClin Neurosci. 2008: 20; 390-480.
[44] Horvitz JC. Stimulus-response and response-outcome learn-ing mechanisms in the striatum. Behav Brain Res. 2009: 199:129-140.
[45] Kalanithi PAS, Zheng W, DiFiglia M, Grantz H, SaperCB, Schwartz ML, Leckman JF, Vaccarino FM. Alteredparvalbumin-positive neuron distribution in basal ganglia ofindividuals with Tourette syndrome. Proc Natl Acad Sci USA.2005: 102; 13307-13312.
[46] Conelea CA, Woods DW. Examining the impact of distractionon tic suppression in children and adolescents with Tourettesyndrome. Behav Res Ther. 2008: 46; 1193-1200.
[47] Eddy CM, Mitchell IJ, Beck SR, Cavanna AE, Rickards H.Social reasoning in Tourette syndrome. Cogn Neuropsychia-try. 2011; 16: 326-347.
[48] Eddy CM, Mitchell IJ, Beck SR, Cavanna AE, Rickards H.Altered attribution of intention in Tourette’s syndrome. J Neu-ropsychiatry Clin Neurosci. 2010; 22: 348-351.
[49] Eddy CM, Mitchell IJ, Beck SR, Cavanna AE, Rickards H.Impaired comprehension of non-literal language in Tourettesyndrome. Cogn Behav Neurol. 2010; 23: 178-184.
[50] Draganski B, Martino D, Cavanna AE, Hutton C, Orth M,Robertson MM, Critchley HD, Frackowiak RS. Multispec-tral brain morphometry in Tourette syndrome persisting intoadulthood. Brain. 2010; 133: 3661-3675.
[51] Concha L, Livy DJ, Beaulieu C, Wheatley BM, Gross DW.In vivo diffusion tensor imaging and histopathology of thefimbria-fornix in temporal lobe epilepsy. J Neurosci. 2010:30: 996-1002.
[52] Castellanos FX, Fine EJ, Kaysen D, Marsh WL, Rapoport JL,Hallett M. Sensorimotor gating in boys with Tourette’s syn-drome and ADHD: Preliminary results. Biol Psychiatry. 1996:39; 33-41.
[53] Bakshi VP, Geyer MA. Multiple limbic regions mediate thedisruption of prepulse inhibition produced in rats by the non-competitive NMDA antagonist dizocilpine. J Neurosci. 1998:20; 8394-8401.
[54] Kodsi M, Swerdlow NR. Prepulse inhibition in the rat is regu-lated by ventral and caudodorsal striato-pallidal circuitry. Be-hav Neurosci. 1995: 109; 912-928.
[55] Abbruzzese G, Berardelli A. Sensorimotor integration inmovement disorders. Mov Disord. 2003: 18; 231-240.
S. Rajagopal et al. / Premonitory urges and sensorimotor processing in Tourette syndrome 73
[56] Verdellen CWJ, Hoogduin CAL, Kato BS, Keijsers GPJ, CathDC, Hoijtink HB. Habituation of premonitory sensations dur-ing exposure and response prevention treatment in Tourette’ssyndrome. Behav Modif. 2008: 32; 2215-2227.
[57] Kimura M, Yamada H, Matsumoto N. Tonically active neu-rons in the striatum encode motivational context of action.Brain Dev. 2003: 25 Suppl; S20-S23.
[58] Singer HS, Szymanski S, Giuliano J, Yokoi F, Dogan AS, Bra-sic JR, Zhou Y, Grace AA, Wong DF. Elevated intrasynapticdopamine release in Tourette’s syndrome measured by PET.Am J Psychiatry. 2002: 159; 1329-1336.
[59] Gilbert DL, Christian BT, Gelfand MJ, Shi B, Mantil J, SalleeFR. Altered mesolimbocortical and thalamic dopamine inTourette syndrome. Neurology. 2006: 67; 1695-1697.
[60] Peterson B, Riddle MA, Cohen DJ, Katz LD, Smith JC,Hardin MT, Leckman JF. Reduced basal ganglia volumesin Tourette’s syndrome using three dimensional reconstruc-tion techniques from magnetic resonance images. Neurology.1993: 43; 941-949.
[61] Krauthamer G, Dalsass M. Differential synaptic modulationof polysensory neurons of the intralaminar thalamus by me-
dial and lateral caudate nucleusand substantia nigra. BrainRes. 1978: 154; 137-143.
[62] Miyazaki M, Fujii E, Saijo T, Mori K, Kagami S. Somatosen-sory evoked potentials in attention deficit/hyperactivity dis-order and tic disorder. Clin Neurophysiol. 2007: 118; 1286-1290.
[63] Sowell ER, Kan E, Yoshii J, Thompson PM, Bansal R, XuD, Toga AW, Peterson BS. Thinning of sensorimotor corticesin children with Tourette syndrome. Nat Neurosci. 2008: 11;637-639.
[64] Schultz W, Tremblay L, Hollerman JR. Changes in behaviour-related neuronal activity in the striatum during learning.Trends Neurosci. 2003: 26; 321-328.
[65] Jackson SR, Parkinson A, Kim SY, Schuermann M, EickhoffSB. On the functional anatomy of the urge-for-action. CognNeurosci. 2011: 2; 227-257.
[66] Leckman JF, Vaccarino FM, Kalanithi PS, Rothenberger A.Tourette syndrome: A relentless drumbeat driven by mis-guided brain oscillations. J Child Psychol Psychiatry. 2006: 6;537-550.
Submit your manuscripts athttp://www.hindawi.com
Stem CellsInternational
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Disease Markers
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation http://www.hindawi.com Volume 2014
Immunology ResearchHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Parkinson’s Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com