Inhibition, Disinhibition, and the Control of Action in Tourette Syndrome
Authors: Georgina M Jackson, Amelia Draper, Katherine Dyke, Sophia E Pépés, Stephen R Jackson
Journal: Trends in Cognitive Sciences (2015)

Tourette syndrome (TS) has been linked to impairment of inhibitory function. Recent evidence provides support for reduced physiological inhibition as a factor in the occurrence of tics, but there is little evidence that TS is linked to impairment in behavioral inhibition. A widely held view is that control over tics is accomplished through increased functional and structural connectivity between frontal brain regions and motor cortex. Emerging evidence provides little support for this view, but indicates that, to the extent that structural and functional connectivity are increased in TS, such connectivity is disorganized and is associated with increases in tic severity. Control over motor outputs in TS, including tics, may be brought about by increases in GABA-mediated 'tonic' inhibition within higher-order motor regions that lead to a reduction in the 'gain' of motor excitability. Tourette syndrome (TS) is a neurological disorder characterized by vocal and motor tics. TS is associated with impairments in behavioral inhibition, dysfunctional signaling of the inhibitory neurotransmitter GABA, and alterations in the balance of excitatory and inhibitory influences within brain networks implicated in motor learning and the selection of actions. We review evidence that increased control over motor outputs, including the suppression of tics, may develop during adolescence in TS and be accompanied by compensatory, neuromodulatory, alterations in brain structure and function. In particular, we argue that increased control over motor outputs in TS is brought about by local increases in 'tonic' inhibition that lead to a reduction in the 'gain' of motor excitability. Tourette syndrome (TS) is a neurological disorder characterized by vocal and motor tics. TS is associated with impairments in behavioral inhibition, dysfunctional signaling of the inhibitory neurotransmitter GABA, and alterations in the balance of excitatory and inhibitory influences within brain networks implicated in motor learning and the selection of actions. We review evidence that increased control over motor outputs, including the suppression of tics, may develop during adolescence in TS and be accompanied by compensatory, neuromodulatory, alterations in brain structure and function. In particular, we argue that increased control over motor outputs in TS is brought about by local increases in 'tonic' inhibition that lead to a reduction in the 'gain' of motor excitability. TS is a childhood-onset hyperkinetic condition affecting approximately 1% of school-age children [1Cohena S.C. et al.Clinical assessment of Tourette syndrome and tic disorders.Neurosci. Biobehav. Rev. 2013; 37: 997-1007Crossref PubMed Scopus (137) Google Scholar]. It is characterized by an evolving repertoire of chronic motor tics and one or more phonic tics. Tics occur in bouts, typically many times in a single day, and are the most common form of movement disorder in children. In child populations with TS the ratio of males to females is estimated at 5.2 to 1, but in adult samples this gender split is closer to parity [2Lichter D.G. Finnegan S.G. Influence of gender on Tourette syndrome beyond adolescence.Eur. Psychiatry. 2015; 30: 334-340Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar]. Motor tics can be simple or complex in appearance, ranging from repetitive movements to coordinated action sequences. Verbal tics can consist of repeating sounds, words or utterances (palilalia), producing inappropriate or obscene utterances (coprolalia), or the repetition of another's words (echolalia). Currently what drives progression from simple to complex tics is unknown; however, clinical descriptions clearly resemble that of habit formation [3Leckman J.F. Riddle M.A. Tourette's syndrome: when habit-review forming systems form habits of their own?.Neuron. 2000; 28: 349-354Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar]. Tics, similarly to habits, are inflexible and repetitive behaviors that are acquired over time. In general tics begin with simple motor tics (e.g., eye blinking, nose twitching, or grimacing) around the age of 4–6 years. About a year later these are joined by simple phonic tics or sounds (e.g., sniffing, grunting). Individuals with TS perceive a relatively constant demand to suppress their tics, particularly in social situations. While the voluntary suppression of tics is possible for many individuals, they nevertheless report that it can be uncomfortable and stressful to suppress their tics, and that the urge to tic becomes uncontrollable after a period of suppression. TS often follows a developmental timecourse in which tics remit or become increasingly more controlled during adolescence in many individuals. TS first presents during early childhood and the severity of tics follows a remitting pattern with increasing age. Tic severity is often maximal between 11 and 14 years, with tics decreasing by early adulthood [1Cohena S.C. et al.Clinical assessment of Tourette syndrome and tic disorders.Neurosci. Biobehav. Rev. 2013; 37: 997-1007Crossref PubMed Scopus (137) Google Scholar]. It has been proposed that the constant need to suppress tics leads to enhanced inhibitory control of motor outputs which generalizes to laboratory measures of cognitive control [4Mueller S.C. et al.Enhanced cognitive control in young people with Tourettes syndrome.Curr. Biol. 2006; 16: 570-573Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar]. Furthermore, it is argued that increases in inhibitory control of motor outputs are associated with the development of compensatory alterations in brain structure and function that lead to enhanced control over motor outputs and a reduction in tics [5Jackson S.R. et al.Compensatory neural reorganization in Tourette syndrome.Curr. Biol. 2011; 21: 580-585Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar, 6Plessen K.J. et al.Imaging evidence for anatomical disturbances and neuroplastic compensation in persons with Tourette syndrome.J. Psychosom. Res. 2009; 67: 559-573Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar]. A substantial minority (∼20–30%) of individuals will continue to exhibit debilitating tics into adulthood, in some cases with symptoms becoming more severe and resistant to treatment, resulting in considerable impairment in social functioning and quality of life [1Cohena S.C. et al.Clinical assessment of Tourette syndrome and tic disorders.Neurosci. Biobehav. Rev. 2013; 37: 997-1007Crossref PubMed Scopus (137) Google Scholar]. Currently we do not understand why some individuals gain control over their tics while others do not. Nonetheless, it is clear that adults who exhibit persistent tics can be viewed as unrepresentative of the more general Tourette population, but may form an important group in which the clinical phenotype is stable, and the compensatory plastic changes that are thought to bring about increased control over tic severity during adolescence [4Mueller S.C. et al.Enhanced cognitive control in young people with Tourettes syndrome.Curr. Biol. 2006; 16: 570-573Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar] have either failed to occur or have been ineffective. In this paper we review evidence that TS is associated with impairments in behavioral and physiological inhibition (see Glossary), but that increased control over motor outputs, including the suppression of tics, may develop during adolescence, and may be accompanied by compensatory, neuromodulatory alterations in brain structure and function. In particular we review new evidence that increased control over motor outputs in TS is brought about by local increases in 'tonic' inhibition that lead to a reduction in the 'gain' of motor excitability. The neural circuits of the brain are established early during development. Milestones include the genesis and migration of neurons, the formation of synapses, and consolidation of synaptic connections. These events typically produce brain networks with balanced excitatory and inhibitory influences and disruption to this balance has been proposed as a basis for several common neurodevelopmental disorders, including TS [7Ramamoorthi K. Lin Y. The contribution of GABAergic dysfunction to neurodevelopmental disorders.Trends Mol. Med. 2011; 17: 452-462Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 8Clarke R.A. et al.Pathogenetic model for Tourette syndrome delineates overlap with related neurodevelopmental disorders including Autism.Transl. Psychiatry. 2012; 2: e158Crossref PubMed Scopus (86) Google Scholar]. TS has been particularly associated with dysfunctional signaling by the neuromodulator dopamine (DA) [9Buse J. et al.Neuromodulation in Tourette syndrome: dopamine and beyond.Neurosci. Biobehav. Rev. 2013; 37: 1069-1084Crossref PubMed Scopus (127) Google Scholar], which is strongly linked to mechanisms of reinforcement learning [10Schultz W. Dopamine neurons and their role in reward mechanisms.Curr. Opin. Neurobiol. 1997; 7: 191-197Crossref PubMed Scopus (591) Google Scholar], and to the neurotransmitter γ-amino butyric acid (GABA) [7Ramamoorthi K. Lin Y. The contribution of GABAergic dysfunction to neurodevelopmental disorders.Trends Mol. Med. 2011; 17: 452-462Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 8Clarke R.A. et al.Pathogenetic model for Tourette syndrome delineates overlap with related neurodevelopmental disorders including Autism.Transl. Psychiatry. 2012; 2: e158Crossref PubMed Scopus (86) Google Scholar]. GABA is the main inhibitory neurotransmitter in the brain, it is present in 25–50% of synapses, and contributes to almost all brain functions. Together, dysfunctional signaling of DA and GABA may each contribute to impairment in the operation of the cortical–striatal–thalamic–cortical (CSTC) brain circuits in TS, which are implicated in motor learning, particularly habit formation, and the selection of actions according to behavioral context [11Graybiel A.M. Habits, rituals, and the evaluative brain.Annu. Rev. Neurosci. 2008; 31: 359-387Crossref PubMed Scopus (1143) Google Scholar]. As a consequence, individuals with TS may acquire relatively automatic and involuntary behaviors (i.e., tics) more readily than is normal, and it may be harder to un-learn maladaptive habits once these have been acquired [11Graybiel A.M. Habits, rituals, and the evaluative brain.Annu. Rev. Neurosci. 2008; 31: 359-387Crossref PubMed Scopus (1143) Google Scholar]. Findings from several converging lines of research support the proposal that TS is linked specifically to alterations in GABAergic signaling. First, magnetic resonance imaging (MRI) studies have consistently reported reduced striatal volumes in individuals with TS [6Plessen K.J. et al.Imaging evidence for anatomical disturbances and neuroplastic compensation in persons with Tourette syndrome.J. Psychosom. Res. 2009; 67: 559-573Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar], and postmortem investigations have demonstrated that there are substantial decreases (approximately 50%) in the number of GABAergic interneurons within the striatum of individuals with TS [12Kalanithi P.S. et al.Altered parvalbumin-positive neuron distribution in basal ganglia of individuals with Gilles de la Tourette syndrome.Proc. Natl. Acad. Sci. U.S.A. 2005; 102: 13307-13311Crossref PubMed Scopus (406) Google Scholar, 13Kataoka Y. et al.Decreased number of parvalbumin and cholinergic interneurons in the striatum of individuals with Tourette syndrome.J. Comp. Neurol. 2010; 518: 277-291Crossref PubMed Scopus (324) Google Scholar]. It is not yet established if similar reductions in interneuron numbers are also observed within the cortex of individuals with TS, however a recent study has suggested that there may be reduced numbers of interneurons within the insular cortex [14Vaccarino F.M. et al.Cellular and molecular pathology in Tourette syndrome.in: Martino D. Leckman J.F. Tourette Syndrome. Oxford University Press, 2013: 205-220Crossref Google Scholar] – a brain region strongly implicated in the cortical genesis of tics. Furthermore, a recent positron emission tomography (PET) imaging study has revealed that there are widespread alterations in GABA-A receptor binding in individuals with TS, and include in particular the striatum, thalamus, and insular cortex [15Lerner A. et al.Widespread abnormality of the γ-aminobutyric acid-ergic system in Tourette syndrome.Brain. 2012; 135: 1926-1936Crossref PubMed Scopus (133) Google Scholar]. Second, physiological studies using single- and paired-pulse transcranial magnetic stimulation (TMS) techniques have consistently demonstrated that there are alterations in cortical–spinal excitability (CSE) and physiological inhibition in TS [16Orth M. Transcranial magnetic stimulation in Gilles de la Tourette syndrome.J. Psychosom. Res. 2009; 67: 591-598Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 17Orth M. Electrophysiology in Tourette syndrome.in: Martino D. Leckman J.F. Tourette Syndrome. Oxford University Press, 2013: 221-237Crossref Google Scholar]. Specifically, paired-pulse TMS studies of physiological inhibition have repeatedly shown that short-interval intracortical inhibition (SICI), a phenomenon that is known to be dependent upon the GABA-A receptor, is reduced in individuals with TS [16Orth M. Transcranial magnetic stimulation in Gilles de la Tourette syndrome.J. Psychosom. Res. 2009; 67: 591-598Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar]. Finally, studies using animal models have directly investigated the relationship between impaired GABA function within the striatum and the occurrence of motor tics. It was reported that microinjection of GABA antagonists within the striatum can produce both tic-like movements and repetitive stereotypical behaviors, and that these behaviors are determined according to the site of the injection [18Bronfeld M. et al.Pharmacological animal models of Tourette syndrome.Neurosci. Biobehav. Rev. 2013; 37: 1101-1119Crossref PubMed Scopus (40) Google Scholar]. Importantly, these studies demonstrate that focal microinjection of a GABA-A antagonist into the sensorimotor region of the striatum produce reversible increases in tic-like movements that are localized to a specific body part, commence within minutes of the injection, and typically last for 1–2 h. Whereas striatal disinhibition has often been viewed as key to the occurrence of tics, recent electrophysiological recording studies in non-human primates confirm the importance of other brain regions that may be more important for the behavioral expression of tics. Specifically, while local field potential (LFP) spikes recorded within the striatum have been observed to precede the occurrence of tic-like movements in primate studies utilizing microinjection of GABA-A antagonists, it has recently been demonstrated that they can also be seen during inter-tic intervals, when no overt tic-like movements occur [19McCairn K.W. et al.Global dysrhythmia of cerebro-basal ganglia-cerebellar networks underlies motor tics following striatal disinhibition.J. Neurosci. 2013; 33: 697-708Crossref PubMed Scopus (62) Google Scholar]. It has been suggested that these LFPs may be physiological correlates of premonitory urges [20McCairn K.W. Isoda M. Pharmacological animal models of tic disorders.Int. Rev. Neurobiol. 2013; 112: 179-209Crossref PubMed Scopus (9) Google Scholar]. By contrast, LFP spikes recorded in the primary motor cortex and the cerebellum always occur within the time-period immediately preceding the occurrence of tic-like movements. MRI studies have repeatedly demonstrated that there are widespread alterations in brain structure and function associated with TS [6Plessen K.J. et al.Imaging evidence for anatomical disturbances and neuroplastic compensation in persons with Tourette syndrome.J. Psychosom. Res. 2009; 67: 559-573Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar]. These include alterations in: grey matter (GM) volume (e.g., [21Worbe Y. et al.Distinct structural changes underpin clinical phenotypes in patients with Gilles de la Tourette syndrome.Brain. 2010; 133: 3649-3660Crossref PubMed Scopus (131) Google Scholar, 22Draganski B. et al.Multispectral brain morphometry in Tourette syndrome persisting into adulthood.Brain. 2010; 133: 3661-3675Crossref PubMed Scopus (115) Google Scholar]), cortical GM thickness (e.g., [23Sowell E.R. et al.Thinning of sensorimotor cortices in children with Tourette syndrome.Nat. 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Disord. 2015; (Published online April 8, 2015)https://doi.org/10.1002/mds.26230Crossref PubMed Scopus (70) Google Scholar]). While some findings have proved to be reliable across studies (e.g., the thinning of cortical GM in sensorimotor cortex and inferior frontal cortex), results from other studies have been mixed, with many inconsistent or seemingly contradictory findings being reported. Several factors likely contribute to these differences including: the presence of co-occurring disorders, the effects of medication, and differences in the age of individuals being scanned. In addition, previous studies have often failed to distinguish between alterations in structural and functional connectivity that (i) could be seen as primary causes of tics in TS, and (ii) those that might be better considered as secondary consequences of TS and are associated with compensatory or adaptive changes that aid in the control of clinical symptoms. This issue is particularly important as it is suggested that individuals with TS gain control over their tics through the development of compensatory self-regulation mechanisms during adolescence (e.g., [4Mueller S.C. et al.Enhanced cognitive control in young people with Tourettes syndrome.Curr. Biol. 2006; 16: 570-573Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar, 5Jackson S.R. et al.Compensatory neural reorganization in Tourette syndrome.Curr. Biol. 2011; 21: 580-585Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar, 6Plessen K.J. et al.Imaging evidence for anatomical disturbances and neuroplastic compensation in persons with Tourette syndrome.J. Psychosom. Res. 2009; 67: 559-573Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar]). Two recent MRI studies have been particularly important in clarifying the nature of the alterations in structural and functional connectivity within the CSTC networks that are observed in adults with TS. First, using rs-fMRI to investigate alterations in functional connectivity within the sensorimotor, associative, and limbic CSTC networks, it has recently been shown that functional connectivity within all three CSTC networks is disorganized in adults with TS, relative to matched controls [32Worbe Y. et al.Functional immaturity of cortico-basal ganglia networks in Gilles de la Tourette syndrome.Brain. 2012; 135: 1937-1946Crossref PubMed Scopus (138) Google Scholar]. Furthermore, abnormalities in functional connectivity were correlated with tic severity. Specifically, functional integration (i.e., interaction between anatomical regions) was substantially increased in TS, with networks exhibiting shorter path lengths between areas, and increased number and strength of functional connections between brain regions. Importantly, CSTC networks in the TS group were characterized by a loss of 'hub' regions that facilitate fast and efficient transfer of information over long distances within brain networks [34Bullmore E. Sporns O. Complex brain networks: graph theoretical analysis of structural and functional systems.Nat. Rev. Neurosci. 2009; 10: 186-198Crossref PubMed Scopus (7514) Google Scholar]. Second, studies using diffusion tensor imaging together with probabilistic tractography techniques to investigate the structural connectivity of CSTC white matter pathways in adults with TS have demonstrated that TS is associated with increased structural connectivity in the white matter tracts linking the striatum and thalamus with cortical sensorimotor regions [29Worbe Y. et al.Altered structural connectivity of cortico–striato–pallido–thalamic networks in Gilles de la Tourette syndrome.Brain. 2015; 138: 472-482Crossref PubMed Scopus (155) Google Scholar]. These increases in structural connectivity are paralleled by alterations in the microstructure of cortical–striatal and thalamocortical white matter tracts. In particular, fractional anisotropy (FA) values in thalamocortical white matter tracts were increased in TS [29Worbe Y. et al.Altered structural connectivity of cortico–striato–pallido–thalamic networks in Gilles de la Tourette syndrome.Brain. 2015; 138: 472-482Crossref PubMed Scopus (155) Google Scholar]. Note that, because FA is thought to reflect several anatomical properties of white matter, that include the density of axon bundles, axonal diameter, and axonal myelination, this finding is consistent with an increase in structural connectivity within CSTC networks in TS. A key question raised by such findings is whether increased functional and structural connectivity within CSTC networks contributes to the occurrence of tics or might participate in their effective control. A consistent finding in each of these studies is that increased structural and functional connectivity (including increases in FA values) is positively associated with increases in tic severity. These findings support the proposal made previously [35Jung J. et al.Cognitive control over motor output in Tourette syndrome.Neurosci. Biobehav. Rev. 2013; 37: 1016-1025Crossref PubMed Scopus (57) Google Scholar] that increased long-range functional and structural connectivity is most often associated with increases in tic severity in TS rather than enhanced control of tics. It has often been proposed that neural disinhibition within CSTC networks gives rise to an impairment of inhibitory control of behavior in TS (e.g., [36Channon S. et al.Tourette's syndrome (TS): inhibitory performance in adults with uncomplicated TS.Neuropsychology. 2009; 23: 359-366Crossref PubMed Scopus (36) Google Scholar]). While this proposal is consistent with the observation that individuals with TS exhibit motor and vocal tics (suggestive of 'disinhibited' behaviors), it is important to note that the occurrence of tics in TS does not necessarily support a conclusion that TS is associated with impairment in the inhibitory control of behavior. Moreover, when the evidence from formal tests of behavioral inhibition or executive control in TS is examined, there is little convincing support for this conclusion because the results from behavioral studies are mixed [35Jung J. et al.Cognitive control over motor output in Tourette syndrome.Neurosci. Biobehav. Rev. 2013; 37: 1016-1025Crossref PubMed Scopus (57) Google Scholar]. While some studies report impairment in inhibitory control or executive function in TS (e.g., [37Dursun S. et al.Antisaccade eye movement abnormalities in Tourette syndrome: evidence for corticostriatal network dysfunction?.J. 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Psychiatry. 1998; 39: 1109-1118Crossref PubMed Google Scholar]), and still others consistently report finding enhanced inhibitory control in individuals with 'pure' or 'uncomplicated' TS (i.e., those without co-morbid disorders such as attention deficit hyperactivity disorder, ADHD) (e.g., [4Mueller S.C. et al.Enhanced cognitive control in young people with Tourettes syndrome.Curr. Biol. 2006; 16: 570-573Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar, 5Jackson S.R. et al.Compensatory neural reorganization in Tourette syndrome.Curr. Biol. 2011; 21: 580-585Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar, 40Jackson G.M. et al.Enhanced cognitive control in Tourette syndrome during task uncertainty.Exp. Brain Res. 2007; 182: 357-364Crossref PubMed Scopus (81) Google Scholar, 41Jung J. et al.Enhanced saccadic control in young people with Tourette syndrome despite slowed pro-saccades.J. Neuropsychol. 2014; (Published online April 16, 2014)https://doi.org/10.1111/jnp.12044Crossref PubMed Scopus (18) Google Scholar]). Such conflicting reports have been explained as the result of differences in task and/or sample characteristics [35Jung J. et al.Cognitive control over motor output in Tourette syndrome.Neurosci. Biobehav. Rev. 2013; 37: 1016-1025Crossref PubMed Scopus (57) Google Scholar]. First, previous studies investigating deficits of inhibitory control in TS have used a variety of behavioral tasks, including the Stroop, Eriksen flanker, and Go/NoGo tasks [35Jung J. et al.Cognitive control over motor output in Tourette syndrome.Neurosci. Biobehav. Rev. 2013; 37: 1016-1025Crossref PubMed Scopus (57) Google Scholar] that likely differ in terms of their cognitive demands. Second, studies that report finding an impairment in inhibitory control or executive function in TS, have often failed to exclude individuals presenting with co-occurring conditions such as ADHD or obsessive-compulsive disorder (OCD) that may themselves be associated with impairment in inhibitory control. Furthermore, when such individuals are excluded, studies invariably report either no behavioral difference between groups or significantly enhanced performance in the TS groups [35Jung J. et al.Cognitive control over motor output in Tourette syndrome.Neurosci. Biobehav. Rev. 2013; 37: 1016-1025Crossref PubMed Scopus (57) Google Scholar]. Finally, studies reporting impairment in inhibitory control in individuals with TS have often been based upon samples of adults with TS or mixed samples containing both adults and children. Again, it has been argued that adults with TS may be unrepresentative of the 'typical' presentation of TS [6Plessen K.J. et al.Imaging evidence for anatomical disturbances and neuroplastic compensation in persons with Tourette syndrome.J. Psychosom. Res. 2009; 67: 559-573Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar]. TS most often follows a developmental timecourse characterized by a reduction in the frequency and intensity of tics during adolescence [1Cohena S.C. et al.Clinical assessment of Tourette syndrome and tic disorders.Neurosci. Biobehav. Rev. 2013; 37: 997-1007Crossref PubMed Scopus (137) Google Scholar]. It has been proposed that individuals gain control over their tics through the development of compensatory mechanisms that lead to enhanced control over motor outputs (e.g., [4Mueller S.C. et al.Enhanced cognitive control in young people with Tourettes syndrome.Curr. Biol. 2006; 16: 570-573Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar, 5Jackson S.R. et al.Compensatory neural reorganization in Tourette syndrome.Curr. Biol. 2011; 21: 580-585Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar, 42Plessen K.J. et al.Altered interhemispheric connectivity in individuals with Tourette's disorder.