REVIEW

Normal and pathological gait: what we learn fromParkinson’s disease

David Grabli,1,2,3,4 Carine Karachi,1,2,3,4,5 Marie-Laure Welter,1,2,3,4 Brian Lau,1,2,3,6

Etienne C Hirsch,1,2,3 Marie Vidailhet,1,2,3,4 Chantal Francois1,2,3

ABSTRACTGait and balance disorders represent a majortherapeutic challenge in Parkinson’s disease (PD).These symptoms respond poorly to dopaminergictreatments, except in the early phase of the disease.Currently, no other treatment is particularly efficientand rehabilitation appears to be the most effectiveapproach. Since these gait and balance deficits areresistant to dopaminergic drugs, their occurrencecould be related to the development ofextradopaminergic lesions in PD patients. We providea comprehensive description of the clinical features ofgait and balance disorders in PD. We also highlight thebrain networks involved in gait and balance control inanimals and humans with a particular focus on therelevant structures in the context of PD, such as themesencephalic locomotor region. We also reviewother neuronal systems that may be involved in thephysiopathology of gait and balance disorders in PD(noradrenergic and serotoninergic systems,cerebellum and cortex). In addition, we review recentevidence regarding functional neurosurgery for gaitdisorders in PD and propose new directions for futuretherapeutic research.

INTRODUCTIONGait and balance disorders are a major problem withunmet therapeutic objectives during the course ofParkinson’s disease (PD). While dopamine (DA)responsive symptoms can be treated, initially withdopaminergic drugs and then with stimulation ofthe subthalamic nucleus when severe fluctuationsor dyskinesia occur, gait and balance disorderscurrently remain untreatable. These symptoms arenot severe early in the course of PD but progresswith time in a majority of the cases and representa heavier burden later in the course of the disease.The increasing impact of gait and balance disordersis mainly explained by lack of efficacy of DAtreatments on these symptoms.1 Likewise, highfrequency stimulation of the subthalamic nucleusfails to improve gait and balance disorders resistantto levodopa and even worsen these symptoms insome cases. With disease progression, the globalburden of axial symptoms increases in direct rela-tionship with the increase in fall frequency andfreezing of gait (FOG). Although the pathophysi-ology of gait and balance disorders in PD remainsinsufficiently understood, several recent studies

have shown that the mesencephalic locomotorregion (MLR) of the brainstem is implicated inthe control of gait and balance in mammals2 andlocomotion in humans.3 4 More specifically, thedysfunction of cholinergic neurons of the pedun-culopontine nucleus (PPN), located in the MLR,likely play a crucial role in the appearance of axialsymptoms in PD. Other neuronal systems,including the locus coeruleus, the raphe nucleus,the cerebellum and the cerebral cortices, mayalso be involved. However, the efficacy of drugstargeting these non-dopaminergic systems(including cholinergic and monoaminergic agents)is still disappointing. Low frequency stimulationof the PPN was recently introduced in PD patientswith drug-resistant gait and balance disorders.Despite initially promising individual case reports(for a review, see5), the overall results of controlledstudies have been disappointing. In the first part ofthis review we describe and discuss the existingliterature on the clinical features of gait andbalance disorders in advanced forms of PD. Wethen focus on the physiology and pathophysiologyof gait control and review the neuronal circuitsinvolved, supported by evidence from experi-mental manipulations in various animal species,in order to propose new directions for futuretherapeutic research.

HYPOKINETIC GAIT AND FESTINATIONS IN PDDopa responsive gait and balance alterations arefrequent in PD and encompass distinct patterns.Hypokinetic rigid gait is mainly characterised bya reduction of gait speed,6 with a reduction of thestep amplitude but an unchanged or slightlyincreased cadence. In early studies of gait atimposed speed, PD patients were able to increasetheir cadence but the step length remainedsystematically lower whatever the speed.7 Thisobservation suggests that gait akinesia was mainlyrelated to a deficit in internal generation of adaptedstep length rather than an inability to increase thecadence. Conversely, cadence increase may beviewed as a compensatory mechanism. In line withthis concept, external visual cues help to increasethe step length, suggesting that only internalprogramming of amplitude is impaired, a findingthat is consistent with general descriptions ofakinesia. Postural disturbances related with hyper-tonia were also described in PD gait. They could beexplained by a flexed and stiffened posture of thetrunk throughout the gait cycle. The range motionof the hip was also reduced. All these changes are

< An additional material ispublished online only. To viewthis file please visit the journalonline (http://dx.doi.org/10.1136/jnnp-2012-302263).1Universite Pierre et MarieCurie-Paris 6, CR-ICM,UMR-S975, Paris, France2INSERM, U975, Paris, France3CNRS, UMR 7225, Paris,France4Assistance Publique-Hopitauxde Paris, GroupePitie-Salpetriere, Paris, France5CENIR, ICM, Paris, France6Department of Neuroscience,Columbia University, New York,USA

Correspondence toDr Chantal Francois, CRICM,UMRS 975, Inserm, UPMC,Hopital de la Salpetriere, 47 Bdde l’Hopital, 75013, Paris,France;chantal.francois@upmc.fr

Received 11 January 2012Revised 16 April 2012Accepted 16 May 2012Published Online First29 June 2012

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well improved by levodopa.6 Another typical and unique gaitpattern observed in PD is festination. Festinating gait isdescribed as rapid small steps done in an attempt to keep thecentre of gravity in between the feet while the trunk is leaningforward involuntarily. The mechanisms of festination and itsrelationship with FOG are still debated. Although festinationwas found to be associated with FOG,8 it is difficult to finda unified view to include the issue of gait initiation in thisparticular symptom.9 Thus festination may also be considered asseparate episodic gait impairment encountered in PD. Early inthe course of PD tandem gait performance is generally normalalthough it is impaired in most atypical parkinsonism.10

However the most impairing gait disruptions are related withbalance deficit and FOG episodes that tend to become resistantto levodopa, thus suggesting the involvement of extranigrallesions.1

FALLS ARE A MAJOR MILESTONE IN THE EVOLUTION OF PDIn PD patients, falls induce an increased risk of mortality andmorbidity mainly related to hip fractures and head injuries. Fallsare a source of major disability leading to dependency, institu-tionalisation, poor quality of life and a residual fear of falling. Theincidence of falls in PD is variable among the different availablestudies, with a 51e68% risk of having a fall in a year in PDpatients.11 The frequency of recurrent falls is about 50% in1 year.12 Once the first fall has occurred, the survival duration issimilar in PD and in atypical parkinsonian syndromes whichusually have a more severe course.13 Clinical predictive factors offalls are a previous fall, fear of falling, disease duration andseverity, abnormal axial posture and tone, cognitive impairment,decrease in arm swing (uni- or bilateral), presence of dyskinesiaand antiparkinsonian treatment.14 Most falls are unrelated toextrinsic factors, such as sliding or a collision, but are dependentupon intrinsic deficits of balance control. Falls occur mainlyduring posture changes, in particular during a half-turn, or whileperforming activities that require a double task demand (cogni-tive or motor).11 The more the second task is difficult, the morethe balance control is altered and fall risk increased.11 Lastly, someauthors reported proprioceptive and vestibular deficits in PD,which can participate in the occurrence of balance disturbances.15

At bedside, postural instability is routinely evaluated with thepull-retropulsion test (item 30 of the Unified Parkinson’s DiseaseRating Scale-part III). However, variability exists in its executionand the reproducibility is low and so is its sensitivity to the earlydetection of fallers.15 In the recently validated Movement DisordersSociety-Unified Parkinson’s disease rating scale (MDS-UPDRS),16

detailed instructions for the examiner may reduce the variability ofthis test. However, the outcome of clinical testing for posturalinstability is not related to the risk of falls.12 Other clinical testssuch as the push and release test have recently been proposed withhigher sensitivity for identifying fallers. Non-specific scales have alsobeen proposed to evaluate balance and risk of falls in parkinsonianpatients, such as the Berg Balance Scale, the Timed Up and Go test,and the Tinetti score, with a good sensitivity to detect fallers amongPD patients.14 Recently, the Functional Gait Assessment, theBalance Evaluation System Test, and the Rapid Assessment ofPostural Instability in PD have been proposed for PD patients withgood test-retest and inter-rater reliability, good sensitivity to detectfallers versus non-fallers and good predictive value.17

POSTUROGRAPHY FOR BALANCE DEFICITS IN PDQuantitative posturographic methods measure oscillations ofthe centre of pressure of the foot with force plates in static or

dynamic position using mobile platforms. Measures include thelimit of stability and the posture sway using the sensory orga-nisation test.18 The perturbation can be a rotation, a translation,or both combined; then the changes in the centre of pressureposition and the pattern and latencies of lower limb muscleactivations can also be measured. In the literature, many studiesreport posturographic data in PD patients, but with contradic-tory results (online supplementary material). Even if significantdifferences exist between PD patients and healthy subjects atthe group level, posturographic parameters are not well relatedto clinical postural instability or risk of falls. Their usefulness forthe management of individual patients has yet to be clearlyestablished, in particular for assessing the effects of therapeuticinterventions on balance deficit in PD patients. Posturographystudies may however provide insights in the mechanisms offalls. For example, Carpenter et al19 stressed the abnormalities ofupper limb movements that could give no protection againstfalls in PD patients. Recently, a change in the vertical velocity ofthe centre of mass has been shown to be sensitive to posturalinstability and to the effects of treatment at the individuallevel.20 However, its utility in clinical practice as well as itspredictive value needs to be further evaluated.

FREEZING OF GAITFOG is an episodic transient disruption of gait that typicallylasts a few seconds and is associated with a unique sensation:patients feel that their feet are glued to the ground, causing themto remain in place despite making a concerted effort to overcomethe motor block and move forward. FOG is not specific of PD. Itmay also be encountered in other degenerative disorders such asprogressive supranuclear palsy, multisystem atrophy or dementiawith Lewy bodies and in focal lesions of various brain structures(brainstem, basal ganglia, supplementary motor area, frontallobes and subcortical regions).9

When FOG occurs during gait initiation, it is characterised byrepeated ineffective anticipatory postural adjustments and leadsto a failure of gait initiation and sometimes to a fall. FOG mayalso occur while patients are walking. There is an abruptdecrease of step length and increase of step frequency and step-to-step variability that precedes a complete blockade of gait andfalls. Another important characteristic is the occurrence of anirregular rapid trembling in both knees.21 FOG is often triggeredby characteristic circumstances such as a half or 3608-turn,22

obstacle (doorway) clearance, spaces with a narrow passage orunexpected visual or auditory stimuli. Fatigue, stressful situa-tions, cognitive load23 anxiety and depression may also elicitFOG.24 Usually, FOG is improved by visual (eg, marks on theground) or auditory cueing (rhythmic sounds). Paradoxically,running, cycling or climbing stairs are performed more easilythan usual gait. Generally, freezing is defined as an abruptdifficulty in starting or continuing rhythmic and repetitivemovements. Freezing is also observed in other motor plans suchas in repetitive bimanual motor tasks (eg, writing) or duringspeech. In line with this concept, freezing (and FOG) may beviewed as an extreme form of akinesia. New tools for FOGassessment have recently been developed. For the purposes ofobjective evaluation, standardised tasks have been designed toelicit FOG during gait with imposed stressors, such as a fastcadence, a slow cadence or obstacle occurrence. An obstacleavoidance task during treadmill walking was also used toprovoke FOG.25 Freezing episodes can be automatically detectedby means of ambulatory devices.26 Given the difficulty inevaluating FOG, more sensitive and specific clinical andneurophysiological approaches need to be developed.

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Because of its high variability, depending on environmentaltriggers, emotional state, cognitive inputs and medication, thefrequency of FOG is difficult to measure in PD populations. In theDeprenyl and tocopherol antioxydative therapy for Parkinson’sdisease (DATATOP) study, FOG was infrequent (7.1%) and rarelyled to fall in early PD. Its frequency rose to 23.6% after 18 monthsof observation. The risk of developing FOG was increased inpatients that started the disease with gait disorders and had higherscores in postural instability, rigidity, bradykinesia and speech atbaseline. In contrast, tremor at onset considerably decreased therisk of subsequent FOG. At the end of follow-up, FOG was nolonger associated with akinesia and hypertonia but correlated withother midline signs (speech deficit and balance disorder) suggestingthat these symptoms are, at least partially, independent ofakinesia.27 After 6e10 years of evolution, FOG was retrospectivelyreported by 48e70% of PD patients.28 Cognitive deficits and, morespecifically, low frontal test scores are also associated with FOG.FOG has a high impact on the quality of life of PD patients farbeyond its motor components since quality of life measured on theParkinson’s disease questionnaire (PDQ) scale is affected in all itsdimensions except stigma and social support.29

The cerebral mechanisms underlying FOG have not been eluci-dated but alterations observed during physiological analysis of gaitmay provide important clues. Alterations of gait rhythm, gaitsymmetry and bilateral coordination in stepping are observed in PDpatients with FOG outside episodes of freezing.30 However, thequestion of whether these alterations are causative is still debated.Electromyographic studies alsopoint todisruptionof thecentral gaitcycle timing: a consistent pattern of premature timing of lower limbmuscle activity before freezingwas observed thatmay contribute todeceleration and interruption of the movement.31 The role ofperceptual stimuli (such as doorways) as a FOG trigger also suggeststhat a perceptual defect may contribute to the motor impairment.Conversely, the improvement of FOG by visual clues may reveala double deficit: increased visual dependence to compensateimpaired kinaesthetic feedback and increased attentional processingin order to bypass the deficit of internal generation of appropriatelower limb movement during the automated gait cycle.32 33

GENERAL ORGANISATION OF THE NETWORK INVOLVED INBALANCE AND LOCOMOTIONThe neuronal networks involved in locomotion have beenextensively studied in animals. They are hierarchically organised

and include: (1) the lower effector levels, including the muscu-loskeletal system and the peripheral nervous system; (2) thecentral locomotion pattern generators composed of organisedgroups of interneurons automatically generating rhythmic andalternating limb activity34 (3) several locomotor areas located atvarious levels in the brainstem, which control the central loco-motion pattern generators and are characterised by their abilityto produce locomotor action when electrically or pharmacolog-ically stimulated. These are the subthalamic locomotor region,the MLR and the dorsal and ventral tegmental field of the caudalpons. The MLR, composed of the PPN and cuneiform nucleus(CN), is the locomotor area known to be the most relevant inPD, and we will focus on the MLR and will not review data onthe structures located in the posterior midbrain; (4) finally, theselocomotor areas are modulated by higher level control systems,including the dopaminergic and other modulatory systems, thebasal ganglia and the prefrontal cortex. These locomotor circuitsare modulated by sensory feedback via sensory afferent systems(somesthetic, vestibular and visual systems) (figure 1A).

MLR IN GAIT CONTROLAnatomical definition and connections of the MLRAmong the different locomotor areas with a direct input to thespinal cord, the MLR is of particular importance in the physi-ology and pathophysiology of gait. The MLR is located in thereticular formation and corresponds to the PPN and CN.35 Boththese structures were identified as groups of neurons located inthe reticular formation. The presence of cholinergic neuronsserves to define boundaries of the PPN in primates. Thecholinergic neurons are distributed within a dense dorsolaterallylocated area called the PPN pars compacta and a sparse moremedially located area called the PPN pars dissipata.36 There arealso non-cholinergic neurons in the PPN that are Gamma-aminobutyric acid (GABA) mediated (GABAergic) and gluta-matergic. About 40% of cholinergic neurons also express gluta-mate in monkeys.37 The CN is located dorsal to the PPN andthus ventral to the superior and inferior colliculi and comprisesglutamatergic and GABAergic neurons.Both the PPN and the CN have reciprocal connections with

the basal ganglia and have major outputs to the descendingreticulospinal pathway and the ascending thalamocorticalpathway (see38 for review). Inputs to the PPN are similar inprimates and in rodents, except that projections from the deep

Figure 1 (A) Anatomy andconnectivity of the pedunculopontine(PPN) and cuneiform nuclei (CN) inprimates. Both nuclei have reciprocalconnections with the basal ganglia(GP, globus pallidus; Pu, putamen;SN, substantia nigra; STN, subthalamicnucleus). They also receive inputs fromthe cerebellum and motor cortices. Theexistence of inputs from the spinal cordremains to be demonstrated in monkeys.The PPN and CN have major outputs tothe descending reticulospinal pathwayand the ascending thalamocorticalpathway through the thalamiccentromedian nucleus. Cholinergic neuronsin the PPN visualised using Nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase histochemistry are also represented in a transversebrainstem section (lower right panel). (B) Anterior view of surgical targets for Parkinson’s disease. Targets are defined in a three-dimensional histologicalatlas, with axial and coronal sections of the corresponding postmortem T1-weighted MRI. The usual targets are visualised on the right hemisphere: GPi,internal globus pallidus; STN, subthalamic nucleus; Vim, ventral intermediate thalamic nucleus. New targets are visualised on the left hemisphere: CM,thalamic centromedian nucleus; CN, cuneiform nucleus; PPN, pedunculopontine nucleus; SNr, substantia nigra pars reticulata.

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cerebellar nuclei have only been demonstrated in monkeys39 andthat projections from the spinal cord have only been reported inrats and cats (for review, see38). Afferents from the basal gangliain monkeys originate from the sensorimotor, associative andlimbic anatomo-functional territories40 suggesting that the PPNis in a position to integrate motor and non-motor inputs.Ascending outputs from the PPN mainly project to dopami-nergic neurons of the substantia nigra pars compacta, subtha-lamic nucleus, pallidum and thalamus. Descending outputsproject to the pontobulbar reticular formation,41 where thereticulospinal pathway originates. Interestingly, a recent studyperformed in rodents using optogenetics demonstrated that theactivation of glutamatergic neurons of caudal hindbrain was ableto elicit locomotor-like activity.34 The connections of the CN areless well known. However, a descending projection has beenreported in primates.41 A recent study also provides evidencethat the substantia nigra pars reticulata (SNr) projects to boththe PPN and CN, whereas the internal pallidum projects mainlyto the PPN.41

Behavioural consequences of MLR experimental manipulationsExperiments in decerebrate animals and in alert cats demon-strated that continuous electrical stimulation (20e60 Hz) of thePPN region elicits stepping on a treadmill (see for review, see5).The frequency of the step cycle changes from a rapid walk toa gallop as the strength of current is increased.42 The PPN andCN could play separate roles, since repetitive stimulation of theCN in decerebrate cats evokes locomotor movements, whereasstimulation of the PPN suppresses postural muscle tone.2 Innormal monkeys, large excitotoxic lesions of the PPN, radio-frequency lesions, local injection of GABAergic agonists, or highfrequency stimulation induce akinesia (for review, see38). Thiswas interpreted as the consequence of a decreased activity of theexcitatory projection from the PPN to the dopaminergicnigrostriatal system. A recent study demonstrated that a smalllesion of PPN cholinergic neurons is instrumental in the devel-opment of gait and balance disorders in monkeys.4 No akinesiawas found in these monkeys but gait disabilities resistant todopaminergic drugs were observed, indicating that PPN cholin-ergic neurons play a central role in controlling gait and posturein primates.

Involvement of the MLR in normal and pathologic gait in humansImaging studies in humans also support a role of the MLR innormal and pathological gait. In healthy volunteers, a positronemission tomography scan study showed that frontoparietalareas and basal ganglia were activated by walking withobstacles,43 while functional MRI studies during the imagina-tion of gait showed activation of a circuit including the frontaland parietal cortices, basal ganglia, cerebellum, midbraintegmentum and pons.44 Interestingly, activation in the mesen-cephalon was also shown during imagined running3 and moreparticularly in the MLR during imagined fast gait,4 suggestingthat this region is involved in the control of gait cadence inhumans, as previously suggested by single cell recording duringlower limb rhythmic movements.45 During imagery of gait, PDpatients with FOG showed more activity in the MLR thanpatients without FOG.46 Moreover, atrophy of grey matter ina small portion of the MLR mesencephalon atrophy has beenreported in parkinsonian patients with FOG.46

A dysfunctioning of MLR cholinergic neurons responsible forgait and balance disorders has recently been highlighted. Indeed,postmortem studies showed that the degree of cholinergicneuronal loss within the PPN in PD patients is correlated with

the level of DA cell loss47 and, importantly, with the occurrenceof falls.4 In this study, no statistically significant difference ofcell loss was found in the CN between faller and non-faller PDpatients. In line with a possible causal relationship betweencholinergic loss in the PPN and falls, cholinergic terminationswithin the thalamus were decreased in faller PD patientscompared to non-faller PD patients.48

Involvement of other structures relevant for gait dysfunctionin PDBrainstemEvidence for relationships between gait disorders andnoradrenalin and serotonin systems is anecdotal and has yet tobe fully elucidated. The hypothesis that noradrenergic neuronsof the locus coeruleus, known to degenerate in PD,49 maycontribute to gait and balance disorders in PD and in otherneurodegenerative disorders has recently been proposed.50

Neurons utilising noradrenalin, an excitatory neurotransmitter,are mainly located in the locus coeruleus and innervate wide-spread areas in the central nervous system including cortex,cerebellum and spinal cord. Because the coeruleocerebellar andcoeruleospinal pathways are involved in autonomic regulationand postural reflexes,51 their degeneration may also explain thepostural instability observed in PD. Serotonin, mainly located inthe raphe nuclei in the brainstem, is also known to modulate therhythm and pattern of locomotion, in particular the accuracy ofalternation between antagonistic discharges.52 Serotonin levelsin cerebrospinal fluid are reduced in PD patients and in particularin PD patients with severe gait and balance disorders.53

Cortex and cerebellumThe motor cerebral cortices and the cerebellum are known to beinvolved in locomotor control. Even if there is currently no directevidence of their role in the pathophysiology of gait and balancedisorders in PD, functional imaging studies suggest interestingcorrelations. FOG has been studied in patients with PD usingradiotracer studies. Gait disorders were related to decreased perfu-sion in various brain areas including bilateral orbitofrontal cortex,54

and parietofrontal areas including the supplementary motor area(SMA) (see9 for review). Single photon emission computedtomography (SPECT) has been used to investigate the mechanismsunderlying the improvement of hypokinetic gait in PD patientswhen exposed to visual stimuli (the ‘paradoxical gait’). PD patientsshowed enhanced activation in the lateral premotor cortex toa significantly greater degree than control subjects,55 suggestingthat the premotor cortex compensates for the impaired supple-mentary motor area function in PD patients. Hypometabolismassessed using 18F-fluorodesoxyglucose positron emission tomog-raphy was more severe in PD patients with FOG than thosewithout FOG in several cortical areas, including parietal regions.56

A hyperactivation has also been found in PD patients in thecerebellum, a structure known to be crucial for motor coordi-nation and balance control.57 This hyperactivation was inter-preted as a strategy of the central nervous system to compensatefor the defective function of the basal ganglia and brainstem butcould also be causative. Thus, unravelling the role of cerebellardysfunction in gait and balance deficits in PD may representa major challenge for the future.

MEDICATION OPTIONS AND REHABILITATIONThe response of gait and balance disorders to levodopa isinconstant and decreases over time. Only a few trials have testeddrugs targeting extradopaminergic systems for FOG or balancedeficits in PD. A recent study demonstrated that a central

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cholinesterase inhibitor reduced the number of falls by 0.12falls/day in comparison with placebo (0.25 falls/day, p¼0.049).58

Thus, the number of patients to treat to avoid one fall was 8.3 inthis study. Another trial suggested that methylphenidate couldimprove OFF-dopa FOG whereas a beneficial effect on FOGpersisting ON-dopa was less obvious.59 However, these resultsremain controversial since a recent study reported that meth-ylphenidate was not effective and could even worsen theseverity of PD symptoms.60 Finally, rehabilitation programstargeting gait and balance are widely used in clinical practicealthough scientific evidence for choosing the optimal method isstill lacking. Interestingly, an experimental study in miceintoxicated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinesuggested that treadmill exercise could improve balance/loco-motion and increase the DA level in the dorsal striatum.61 In PDpatients, various rehabilitation approaches were evaluated incontrolled trials (see online supplementary material). Nearly alltypes of rehabilitation methods are beneficial in comparisonwith no intervention. Interestingly, home based exerciseprograms could also be efficient to reduce the risk of injuriousfalls and recurrent near falling.62

Given the seminal importance of the cholinergic lesion of thePPN in the pathophysiology of gait disorders, drugs targetingthis system should be further explored. Despite the relative lackof response to inhibitors of cholinesterase, this strategy shouldnot be discarded, since the procholinergic effect could behampered by the degeneration of terminations within thetargets of PPN cholinergic neurons. From a pathophysiologicalstandpoint, there is evidence to support the use of directcholinergic agonists. Nicotine would be convenient to use andits effects on gait and balance parameters could be tested.However, as nicotine is not specific to the PPN cholinergicsystem, its potential effects could be masked by the action onother targets such as cerebral cortex and striatal interneurons.Thus, further research aimed at identifying the subtypes ofcholinergic receptors involved in gait and balance may help withthe process of screening new drugs. Interestingly, a recent studyperformed in the lamprey63 suggested that muscarinic cholin-ergic receptors could be critical for driving activation of thereticulospinal pathway from the MLR. Thus, further studyfocused on the role of muscarinic receptors in mammals couldprovide new therapeutic options for gait disorders in PD. Similarapproaches could be applied to the noradrenergic system, whichcould also be involved in gait and balance disorders in PD patients.Even though an improvement of gait has been reported in PDpatients after administration of the 5-HT2 serotonin receptorantagonist ritanserin (an anxiolytic substance),64 the specificeffect of serotoninergic drugs on gait has never been studied.

FUNCTIONAL SURGERYUsual targets for deep brain stimulation (DBS)The effect of each DBS target used to treat PD patients wasevaluated on gait and balance disorders (for review, see65). Bothshort- and long-term follow-up studies indicate that highfrequency stimulation of the ventral intermediate thalamicnucleus has no effect on parkinsonian gait and balance disor-ders.66 High frequency pallidal stimulation can mildly improveonly dopa-responsive postural deficit and FOG, but this effectdisappears in 3e4 years.67 Bilateral high frequency stimulationof the subthalamic nucleus is also effective on dopa-responsivegait disorders in PD patients. Quantitative posturographicmethods showed an improvement of the amplitude of antici-patory postural adjustments and of the ability to actively brakethe falling phase in the centre of gravity.20 The improvement

was also significant in reducing anticipatory phase duration andpostural oscillations, with a reduction of falls. For the majorityof patients in long-term follow-up, gait and balance disordersbecame resistant to levodopa and to subthalamic DBS and couldeven be worsened by DBS.68 Manipulating stimulation param-eters can sometimes specifically reduce gait and balance disor-ders. Low frequency (60 Hertz) stimulation of the subthalamicnucleus has been shown to significantly reduce FOG,68 but thissetting was less effective at alleviating the cardinal symptomsand cannot be proposed as a chronic treatment for severe PDpatients (figure 1B).

Surgical treatments: state of the art and future perspectivesAcute high frequency stimulation of the SNr has been shown toimprove axial symptoms and postural control during gait buthad no effect on cardinal symptoms.69 The mechanism of actionto explain this specific effect on postural control could bea modulation of the descending non-dopaminergic networklinking the SNr to the MLR. However, SNr projections to MLRin humans are not as prominent as those from internal pallidumin non-human primates and rodents.5 If SNr-DBS cannot beproposed alone as a treatment for advanced PD patients, thisspecific gait improvement may represent a new surgicalapproach in association with other therapies in PD patients.Within the MLR, it has recently been proposed that the PPN

specifically controls axial symptoms resistant to levodopa, andmay be a promising target for DBS. The aim was to activate theremaining PPN cholinergic neurons to improve axial symptomsincluding FOG and balance deficits in PD patients. The firststudies in humans involved advanced PD patients with DBSelectrodes already implanted in the subthalamic nucleus, andconcluded that the addition of bilateral PPN low frequencystimulation could be effective to control gait and balancedisorders (for review see5). The clinical results obtained and thelocations of the electrodes have been discussed elsewhere.70

Three years later, two double-blind controlled studies in six PDpatients each concluded that: (1) FOG can be improved by PPNstimulation but the overall results remain disappointing71;(2) unilateral PPN stimulation in patients without subthalamicnucleus stimulation may be sufficient to reduce falls signifi-cantly.72 These heterogeneous outcomes emphasise the need todetermine optimal inclusion criteria as well as the optimalsurgical target within the MLR. In fact, the CNmay also providean interesting target to treat gait and balance disorders. Thesenuclei of the brainstem are not easy to target using conventionalMRI methods, although specific MRI protocols allowingaccurate targeting have recently been validated in humancadavers73 (figure 1B).Given the ascending and descending projections of the PPN to

the thalamic centromedian nucleus and to the reticulospinalpathway, it may be worthwhile to investigate stimulation ofthese two structures for treating gait and balance disorders inPD. The centromedian nucleus is also easier to target and lessrisky than nuclei within the brainstem. This target should beevaluated, first experimentally in animal models and subse-quently in patients for this specific indication. Spinal cordelectrical stimulation using epidural electrodes is anotherpotential surgical target, which would also be less invasive. Inparkinsonian rodents, epidural thoracic electrical stimulationof the dorsal columns in the spinal cord was able to restorelocomotion.74 However, a subsequent human study reported notherapeutic effect of spinal cord stimulation in two PDpatients.75 It is possible that the development of new electrodesto stimulate the spinal cord may improve the outcome of spinal

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cord stimulation for gait disorders. The development ofnew stimulation technology and surgical approaches is animportant avenue for future research, and it will be important totest and validate these developments in parkinsonian monkeyswith gait disorders4 to evaluate their therapeutic potential inhumans.

Acknowledgements The authors would like to thank Dominique Tande, NicolasWattiez and Morgane Montfort for technical assistance during animal experimentsand Nick Barton for language editing.

Contributors All the authors were involved in the conception, the drafting and thecritical revision of this review. DG, CK, MV, CF contributed equally to this work.

Funding Part of the work presented in this review was funded by INSERM, theFondation de l’Avenir and the Michael J. Fox Foundation.

Competing interests None.

Provenance and peer review Commissioned; externally peer reviewed.

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Table 1. Static and dynamic posturographic studies in PD patients

Methods Parameters studied Presence of clinical postural

instability

OFF ON Results References

Quiet standing

with eyes open

and with eyes

closed

CP displacement, sway area - X X Normal postural sway 1,2,

Patients with clinical postural

instability

- X Forward shift of the CP 3

Patients with no detectable

postural instability and

severely affected

X X Increase or decrease in postural sway 3, 2

- - - Increase in postural sway during dual-

task (motor or cognitive)

1

- - - 4

- X X No effect or aggravation with levodopa

treatment

5,6

Target pointing - X - Decreased CP displacements with eyes

closed with no difference in pointing

accuracy

7

Perturbed

stance position

Reflexes; EMG responses Patients with advanced PD X X Normal latency and pattern of lower limb

EMG activity

6

- X X Increase or decrease in latency 8

Patients with advanced PD X X Increase or decrease in amplitudes 8,6

Patients with moderate and

advanced PD

X X Inability to shape or scale the muscular

activity in response to the perturbation

and deficit in habituation

6

- - - Interest of the first trial response 9

- Partial improvement with levodopa

treatment

8,6

SOT: visual, vestibular and

somatosensorial inputs

- X X Normal SOT scores 10

- X X Decrease in SOT score for combined

visual and somatosensory input

deprivation

10,11

- - - Improvement or aggravation with

levodopa treatment

10,11

Limits of stability (LOS) - X X Decrease in LOS 11

Joint angles and movements Patients with and patients

without detectable postural

instability

X X Decrease in trunk, head, and ankle torque

angles with co-contraction

11,12,9

First step in response to a

backwards waist pull

Patients with no detectable

postural instability

- - Less consistent in the choice of stepping

limb, with increased time for weight shift

and more posterior CP placement at

landing.

13

Postural

control during

gait

Sit to walk test - - - Longer delay between seat-off and gait

initiation

14

Gait initiation Patients with clinical postural

instability

X X Decrease in the ability to decrease the

fall in the CoM prior to foot contact

12

- - - Partial improvement with levodopa

treatment

12

CP: center of foot pressure, EMG: electromyographic, LOS: limits of stability, SOT: sensory organisation test, CoM: center of mass. OFF and ON correspond to the OFF or

ON medications conditions. X indicates in which condition the parameters were measured.

Table 2. Overview of various rehabilitation approaches tested in PD patients

Methods

Study design Patient (number) Outcome References

Exercise program targeting leg muscle

strength, balance and freezing (30 minutes, 3

time a week, 6 weeks) or usual exercise

Randomized

controlled trial

PD patients with

previous fall or at risk

of falling (n = 48)

- 7% (p = 0.26) of PD falls risk score

- 2.8 ( p = 0.03) FOGQ

-1.9 sec ( p = 0.03) stand-to-sit time

15

Treadmill training with auditory and visual

cueing (group 1) or cueing without treadmill

(group 2) (20 minutes, everyday, 4 weeks)

Randomized

controlled trial

PD patients with FOG

(n = 40)

Overall improvement of both groups

Comparison between group 1 and Group 2

-2.2 (p = 0.007) FOGQ

+ 73 m (p = 0.0004) for 6MWT

16

Incremental speed-dependent treadmill

training (8-week program)

Randomized

controlled trial

PD patients (n=31) Increase in walking distance (266.41 m to 726.36

m), improvement of BBS, FES in the training

group. No difference in the control group

17

At home cueing device or no training (3

weeks for each period, evaluation after 6

weeks FU)

Single-blind

crossover

randomized trial

PD patients ( n = 153) 4.2% improvement FOG score ( p = 0.005)

-5.5% severity of FOG in freezers ( p = 0.007)

Improvement of gait speed, step length

18

Metronome pacing or normal gait Short-term single-

blind crossover

randomized trial

PD patients with On-

drug FOG (n = 12)

Slower deambulation

No effect on FOG after 1 week chronic use

19

Visual cueing or normal gait Short-term

randomized

controlled trial

PD patients with On-

drug FOG (n = 28)

No effect on FOG

20

Tango exercise or usual exercise (20

sessions)

Randomized

controlled trial

PD patients ( n = 19) BBS improved in tango group 21

20 dance lessons (over 13 weeks) of either

tango, waltz/foxtrot. Control group (no

intervention)

Randomized

controlled trial

PD patients, tango

group (n =17),

waltz/foxtrot group (n =

14) and control group

(n=17)

Improvement of BBS and 6MWT in both dances

group; no improvement in control group

22

Visual, auditory or somatosensory cueing Crossover trial in

randomized order

PD patients freezers

(n=68) and non-freezers

(n = 65)

180° turn improved in all cued conditions

Larger improvement with auditory cueing

23

Intensive exercise program targeting aerobic

capacity (group 1) or flexibility program

(group 2)

Randomized

parallel groups trial

PD patients group 1 (n =

21) and group 2 (n = 13)

Improvement of mobility and balance without

difference between groups

24

PD: Parkinson’s disease, FOGQ: freezing of gait questionnaire, FOG: freezing of gait, 6MWT: six meter walking test, BBS: Berg Balance Scale

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