Selective dysfunction of basal ganglia subterritories: From movement to behavioral disorders

Selective Dysfunction of Basal Ganglia Subterritories: From Movementto Behavioral Disorders

L�eon Tremblay, PhD,1* Yulia Worbe, MD, PhD,2 St�ephane Thobois, MD, PhD,1,3,4 V�eronique Sgambato-Faure, PhD,1

and Jean F�eger, PhD2

1Centre de Neurosciences Cognitives–UMR 5229, CNRS-Universit�e de Lyon 1, Bron, France2UPMC Universit�e Paris 6, UMR-S975, CRICM–Centre de Recherche de l’Institut du Cerveau et de la Moelle �epiniere, Paris, France

3Hospices Civils de Lyon, Hopital Neurologique Pierre Wertheimer, Neurologie C, Lyon, France4Universit�e de Lyon, Universit�e Claude Bernard Lyon 1, Facult�e de M�edecine Lyon Sud Charles M�erieux, Lyon, France

ABSTRACT: Historically, Parkinson’s disease(PD) was defined as a pure movement disorder. Cur-rently, it is widely accepted that this disease is alsocharacterized by nonmotor signs, such as depression,apathy, and anxiety. On the other hand, the considera-tion of Gilles de la Tourette syndrome (GTS) as a neuro-psychiatric disorder has also been debated. In thisreview, we will focus on these two disorders, whichcombine both motor and behavioral features and inwhich dysfunction of cortical and subcortical regionswas suggested. Anatomical, experimental, and clinicaldata are reported to support the involvement of basalganglia (BG) in cognitive and motivational functions inaddition to motor control. In PD, the nonmotor signscould result from the heterogeneity of dopaminergiclesions and excessive activation of the dopaminereceptors, particularly within the limbic neuronal net-works. Experimental results obtained on nonhuman pri-mates using local disinhibition within functionalterritories of BG allowed the precise mapping of theirmotor and nonmotor functions. Thus, impairment of

inhibitory control inside specific striatal territoriesinduced behavioral disorders and abnormal movements,which had striking similarities to clinical expressions ofGTS. Establishing such a relationship between BG sub-territories and motor and behavioral disorders couldpotentially be helpful for future target choices for DBSin many neuropsychiatric disorders. Furthermore, it isalso of great interest for therapeutic research and forthe efficient targeting of symptom relief to determinethe precise pharmacological effects of the two mainmodulators of BG function, which are dopamine andserotonin. VC 2015 International Parkinson and Move-ment Disorder Society

Key Words: basal ganglia; Parkinson’s disease;Tourette’s syndrome; nonhuman primate; MPTP; GABAinhibition; fast spiking interneurons; striatum; pallidum;deep brain stimulation; dopamine; serotonin; dyskinesia;impulse control disorders; dopamine dysregulationsyndrome

Currently, it is recognized that dysfunctions withinthe basal ganglia (BG) induce cognitive deficits orbehavioral disorders in addition to the motor symp-toms in disorders such as Parkinson’s disease (PD),Huntington’s chorea, or Gilles de la Tourette syn-drome (GTS). Nonetheless, historically, most of theresearch attention in these disorders has been focusedon abnormal movement, given that BG were consid-ered as brain structures purely dedicated to the controlof motor function. It is only since the end of the1990s that the cognitive and motivational role of theBG has been recognized. Advances in the understand-ing of nonmotor BG functions have suggested BGimplications in behavioral disorders. This has resulted

------------------------------------------------------------*Correspondence to: L�eon Tremblay, Centre de Neurosciences Cogni-tives–UMR 5229, CNRS-Universit�e de Lyon 1, 67 Bd Pinel 69675,Cedex, Bron, France; [email protected]

Funding agencies: Writing this article was supported by the FrenchNational Agency of Research (grant nos.: ANR-11-LABX-0042 andANR-11-IDEX-0007).

Relevant conflicts of interest/financial disclosures: Nothing to report.Full financial disclosures and author roles may be found in the online ver-sion of this article.

Received: 9 October 2014; Revised: 14 January 2015; Accepted: 6February 2015

Published online 00 Month 2015 in Wiley Online Library(wileyonlinelibrary.com). DOI: 10.1002/mds.26199

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Movement Disorders, Vol. 00, No. 00, 2015 1

from: (1) studies on the anatomical and functionalorganization of the BG, which revealed their func-tional compartmentalization in close relation to differ-ent cortical territories; (2) animal models, especiallystudies on nonhuman primates, which have allowedresearchers to establish a causal link between dysfunc-tions inside the BG and specific motor and nonmotor

symptoms (NMS); and (3) clinical studies (dopa ther-apy or DBS).

In this review, we will focus on the evolution of theconcepts of BG functional organization through theunderstanding of the pathophysiology of PD and GTS,two very different disorders with expression of bothmovement and behavioral symptoms.

FIG. 1. Illustration of the parallel circuits model initially proposed by Alexander et al. in 1986 (A) and a more recent anatomical representation of thecortico-BG circuits (B) behind the hypothesis of BG implication in goal-directed behavior and in movement and behavioral disorders. According tothis model, BG appear to be divided into functional territories in close relation to different territories of the frontal cortex. It is now generallyaccepted to dissociate three large functional domains inside all structures of BG: sensorimotor (SM), associative (Ass), and limbic (Lim), which areimplied, respectively, in the selection and execution of movement (yellow), the selection of action (green), and the goal selection or the motivationalprocesses upstream of all these functions (blue). It is this model of organization into functional circuits that provides the main argument for the impli-cation of BG in a large spectrum of movement and behavioral disorders, as observed in neurology and psychiatric pathologies (listed in part A).This model also explains the presence of motor symptoms and NMS in GTS and PD. Part B illustrates the separation of the functional territoriesinside the BG and the frontal cortex, with the known functions of these cerebral areas in the different functional steps that lead to a behaviordirected toward a goal: from intention to movement. The cortico-BG circuit illustrated in part B represents the circuit of motivation. This circuitincludes the direct (in black) and indirect (in red) pathways of BG. The question mark (?) on this circuit indicates a potential open loop from the moti-vation circuit to influence the cognitive circuit by return thalamic projection to the cortex. Part A was adapted from the review of Alexander et al.1 of1986 with permission from Annual Reviews. AC, anterior commissure; ACA, anterior cingulate area; APA, arcuate premotor area; Ass, associativefunctional territory; CD, caudate nucleus (b) body (h) head; DLC, dorsolateral prefrontal cortex; EC, entorhinal cortex; FEF, frontal eye fields; HC, hip-pocampal cortex; ITG, inferior temporal gyrus; Lim; limbic functional territory; LOF, lateral orbitofrontal cortex; MC, motor cortex; MD, mediodorsalthalamus; PPC, posterior parietal cortex; PUT, putamen; SC, somatosensory cortex; SM, sensorimotor functional territory; SMA, supplementarymotor area; STG, superior temporal gyrus; VA, ventralis anterior thalamus; VL, ventralis lateralis thalamus; VP, ventral pallidum; VS, ventral striatum;cl-, caudolateral; cdm-, caudal dorsomedial; dl-, dorsolateral; l-, lateral; ldm-, lateral dorsomedial; m-, medial; mc, magnocellularis; mdm, medialdorsomedial; o, oralis; pc, parvocellularis; pl, paralamellaris; pm, posteromedial; rd-, rostrodorsal; rl-, rostrolateral; rm-, rostromedial; vm-, ventrome-dial; vl, ventrolateral.

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2 Movement Disorders, Vol. 00, No. 00, 2015

Model of Cortico-BG Circuits andthe Pathological Implications

Within the BG, and, in particular, within the stria-tum, the processing of motor and nonmotor informa-tion arises from the massive topographically andfunctionally organized cortical projections that provideanatomical evidence for the functional subdivisioninto sensorimotor, associative, and limbic territorieswithin the BG.1-3 One of the first models of BG func-tionality only considered BG as motor structures inwhich different inputs converge on only one outputpathway, dedicated to the execution of a movement.Indeed, the anatomical approach showed that almostall cortical regions projected to the striatum in a topo-graphical manner and they thus define striatal func-tional territories, where the sensorimotor cortexprojects to the putamen, the associative cortex to thecaudate nucleus, and the limbic cortical areas to thenucleus accumbens or ventral striatum.4 However,taking into account the high ratio between projectionneurons from the striatum to those localized in theinternal segment of the globus pallidus (GPi) and inthe SNr, and the presence of large dendrites on pal-lidal and nigral neurons,5 a large functional conver-gence was suggested in the cortico-BG circuit. Inaddition, owing to the fact that the returning projec-tion from the BG goes only to the motor cortex andthe supplementary motor area, which were welldescribed at this time, this strengthened the view thatthe BG could exclusively influence motor function.

In 1986, Alexander et al.1 presented an alternativeview of cortico-BG organization, with several func-tional parallel loops, rather than a unique functionalconvergence, for motor control (Fig. 1A). In accordwith this model, different BG territories encode andprocess different functional information throughoutdistinct territories of the BG output structures (GPiand SNr) and back to specific cortical areas by thethalamus. This model further suggested BG involve-ment in cognitive and motivational functions. Thisrevolutionary model of cortico-BG network organiza-tion was also strengthened by nonhuman primatesanatomical data using rabies virus tracing (a retro-grade trans-synaptic tracer) that showed: (1) the BGoutput pathways to the cortex are truly organized indistinct parallel circuits, where different functionaldomains could be processed independently, and (2)the BG output pathways indeed project to the motorcortex, but also to the prefrontal cortex related to cog-nitive and motivational information processing.6-8 Therelationship between the ventral striatum and the orbi-tofrontal and cingulate cortices (Fig. 1B) and recogni-tion of the return pathways to these areas suggested aspecific motivational processes for goal selectionwithin this network, without necessarily exerting a

direct influence on the selection or execution of anaction. A second circuit (Fig. 1B, in green), from thedorsolateral prefrontal cortex to the caudate nucleus,was associated with cognitive processes for actionselection, and a separate third circuit (in yellow in Fig.1A,B), involving the premotor and motor corticestogether with the putamen, appeared to be more spe-cifically dedicated to movement selection and execu-tion. Therefore, at least three cortico-BG loops areimplicated in the different functional processes fromintention to movement execution. The circuit from theventral striatum to the cortex could specifically pro-cess the motivational information for goal selection,through bottom-up return projections to the orbito-frontal and/or anterior cingulate cortex, and couldalso influence the processes of action selection by pro-jection to the dorsolateral prefrontal cortex (illustratedin Fig. 1B by an arrow with a question mark [“?”]),or to the premotor cortex, as suggested by recent ana-tomical results using a retrograde trans-synaptictracer.9

The interaction between these different BG loopscould arise from the hierarchical cortico-cortical pro-jection from the anterior prefrontal areas to the pre-motor and motor cortex,10 further providing the linkbetween the parallel cortico-BG circuits. In addition,the thalamic relay nuclei (the ventral-anterior, ventro-lateral, ventromedial, and mediodorsal nucleus) thattransmit BG output information to the frontal cortexprovide not only a feedback closed-loop projection,but also initiate feed-forward, open-loop projectionsto the cortical areas involved in the different func-tional circuits.11

Neuronal recording in nonhuman primate and neu-roimaging studies in humans have largely contributedto delineate these functional domains inside the stria-tum.12 Briefly, these studies showed that (1) the ven-tral striatum processes the motivational information,the expected outcome, and reward,13-16 (2) the cogni-tive aspects regarding the selection of conditionedstimuli that guide action toward the goal are treatedin the caudate nucleus, with an increasing proportionof neurons expressing anticipatory activity for the con-ditioned stimuli in the most anterior levels,17,18 and(3) movement preparation and execution are processedin the putamen.19-22 On the bases of anatomicalresults, these circuits have been subdivided into severalcircuits dedicated to more-specific cognitive and motoractivities,6 whereas behavioral studies have identifiedspecialized circuits, treating opposite motivationaldomains according to pleasant or unpleasant stimuli,23

or processing the motivation for a food reward versusthe hedonic value of this reward.24

The incredible impact of this model of BG organiza-tion is in advancing the view that BG could be impli-cated in several psychiatric disorders, as listed in the

S E L E C T I V E D Y S F U N C T I O N O F B G S U B T E R R I T O R I E S


bottom part of Figure 1A. The BG appear now to beinvolved in cognitive symptoms of schizophrenia,25

obsessive-compulsive disorders (OCDs),26 attentiondeficit and hyperactivity disorders27 (AD/HDs), someforms of anxiety disorders, such as phobias and panicattacks,28-30 depressive states,31 and eating disorders,such as anorexia or bulimia.32,33 Moreover, the rolesof the ventral striatum (or nucleus accumbens) and thedopaminergic projection from the ventral tegmentalarea (VTA) in the abuse of drugs and addiction werelargely demonstrated.34-36 These last behavioral disor-ders still represent a very broad field of research,which, by itself, shows the importance of the BG inmotivational processes.

This model of BG organization (Fig. 1) can alsoexplain the high association of motor and behavioralsymptoms in disorders such as PD and GTS. GTS is aneurodevelopmental disorder characterized by simpleand complex motor tics often associated with AD/HDand OCDs.37,38 In PD, degeneration of dopamine neu-rons39 results in a triad of motor symptoms (akinesia,rigidity, and resting tremor) and is now completed byNMS, including cognitive deficits, depression, apathy,and anxiety.30,40-44 In some PD patients under dopa-mine replacement therapy, the appearance of a dopa-mine dysregulation syndrome or impulse controldisorders (ICDs; pathological gambling or hypersex-uality) reinforce the idea that BG dysfunctions drivenby overstimulation of dopamine transmissions cantrigger addictive-like behaviors in PD patients.45-47

Although differences in information processing canexist between the different functional territories of BG,

it can be further postulated that a similar neuronal dys-function could be at the origin of movement or behav-ioral disorders, depending on the affected BGterritories. For example, apathy (loss of the motivationto act) in some PD patients could result from a reduc-tion of dopamine modulation in the limbic BG (ventralstriatum) territory and akinesia (loss of the ability toact) results from the same process in the sensorimotorBG (posterior putamen). In contrast, impulsive andcompulsive behaviors could result from an aberrantactivation of limbic BG circuits, similar as for dyskine-sia, primarily originating from abnormal activity of thesensorimotor territories of the BG (see the hypothesis ofVolkmann et al.39 and the illustration in Fig. 2B). In thecase of GTS patients, we can hypothesize that a similarneuronal dysfunction could produce movement disor-der (simple motor tics) if located in the sensorimotorterritories of BG, as well as behavioral disorders (AD/HD and OCDs) if the dysfunction could be inducedinside the associative and limbic BG territories. Thesetwo assumptions were tested in nonhuman primatesand have provided key findings, which are discussedbelow in the context of PD and GTS.

Pathophysiology of PD: The Roleof Dopamine Inside BG,

Heterogeneity of DopamineDepletion and NMS of PD

Among pathologies involving BG, PD is the moststudied. Given that loss of dopamine neurons within

FIG. 2. Dopaminergic lesion heterogeneity in a parkinsonian MPTP monkey (A) and the illustration of the striatal territories probably involved in thedifferent motor symptoms and NMS expressed during the hypo- and hyperdopaminergic states in PD patients (B). (A) The brain sections at the stria-tum and SNc level labeled for the tyrosine hydroxylase (TH) from a normal monkey and an MPTP parkinsonian monkey demonstrates the preferen-tial dopaminergic cell loss inside the SNc, which projects to the associative and sensorimotor striatal territories, whereas the neurons of the VTA,which projects to the limbic striatum territories, remain relatively preserved in MPTP monkeys. (B) This illustration represents the striatal functionalterritories at the origin of the motor symptoms and NMS expressed during the hypodopaminergic state (DA level too low) and the hyperdopaminer-gic state (DA level too high) during dopaminergic treatment. It was adapted from the model that was originally proposed by Volkmann et al.39 withpermission from Nature Publishing Group. It is important to note that, based on behavioral results obtained in MPTP monkeys56,83 and on normalmonkeys by reversible disturbances inside the striatum,81 some behavioral disorders are not attributed to the same territories as those initially pro-posed by Volkmann et al. Cd, caudate nucleus; Put, putamen; Ass, associative territory; Limb, limbic territory; SM, sensorimotor territory.



the SNc is at the origin of this pathology, this makesit quite easy to obtain animal models. Animal modelstudies have largely contributed to our knowledge ofneuronal dysfunctions underlying PD symptoms.Moreover, they lead to a second model of BG organi-zation that has helped to explain the opposite states(hypo- and hyperkinetic states) observed in PDpatients, with and without dopaminergic treatments.This model of “direct and indirect pathways,” whichessentially addresses the intrinsic BG organization andthe interactions between its structures, was originallyproposed by Albin et al.48 and subsequently adaptedby Delong49 for the pathophysiology of PD. Thismodel can be combined with the parallel loop model(Fig. 1B) in each of its functional loops. It has beenwidely described in other reviews50 and therefore willnot be directly addressed in this review. However, it isnoteworthy that the modeling of BG organization hasinspired much research on animal models in order todetermine: (1) the real dysfunctions behind the expres-sion of the different PD symptoms, using neuronalrecording; (2) the causal link between BG activity andthe specific symptoms induced by local and reversiblemodifications of neuronal activity in the nonhumanprimate; and (3) the best BG site to apply DBS, anovel therapeutic approach that improves symptomsof PD. For this last objective, the work on MPTP-treated monkeys, the gold-standard animal model ofPD, has been of importance to identify the STN51,52

as a target for stimulation.Three important conclusions arise from the investiga-

tions carried out on the nonhuman primate model ofPD in relation to expression of the different PD symp-toms. First, dopamine depletion leads to a reduction ofthe selectivity of information that passes through thesegregated cortico-BG functional circuits.53-55 This iscommonly attributed to a decrease of the ratio betweenpertinent information and noise (information with lowlevel or irrelevant) that results in selection deficitbetween information of high and low priority in motor(what part of the body to move?), cognitive (whichaction to do?), and motivation (what is the goal toseek?) domains of BG, which could contribute to themotor symptoms or NMS observed in PD.56-58 This lossof selectivity was well demonstrated within the sensori-motor territories of the pallidum,59 thalamus,54 and onthe cortical level60 by using passive joint manipulationsin the nonhuman primate. The disrupted focalization ofstriatopallidal transmission was also demonstrated bycoupling pallidal recordings and microstimulationwithin different striatal territories.53 This loss of infor-mation selectivity within the BG also explains a higherlevel of correlated activities between STN neurons61

and the synchronized oscillations between pallidal andthalamic neurons and rhythmic activities related to PDtremor,62,63 as shown in monkeys with MPTP lesions.

The loss of spatial focalization of the informationinside the sensorimotor territories of BG induces aninformation overflow back to the cortex, which cre-ates confusion between the motor programs thatshould be initiated to produce a movement adapted toa given context. This may induce a delay in the initia-tion of movement and may also simultaneously triggerantagonistic movements that explain muscle rigidity,both classically observed in PD patients. The deficit inthe selection of information by loss of dopamine insidethe associative and limbic territories of BG could alsoexplain the deficits in action selection and the loss ofinternal motivation that leads patients to act.

In contrast, activation of dopamine receptors afterlevodopa or dopamine agonist intake may restore theratio between pertinent information and irrelevantinformation (the signal-to-noise ratio) and thus helpthe spatial focalization processes inside the BG, whichallow selection and initiation of a context-adaptedbehavior, including the three functional domains(goal, action, and movement). It is well known thatdopamine depletion in PD can induce a hypersen-sitivity of postsynaptic dopamine receptors inside thestriatum.64 It is likely that, with dopamine pharmaco-therapy, this hypersensibility could induce a hyperfoc-alization on specific information and inducesabnormal movement (dyskinesia), nonadapted actions(punding), or goals (impulsive-compulsive behaviors),according to the striatal subterritory expressing thissensitization to dopamine overstimulation (Fig. 2B).This is a similar conclusion that was reached by Voonet al.,65 who discussed the clinical link between thesethree disorders (dyskinesia, punding, and compulsivebehaviors) observed in PD patients and the functionalorganization of BG.

As a matter of fact, the degenerative process withinthe dopamine system irregularly affects the BG, partic-ularly in the striatum, as observed both in the MPTPmonkey model56,66-68 and in PD patients.69,70 The lev-els of dopamine depletion are different, dependent onthe functional territories inside the striatum: The levelis greater in the sensorimotor territory than the asso-ciative territory and less in the limbic territory (Fig.2A). Inside the striatum, this heterogeneity is charac-terized by double anteroposterior and dorsoventralgradients: The posterior parts of the putamen and cau-date nucleus are more affected than their anteriorparts; and the ventral striatum is the least affected bythe dopamine depletion, compared to the dorsal part.With progression of PD and at the late stages of dis-ease, all functional territories are ultimately affectedby dopamine loss. However, it seems that the thresh-old of dopamine loss to induce the specific symptomsin each of these territories is different. Indeed, in mon-keys with progressive MPTP treatment, the first symp-toms to appear were cognitive56 and executive



deficits,71 which suggested that they were under thecontrol of the anterior striatum (associative territo-ries). Such a deficit is also observed in PD patientsduring the early stages of the disease,72,73 and it ispotentially related to the loss of selective informationpassing through the associative territories, which areinvolved in action selection. These symptoms precedethe motor deficit, related to the posterior sensorimotorterritories. Thus, whereas the sensorimotor territoriesare more strongly affected, compared to the associa-tive territories, it is only after stronger dopaminedepletion that the deficits in sensorimotor territoriesresult in the classic motor symptoms of PD (akinesia,rigidity, and tremor). As previously shown, dopamineinnervation of other BG structures, such as the pal-lidum, can compensate for this dopamine depletionwithin the striatal sensorimotor territory.68,74 In con-trast, hyperactivation of the associative territories aftera dopaminergic treatment can induce a hyperactivestate, aimless actions, or repetitive behaviors, alsocalled punding (see Fig. 2B). Long-term L-dopa admin-istration to recovered MPTP monkeys (i.e., monkeyswith a less-severe lesion and that are able to recoverfrom their motor symptoms, compared to theones who stay symptomatic) induces behavioralhyperactivity.75

According to the concept of different denervationthresholds among the BG functional territories, a lowdopamine level in the ventral striatum may lead toearly symptoms, such as depression, apathy, and anxi-ety, in some PD patients.41,42 This brings us toanother important consideration in PD, which is theheterogeneity of the symptom expressions amongpatients. Indeed, some PD patients develop NMS, suchas depression, and others do not. Why do these differ-ences occur? A different pattern of dopamine deple-tion among PD patients could potentially explain thisheterogeneity. Thus, Remy et al.76 showed, using PETimaging with [11C]-RTI-32, a nonspecific marker ofdopamine and noradrenaline, some differencesbetween depressive and nondepressive PD patients.Moreover, the level of apathy measured in PD patientswas negatively correlated with the level of this markerin the ventral striatum.76 Also, the level of dopaminedenervation in the ventral striatum could cause apathyin some PD patients.41 This greater dopaminergic,mesolimbic degeneration predisposes some STN-stimulation–implanted patients to develop apathy,depression, and anxiety after surgery, as demonstratedin a PET [11C]-raclopride study.77 In contrast, anoveractivation of neurons inside the ventral striatum,by a stronger dopamine release45 or a postsynaptichypersensibility, could result in the ICDs, such aspathological gambling, hypersexuality, binge eating,and compulsive shopping, as observed in some PDpatients under dopamine therapy (see Fig. 2B).

Interestingly, as will be shown in the next section, wehave induced behavioral disorders in the nonhumanprimate affecting respectively sexual, aversive, andfood motivations. This strongly suggests that thedopamine preferential activation of one of the subter-ritories within the ventral striatum could result indiverse ICDs in PD patients. In particular, as wasshown in the nonhuman primate, aberrant activity ofa medial part of the ventral striatum could lead tohypersexuality, whereas eating disorder could ratherresult from the lateral part. Moreover, dysfunction inthe central part, which is probably involved in theevaluation of the negative cost of decisions, couldinduce pathological gambling or compulsive shopping.

Finally, owing to the fact that many behavioral dis-orders observed in PD are certainly the result of dys-functions of the associative and limbic BG territories,this supports the view of PD as a neuropsychiatric dis-order, in contrast to a pure motor disorder.

Research of Causalities and theFirst Evidence in Nonhuman

Primates of Behavioral DisturbancesAscribable to Dysfunctions Within

the BG

We have shown that the associative and limbic terri-tories of BG structures are implicated in the expressionof behavioral disorders78,79 (Fig. 3A). For instance, byincreasing neuronal activity in the posterior part of theexternal segment of the globus pallidus (GPe) in normalmonkeys with a local injection of a gamma-aminobutyric acid (GABA) antagonist (bicuculline), wewere able to induce dyskinetic movements.81 Injectionof the same substance into the anterior GPe inducedabnormal behavior.78 Furthermore, we also showedthat attention deficit, with or without hyperactivity,could be obtained from the associative territories (dor-sal part) and stereotyped behaviors from the limbic ter-ritory (ventral part) of the GPe in the normalnonhuman primates 78 (Fig. 3B). These results strength-ened the original hypothesis that the same dysfunctionwithin a structure can impact movement or behavior,depending on the territory involved.

Extension of the experiences to the anterior part ofthe striatum showed the ability to induce of a set ofabnormal movements and behaviors, showing againthe involvement of BG in a wide spectrum of motorsymptoms as well as behavioral disorders79 (see Fig.3C). Within the ventral striatum, which correspondsto the limbic territory, the effects produced by locallyincreasing activity of the output of striatal neu-rons79,82 induced by bicuculline microinjections couldbe grouped into three different classes of abnormalbehavior, each associated with different anatomical



subregions of the ventral striatum. Microinjectionsinto the lateral part of the ventral striatum (inside theanteroventral putamen; see Fig. 3C) induced a behav-ioral effect that we have called an apathetic state,characterized by a diminished global behavioral activ-ity and an altered performance of a food retrievaltask.79 The task execution was characterized by adecrease in frequency of food retrieval associated withan increase in latency to initiate choices, both parame-ters previously described as behavioral markers ofmotivational processes in parkinsonian monkeys.83 Incontrast to parkinsonian monkeys, this apathetic stateinduced by bicuculline microinjection was associatedneither with freezing nor with motor slowness

(bradykinesia).56 The association of a diminished foodmotivation with a global behavioral hypoactivity inmonkeys could be compared to the apathy that hasbeen characterized, in patients, as the quantitativereduction of self-generated voluntary and purposefulbehaviors.59 As mentioned above, it is precisely in thesame region of the ventral striatum where Remyet al.76 observed, in PD using PET imaging with amarker of both dopamine and noradrenaline trans-porter, binding levels that were inversely correlatedwith apathy score.76 Moreover, in a PET study onpatients with bipolar II type depression, the glucosemetabolism was shown to be abnormally increased inthis same anteroventral putamen.84

FIG. 3. Set of results obtained in nonhuman primates by seeking the causal link between changes in specific activities within the functional territo-ries of the pallidum and striatum and movement and behavioral disorders. (A) Opposite activity changes inside the GPe and the GPi on monkeysexpressing dyskinesia induced by dopaminergic therapy (reprinted from Filion et al. [1991]80 with permission from Elsevier). (B) By recreating thisGPe increased activity through blockage of GABAergic inhibitions inside the sensorimotor territory, we reproduced the same dyskinesia in normalmonkeys.81 However, by recreating the same GABAergic inhibition inside the other functional territories of GPe, we switched from abnormal move-ments to behavioral disorders with two main effects (from Grabli et al. [2004]78): hyperactivity associated with attentional disorder (HD/AD) in theassociative territory and stereotyped behaviors in the limbic territory. (C) Injections inside the ventral striatum have induced three different motiva-tional disorders from the lateral to the medial part: an apathetic state, with loss of food motivation in the lateral ventral putamen; stereotyped behav-iors inside the central part; and sexual manifestations inside the most medial part (reprinted from Worbe et al. [2009]79 with permission from OxfordUniversity Press). At the same anterior striatum, the local dysfunctions induced inside the dorsal part produced GTS-like symptoms (simple andcomplex tics, AD/HD, and the stereotyped behaviors previously mentioned as a model of compulsive disorders). (D) Anatomical tracer (Biotin Dex-tran Amine; BDA) injections in these same striatal territories indicated the specific cortico-BG circuits involved in the different GTS symptoms(reprinted from Worbe et al. [2013]101 with permission from Elsevier). Cd, caudate nucleus; Put, putamen; AC, anterior commissure.



A second behavioral effect was obtained from themedial part of the anterior striatum and was charac-terized by sexual manifestations of erection and ejacu-lation (Fig. 3C). Anatomical data in monkeys showthat the most medial part of the head of the caudatenucleus receives projections from the medial prefrontalnetwork, with known sensory-visceromotor functions,and is also critical for guidance of reward-relatedbehaviors and mood setting.85,86 Consequently, ourdata suggest that the ventromedial striatum, as a partof this medial prefrontal network, serves as a nodelinking motivational and emotional components ofsexual behavior with the peripheral autonomic compo-nent. In addition, neuroimaging studies in humansaddressed the neuronal correlates of human sexualbehavior and demonstrated activity in the limbic brainareas in general, and the ventromedial striatum in par-ticular.87,88 This is the subregion where we observedthe sexual behavior in our monkey model after bicu-culline microinjections. Similarly, in PD patients withhypersexuality, a recent functional MRI study showedcorrelation of activity in the ventral striatum89 withsexual desire.

Finally, the third class of behaviors observed afterbicuculline injections in the central part of the ventralstriatum was characterized by a persistency of a spe-cific type of behavior (biting fingers and compulsivegrooming).79 The abnormal repetition of such behav-iors has led us to classify them under the term of ster-eotyped behavior (Fig. 3C). We now have argumentsbased on our anatomical results90 and behavioralexpression91 that this specific type of stereotypedbehavior in monkeys could reflect a state of anxiety.Indeed, the ventral striatum, and, in particular, its cen-tral part, are related to expression and contextual reg-ulation of anxiety in monkeys.92 In humans, a recentmeta-analysis has clearly shown dysfunctions withinthis central region of the anterior ventral striatum inanxiety spectrum disorders and particularly inOCDs.28 From a neurobehavioral point of view, theanticipation of a negative event is a key component ofanxiety and can lead to behavioral, emotional, andphysiological adjustment in preparation for or preven-tion of aversive outcomes. The role of the ventralstriatum, and, particularly, that of the central part, inthe processing of aversive events, such as pain orunpleasant events, has been evidenced not only in ani-mal studies,93,94 but also in human functional imagingstudies.95-98 Taken together, these results providestrong evidence that a part of the ventral striatum isengaged in the emotional anticipation of aversiveevents and their behavioral avoidance.

Using local microinjections into the ventral striatumin primates, we clearly confirmed the functional heter-ogeneity of the limbic striatal territory. These resultsimplicate the ventral striatum in the regulation of

different aspects of motivation, from behavioral initia-tion or motivation to move and take food to sexualmotivation, as well as aspects of negative motivationin an aversive context (Fig. 3C). In the context ofbehavioral disorders induced by dopamine treatmentsin PD, these results therefore identify specific subre-gions inside the ventral striatum where dopamine dys-function could produce the three main types of ICDsobserved in patients: hypersexuality; gambling or com-pulsive shopping (disturbances of negative conse-quence of choices and actions); and binge eating.

The experiments with bicuculline microinjectionsinto the striatum are also important for understandingsome pathophysiological aspects of GTS. Thus, injec-tions into the anterior and dorsal parts of the caudatenucleus and putamen produced a series of effects simi-lar to GTS symptoms (see Fig. 3C). In particular,abnormal movements characterized by abrupt, brief,and rapid muscle contractions, involving mostly theface and the upper limbs, were obtained from theanterodorsal putamen and were close in expression tosimple motor tics. Complex movements, includingthose with a goal to touch objects around the animal(that we named “touching behavior”) were induced byinjections into the caudate nucleus. It is noteworthythat this touching behavior is the frequently observedcomplex tic in GTS patients.99,100 In addition, thiseffect was often associated with a hyperactivity stateresembling AD/HD. Finally, close to the territorywhere all of these previously listed effects were pro-duced, we have also induced the stereotyped behav-iors, which are close to the expression of thecompulsions that could also be present in GTS ascomorbidity. Indeed, all these different behavioraleffects induced by blockage of the inhibitory functionin neighboring territories of the anterior striatumcould explain the heterogeneity of the GTS symptoms.Moreover, these behavioral effects could also beinduced by the electrical microstimulationapproach,101 and the activation of the different striatalregions also involves different cortical areas, as shownin Figure 3D. Using anatomical tracer injections intothe sites of behavioral effects,102 allowed an anatomi-cal and functional validation of this primate model,because it showed the similarities in the neuronal net-works involved in various behavioral effects in mon-keys and expression of symptoms in GTS patients, asindexed by structural brain imaging.103

Pathophysiology of TS and MultipleInhibition Controls Inside the BG

Multiple persistent tics (motor and vocal) are thecardinal symptoms of GTS. Tics are often associatedwith psychiatric comorbidities and mostly with OCDsand AD/HD. The empirical effect of dopaminergic



blockers on tics oriented the first pathophysiologicalhypotheses on BG dysfunction in GTS. However, therelative rarity of GTS and unknown neuroanatomydid not allow the development of animal models ofthis disorder because it was a case for PD. Conse-quently, the first pathophysiological hypotheses ofGTS have only recently emerged. Based on the knowl-edge of the BG functional organization, JonathanMink proposed a model of inhibitory control dysfunc-tion within the BG to explain the presence of involun-tary movements (tics) and behaviors in GTSpatients.104 He suggested that aberrant activities ofthe striatal neurons caused the motor tics. Recent neu-ropathological data reported by Vaccarino’steam105,106 showed a loss of parvalbumin inhibitoryinterneurons in the anterior striatum, associated witha decreased volume of the caudate and putamen107,108

in GTS patients, which fits the proposed model of BGdysfunction in GTS. Our data with bicuculline injec-tions also strengthened the hypothesis of an inhibitorycontrol disorder inside the striatum. According toKalanithi et al.,105 neurodevelopmental abnormalityleading to impairment of the migration of parvalbu-min neurons to both the GPe and the striatum resultsin the decreased density of parvalbumin-positive inter-neurons in the striatum and increased density of theseinterneurons in the GPi. These parvalbumin-positiveGABAergic interneurons, also called “fast spiking”(FS) interneurons, represent only 1% of the striatalpopulation, but exert a powerful inhibitory controlinside the striatum. Owing to their morphologicalcharacteristics,109,110 their axonal ramifications canreach hundreds of neighboring medium spiny neuronsdirectly in their somatic region and inhibit spiking ini-tiation.110,111 Because FS interneurons express a hightonic activity, they keep the discharge rate of mediumspiny neurons to a very low level.112,113 Altogether,these results strongly support the pathophysiologicalhypothesis of an inhibitory dysfunction inside theanterior striatum, which can affect different cortico-BG circuits and lead to motor tics and behavioral dis-orders expressed in GTS.

Using the same primate model with bicuculline-induced motor tic expression, McCairn et al.82,114

showed that the motor tics are preceded by a peakactivity of the medium spiny neurons, which projectoutside the striatum. This disinhibition of the outputstriatal neurons inside the putamen induces activitychanges of downstream structures inside the BG (theGPe activities increase and decrease into the GPi) toultimately generate increased neuronal activity insidethe primary motor cortex directly involved in theinduction of motor tics. This is probably the samemechanism by which bicuculline injected inside otherstriatal territories induces increased activity insidesome frontocortical areas, given that the premotor and

-frontal regions are well known to be involved in dif-ferent functional processes, such as action selection orattentional and motivational processes. This recalls thefirst hypothesis proposed by Mink on the “aberrantactivities” that emerge from the striatum and whichcause the different GTS symptoms104,115 (Fig. 4).

Although the hypothesis of aberrant neuronal activ-ity emerging from the striatum appears attractive, itleads to the question: What can cause this activity inpatients? To answer this question, we must return tothe normal functioning of the BG and their role in theselection of action-relevant information. The striatum,which is the main information entrance of BG,receives a strong convergence of information from thecerebral cortex, which triggers context-appropriateaction. This information must go through many inhib-itory processes present inside the BG. Thus, it isremarkable to see the importance and diversity ofthese inhibitory mechanisms present in the BG. Mostof these known inhibitory controls are illustrated inFigure 4A in conjunction with the action and move-ment selection process during the normal state. Itappears likely that, in the normal state, all these mech-anisms allow the selection of relevant informationwhile blocking noise or competitive information thatcould induce movements or actions inappropriate tothe context.116

In GTS patients, it is possible that one or more ofthese mechanisms is faulty. It is also likely that effec-tive therapeutic agents in the GTS are acting throughthese inhibitory controls. Furthermore, the loss of FSinterneurons could cause poor selection of informationthat could produce the involuntary movements (simplemotor tics) and inappropriate actions (complex tics)or behaviors observed in GTS patients. The extent andpreferential localization of the loss of FS interneuronsinside the striatal territories can explain the variationsin symptom expression in GTS patients.

The Associative and LimbicTerritories of BG Can Be

Therapeutic Targets for PsychiatricDisorders

The BG are major target structures for therapeuticactions by pharmacological treatments (targetingmainly a dopamine transmission) and DBS. The stimu-lation of STN, the target most frequently used fortreatment of PD, also showed the nonmotor effect ofthe stimulation of this nucleus. As seen in Figure 1A,the STN has a strategic position inside BG because itis connected to both BG output structures (GPi andSNr) and therefore can modulate the flow of informa-tion passing through BG. Furthermore, the cognitiveand limbic functions of the STN are supported by



anatomical data. First, a part of the strong reciprocalconnections between the external pallidum and theSTN122 arises from the ventral pallidum, the limbicpart of this structure.123,124 Second, the corticosubtha-lamic projection, forming the hyperdirect circuit,arises not only from the motor cortex,125,126 but alsofrom the associative and limbic part of the prefrontalcortex.127

Numerous other observations are related to behav-ioral changes noted during the application ofDBS.39,43,128 For instance, emotional salient stimuli129-

131 changed the local field potentials recorded duringthe implantation of stimulation electrodes into theSTN. Increased impulsivity also appears as one of themost noticeable adverse effects of STN stimulation inPD patients.132,133 These results are in agreement withprevious experimental results, obtained on rodentmodels, emphasizing the importance of STN in atten-tional processes, impulsivity, and perseverative behav-ior.134-138 In consequence, stimulation of STN couldbe effective to reduce or modulate behavioral disor-ders. Thus, STN stimulation alleviates pathologicalgambling in PD patients, an effect that could be attrib-uted to both a reduction in dopaminergic treatment

and to the DBS.139 In rodent models, reduced motiva-tion for cocaine was also obtained by STN-DBS.140

These results fit well with the idea that DBS applied tononmotor territories of the STN could improve behav-ioral disorders. Thus, stimulation of nonmotor territo-ries of the STN in a monkey model of stereotypedbehaviors, induced by bicuculline injections into theventral pallidum, showed that this concept can beapplied to therapeutic effects in compulsive behav-ior.141 The DBS of the anterior nonmotor territoriesof the STN is now applied to improve OCDs.142,143

Taking into account the association of motor andbehavioral disorders in GTS, the stimulation appliedto the anterior portion of the STN could be effectivefor treatment-resistant GTS patients.

The neural activity of different functional territoriesof BG is mainly the result of a balance between gluta-matergic excitatory and GABAergic inhibitory neu-rons. However, these activities are also under thestrong influence of dopaminergic and serotonergic sys-tems (see Fig. 5). These two modulatory systems arethe main targets of pharmacological treatments forseveral psychiatric disorders, as well as for the NMSin PD and GTS. Dysfunction of these modulatory

FIG. 4. Multiple levels of inhibitory control inside the basal ganglia and the recent physiopathology hypothesis of GTS. (A) Schematic representationof the different levels of inhibitory controls within the BG that appear to be involved in the process of information selection to determine the relevantaction for the goal seeking, while inhibiting competitive options. (1) Recurrent collaterals of the medium spiny neurons can inhibit the activity ofneighboring neurons. (2) The FS interneurons that exert a broad and powerful inhibitory control within the striatum.111-113 These interneurons exerttheir effects preferentially on neurons of the direct pathway117 and to be under the excitatory control of cortical afferents118 and (3) inhibitory GPeafferents that project back to the striatum, specifically on these FS interneurons.111,119-121 (4 and 5) Much evidence also emphasizes the importanceof the double inhibitory control passing through the GPe and to the GPe on both output structures (GPi/SNr), without forgetting the GPe inhibitoryprojection on the only BG structure that uses glutamate as a neurotransmitter, the STN. Dysfunction affecting this last inhibitory projection couldcompletely disrupt the information flow coming out of the BG and thus induce irrelevant or poorly context-adapted actions. Conversely, the STNactivation is able to exercise a general rise of output neuronal activities and thus remove erroneous information coming out of BG. (B) Recent workby Vaccarino’s team105,106 has shown, on brain tissue, that GTS patients have fewer parvalbumin interneurons (1) and cholinergic interneurons (2) inthe anterior parts of the striatum, compared to healthy individuals. Given the important role of the FS interneurons (these interneurons are the par-valbumin interneuron type) in the inhibitory control of the striatum, their much smaller number in the anterior territory of the striatum may explain theproduction of involuntary movements (motor tics) or behaviors (complex tics or compulsive behaviors) observed in these patients. Ch, cholinergicinterneurons.



systems can also cause behavioral disorders, such asICDs induced by dopaminergic agonists.65 This reviewis not focused on the role of dopamine and serotoninin BG neuronal activities, given that many previousreviews have already addressed this in the context ofPD,65,144-146 GTS,147-150 and other psychiatric disor-ders.151-155

We just emphasize here that associative and limbicterritories of BG are important targets of both modu-latory systems. This strongly suggests that the thera-peutic effects of agents targeting these neuromodulatorsystems (neuroleptic drugs and selective serotonin re-uptake inhibitors [SSRIs]) can act on the informationprocessing inside the associative and limbic territoriesof BG. The difference within the functional BG territo-ries targeted by dopamine and serotonin projectionsstrongly supports the idea that serotonergic agentsmay have preferential action on the limbic territory,involving them particularly in the processing of emo-tions and motivations, whereas dopamine can actmore widely, affecting all functional territories, includ-ing motivation, executive functions (attention andaction selection), and the selection of movement.

Given that serotonin and dopamine systems bothreach the cerebral cortex, some cortical regions canindeed be responsible for the therapeutic effects ofdopamine and serotonin drugs.

Given that DBS can be applied in a specific locationinside the BG, the pharmacological approach by usingsubstances targeting receptor subtypes preferentiallylocalized in the associative and limbic territories ofBG could be effective to specifically improve thebehavioral disorders presents in PD, GTS, or psychiat-ric disorders. We therefore believe that there is a realchallenge for research to understand about the prefer-ential modulation effects on neuronal activities of theassociative and limbic territories of BG by agents tar-geting receptors of dopamine or serotonin specificallypresent in these territories. We know, for example,that D3 receptors are primarily located in the pal-lidum and ventral striatum156 and appear to beinvolved in ICDs in PD patients treated with dopa-mine agonist drugs.157 The 5-HT1B type of serotoninreceptor is also preferentially located in the pallidumand ventral striatum158 and could contribute to theexpression of depressive symptoms159 or be a potential

FIG. 5. Hypothetical representation of functional territories found inside the anterior striatum by selective perturbations79 on nonhuman primates (A)linked with the dopamine and serotonin afferents on the striatum. These were revealed in monkeys and humans by PET imaging using two selectivemarkers; one for the dopamine transporter, [11C]-PE2I, and the other one for the serotonin transporter, [11C]-DASB (B). (A) The results obtained fromreversible disturbances (by bicuculline injections) inside the anterior striatum strongly suggest a striatal partition into different areas involved in theselection and preparation of actions inside the dorsal part, whereas the ventral part could be divided into subareas, which are all involved in motiva-tion, but for different domains, from the medial to the lateral striatum; the types of motivation are sexual, defensive, and food motivation. Modulatoryaction, by serotonergic afferents from the raphe nucleus, could have a greater effect on motivational processes (ventral striatum), whereas dopami-nergic afferents from the SNc and the VTA can have a greatest effect on all the functions owing to their wide distribution throughout the striatal terri-tories (dorsal and ventral regions). (B) Images of the anterior striatum for monkeys (mean of 4 animals) and humans (mean of 15 subjects), with[11C]-PE2I and [11C]-DASB, showing a difference in distribution of BPND (Binding PotentialNon-Displaceable) between the dopamine and serotoninmarkers into the striatal territories. This is present in both primate species (humans and monkeys). Images from humans have been kindly lent byS. Thobois and A. Maillet.



site of therapeutic action of the SSRIs.160 Specifically,for the serotonin agents, there is still much to do todetermine where the SSRIs are acting in the brain?Does the therapeutic effect of the SSRIs on anxietydisorders and depression take place in the BG?Answering this question could upset the viewpoint ofthe involvement of BG nonmotor territories in behav-ioral disorders. More generally, the challenge forresearch in the neuropharmacological field will be todetermine the relative contribution between BG andother brain targets behind the therapeutic effects ofdopamine and serotonin drugs. What are the respec-tive roles of these two modulators inside the BG struc-tures and how do they interact together? Finally, howdo these two modulatory systems interact in patholog-ical states and when treatments are applied? Given thesimilarity of the distribution of these two modulatorysystems between humans and primates (see Fig. 5), itappears that research at the preclinical level on mon-keys could be important to address many of thesequestions, given that nonhuman primates have greatlyhelped to aid in the understanding of the pathophysi-ology of PD and GTS and the involvement of BG dys-functions in movement and behavioral disorders.

Conclusions

For a long time, the BG have been viewed exclu-sively as motor control structures. Over the last 30years, research on the role of the BG in motor proc-esses has greatly advanced. In 1982, Marsden, in hisreview,161 had reported PD symptoms that appearedto him not to be a result of the dysfunction of motorcontrol and led him to the review title of “The myste-rious motor function of the basal ganglia.” He pio-neered this view of BG functionality a long timebefore the model of cortico-BG organization in func-tional circuits had been proposed and before numer-ous studies on animals and humans provided theevidence of BG implications in a broad spectrum ofbehavioral disorders. The studies discussed in thisreview provide experimental evidence that the associa-tive and limbic territories of these structures might beinvolved in the expression of many behavioral disor-ders and also might become a target for treatment ofthese disorders. The evolution of knowledge about thenonmotor function of BG led to a better understand-ing of the NMS in PD and GTS. More specifically,models using nonhuman primates, highlighted in thisreview, could also be useful in future studies on thera-peutic drug targeting or DBS applied to behavioraldisorders.

Acknowledgments: The authors thank Audrey Maillet and EliseMetereau for TEP imaging, which illustrated the striatal territories tar-geted in humans by the dopamine and serotonin systems. The authorsthank Christopher Kennard for checking the English in this publication.

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Selective dysfunction of basal ganglia subterritories: From movement to behavioral disorders

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