premonitory urges and sensorimotor processing in tourette syndrome

10
Behavioural Neurology 27 (2013) 65–73 65 DOI 10.3233/BEN-120308 IOS Press Premonitory urges and sensorimotor processing in Tourette syndrome Sangeerthana Rajagopal a , Stefano Seri b and Andrea Eugenio Cavanna a,c,a The Michael Trimble Neuropsychiatry Research Group, Department of Neuropsychiatry, BSMHFT and University of Birmingham, Birmingham, UK b School of Life and Health Sciences, Aston Brain Centre, Aston University, Birmingham, UK c Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology and University College London, London, UK Abstract. Most patients with Tourette syndrome report characteristic sensory experiences (premonitory urges) associated with the 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 review of the published studies addressing the pathophysiological mechanisms of premonitory urges. We identified some preliminary evidence for specific alterations in sensorimotor processing at both cortical and subcortical levels. A better insight into the brain correlates of premonitory urges could lead to the identification of new targets to treat the sensory initiators of tics in patients with Tourette 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, the onset 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 vocal tics vary in localisation over time and peak in sever- ity at around 10–12 years [4–6]. Interestingly, although first described and popularised by Georges Gilles de la Tourette, an earlier publication by Armand Trousseau seems to offer a description which is more represen- tative of our modern day TS construct with minimal sampling bias [7]. In clinical practice the distinction between tics and habits or repetitive behaviours can be challenging, as all are characterised by various levels of awareness and volitional control [8]. Corresponding author: Prof. Andrea Eugenio Cavanna, MD PhD, Department of Neuropsychiatry, The Barberry National Cen- tre for Mental Health, Birmingham B15 2FG, UK. Tel.: +44 121 3012317; Fax: +44 121 3012291; E-mail: [email protected]. Premonitory urges (PUs) are not part of the DSM-IV criteria 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 through performance of movements (motor tics) or vocali- sations (vocal tics) [13–16]. A study by Leckman et al. [17] found 10 years to be the mean age of PUs awareness, averaging 3 years after tic onset. The awareness latency is suggested to reflect a transition of the processing of sensory information to conscious awareness [18,19]. Studies with the Premonitory Urge for Tics Scale (PUTS), a psychometric tool specifically developed to measure the severity of PUs [20,21], have highlighted 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 localise them exclusively in the muscle, and the remainders in their joints or skin. The percentage of patients with TS or other chronic tic disorders experiencing PUs varies depending on how the urge is defined [21–23]. ISSN 0953-4180/13/$27.50 c 2013 – IOS Press and the authors. All rights reserved

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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

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68 S. Rajagopal et al. / Premonitory urges and sensorimotor processing in Tourette syndrome

Tabl

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Prem

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ryU

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ttent

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fMR

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Func

tiona

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A=S

uppl

emen

tary

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orA

rea,

AC

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Ant

erio

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ingu

late

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tex,

DL

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orso

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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.

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