Neuromodulation forMovement Disorders

Rob Dallapiazza, MD, PhDa, M. Sean McKisic, MDa,Binit Shah, MDb, W. Jeff Elias, MDa,*

KEYWORDS

� Neuromodulation � DBS � Stereotactic surgery � Focused ultrasound � Essential tremor� Parkinson’s disease

KEY POINTS

� Since the advent of stereotactic neurosurgery, various neuromodulation modalities have been usedto confirm target localization.

� Electrical stimulation is themost common form of neuromodulation and is highly effective in treatingessential tremor and Parkinson disease.

� Further experimental refinement of chemical and ultrasound neuromodulation may lead to highlyselective and minimally invasive treatments of movement disorders.

� Magnetic and ultrasound neuromodulation have the potential for neuromodulation without opencranial surgery.

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INTRODUCTION

The treatment of movement disorders representsan ideal application for neuromodulation of thecentral nervous system. Essential tremor (ET)and Parkinson disease (PD) are the most commonmovement disorders that are treated surgically.Although there are no curative therapies, the sym-ptoms of both diseases are managed initially andeffectively with medicine, but severe and refrac-tory impairments occur during disease progres-sion, requiring surgery to maintain quality of life.Over the past 2 decades, surgical neuromodula-tion has seen a dramatic resurgence in the treat-ment of ET and PD with the popularization andrefinement of high-frequency, deep brain stimula-tion (DBS).

The critical element for successful DBS, or anystereotactic intervention, is precise anatomiclocalization and method for physiologic verifica-tion. This has significantly improved with modernneuroimaging, stereotactic equipment, and elec-trophysiology. However, even during the pioneer-ing days of stereotactic neurosurgery when

a Department of Neurosurgery, University of Virginib Department of Neurology, University of Virginia Schoo* Corresponding author.E-mail address: wje4r@virginia.edu

Neurosurg Clin N Am 25 (2014) 47–58http://dx.doi.org/10.1016/j.nec.2013.08.0021042-3680/14/$ – see front matter � 2014 Elsevier Inc. All

pallidotomy and thalamotomy were common pro-cedures for the treatment of involuntary move-ments, surgeons recognized the need for preciselocalization and reversible means to confirm theirtarget. This ensured the best outcomes. Surgeonscreatively modulated neural circuitry with a varietyof methods, including chemical inhibition, thermo-regulation, focused ultrasound, and electricalstimulation.

Modern movement disorder surgery uses neu-romodulation in 2 ways. First, it is used intrao-peratively to verify the stereotactic target in thethalamus or basal ganglia bymeasuring the clinicalor electrophysiologic responses to electrical stim-ulation. Second, neuromodulation is used chroni-cally with DBS for treatment (Figs. 1 and 2).

Chemical Neuromodulation

Chemical neuromodulation refers to injection orinfusion of a pharmacologically active substancewithin the nervous system. This applicationhas the theoretical benefit of targeting specific re-ceptors with precise effects. While chemical

a School of Medicine, Charlottesville, VA, USA;l of Medicine, Charlottesville, VA, USA

rights reserved. neurosurgery.th

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Fig. 1. Therapeutic zones by each neuromodulation modality. (A) Monopolar DBS electrodes produce a sphericalzone of effect. (B) Bipolar DBS electrode configuration produces an elliptical-shaped zone. (C) Chemical infusionshave a spherical zone of effect with a tail that tracts up the catheter. (D) Focused ultrasound lesions are elliptical ordisc-shaped secondary to the configuration of the ultrasound transducers around the head during treatment.

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neuromodulation is principally used in animalmodels for experimental purposes, there areseveral studies that have reported chemical neuro-modulation in the human brain for movement

Fig. 2. Targets for DBS. (A–C) Targeting of the Vim nucleuselectrode implantation. (D–F) In the coronal plane, the GPito the putamen. (E, F) T1 MRI with an electrode targeting tcerebral peduncle, often the STN can be seen. (H, I) EleMcKisic.

disorders. In 1955, Cooper published a series of5 patients in whom he injected procaine into theglobus pallidus before creating a permanent lesionwith ethanol for tremor in advanced PD.1,2 He used

is shown in the axial plane before (B) and after (A) DBScan be seen lateral to the internal capsule and medialhe GPi. (G–I) Axial T2 MRI showing the red nucleus andctrode targeting of the STN. Illustrations by M. Sean

Neuromodulation for Movement Disorders 49

roentgenography for initial catheter placementwith minor modifications of catheter positionbased on small volume tests of procaine until the“physiologic landmark” was identified by reducedtremor and rigidity in the contralateral limbswithout evidence of motor weakness. He reportedimproved tremor and rigidity in 6 months of followup for 3 of these patients. Similarly, Narabayashiand colleagues3,4 used early stereotactic methodsto inject procaine into the pallidum before perma-nent lesioning in patients with choreoathetosis. Aswith Cooper, small volumes of local anestheticwere used to determine whether the site of puta-tive lesioning would be safe. In the series of 80 pa-tients, improvement in athetosis was reported inapproximately 60% of patients.

Infusion of local anesthetic was also appliedto the thalamus during treatment of tremor. Duringradiofrequency thalamotomy, Parrent and col-leagues5 first infused 1 to 2 mL of lidocaine in10 patients with tremor. They observed a transientsuppression of tremor with a mean onset of69 seconds and duration of 171 seconds. Interest-ingly, the lidocaine infusions correlated with mi-crostimulation effects in 67% of cases.

As the understanding of neurotransmitter sys-tems advanced with the use of selective antago-nists and agonists, so did its application tomovement disorders. In 1984, Penn and Kroin6,7

used intrathecal baclofen, a GABA-B receptoragonist, to alleviate spasticity of spinal origin.Shortly thereafter, they targeted the globus pal-lidum with muscimol, a GABA-A receptor agonist,during pallidotomy surgery for a patient with PD.Within 20 minutes, bradykinetic movements in-creased and rigidity resolved, although tremorworsened.8

Intraoperative microinjections of muscimol intodeep brain nuclei of patients with PD have been

Table 1A summary of chemical infusions into the human thdisorder surgery

Study n Target

Cooper,1 1955 5 GPi

Narabayashi et al,4 1960 80 GPi

Parrent et al,5 1993 10 Thalamus

Penn et al,8 1998 1 GPi

Levy et al,9 2001 4 STN2 STN

Pahapill et al,10 1999 6 Thalamus3 Thalamus

Abbreviations: GPi, globus pallidus internus; STN, subthalamic

reported to transiently inhibit either the globus pal-lidus internus (GPi) or subthalamic nucleus (STN)neurons. The effect of muscimol infusion elicits atemporary clinical effect that is similar to stimula-tion or lesioning. Levy and colleagues9 targetedthe STN with muscimol in 7 patients with PD. Mod-ern microelectrode recording techniques wereused to confirm target location, and small dosesof lidocaine and muscimol were injected into theSTN with simultaneous microelectrode recordingin 2 patients. Injection of lidocaine blocked nearbyneural firing within minutes and improved contra-lateral limb rigidity with peak effect 10 to 20 mi-nutes after injection. Dyskinesias were notedwhile blocking the STN with lidocaine. In 2 of 3 pa-tients, these effects wore off during the procedure.Muscimol injection had a similar effect by de-creasing tremor in the contralateral limb of bothpatients tested, and altered the spectrum of asingle neuron oscillatory frequency. No adverseevents were noted with injection of muscimol.The clinical improvements with muscimol infusionwere correlated closely with successful final treat-ment effects.

Pahapill and colleagues10 reported infusion ofmuscimol into the Vim nucleus of patients withET. Similarly, microelectrode recordings wereused to confirm tremor-synchronous neuronsin the lateral thalamus, and microelectrode stimu-lation ceased tremor. Subsequent microinfusionof muscimol reliably reduced tremor with a la-tency of 7 minutes and for a mean duration of9 minutes.

Although chemical neuromodulation is princi-pally used in experimental models, these exam-ples in humans are important advances inunderstanding the basic pathophysiology ofmovement disorders and its potential applicationas a therapeutic tool (Table 1).

alamus and basal ganglia during movement

Drug Concentration Dose/Infusion

Procaine NS <250 mL

Procaine NS 1–2 mL

Lidocaine 2% 1–2 mL

Muscimol 8.8 mM 2.5 mL

Lidocaine 2% 3.5–23 mLMuscimol 8.8 mM 5–10 mL

Muscimol 8.8 mM 1–5 mLSaline

nucleus.

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Cryogenic Neuromodulation

During the 1950s, scientists and surgeons wereexamining the effects of cooling on nervous tis-sues and function. Results from these experi-ments showed that cooling various structures ofthe brain to 0 to 10�C produced a reversible inhibi-tion of neural activity, and that cooling below–20� could create a permanent lesion. In 1961,Mark and colleagues11 used a refrigeration probeto cool the region of the third nerve nucleus incats and demonstrated reversible pupillary dila-tion. Rowbotham and colleagues12 applied thisconcept to humans for the treatment of glioma.Cooper published a report of 100 cryothalamoto-mies for parkinsonism and concluded that the pro-cedure was the ideal technique for movementdisorder surgery, as it provides a reversible, phy-siologic test before the creation of a stablelesion.13–15 Although the study does not specif-ically cite examples of neuromodulation duringthe course of the target localization, subsequentcommentary notes, “I have had the pleasure ofseeing Dr Cooper turn a Babinski on and off byadjustment of a valve. This is truly impressive(Cambell JB).”

Thermal Neuromodulation

During the same period as cryogenic thalamoto-mies, radiofrequency waves were also beingused to produce thermal lesions within the brain.Experimental models demonstrated reversible in-hibition of neural activity. Using a model similarto Mark and colleagues,11 Brodkey and collea-gues16 used radiofrequency stimulation to heatthe Edinger-Westphal (EW) nucleus in cats. Theyfound that heating the EW nucleus to 44 to 49�Cproduced a reversible dilation of the pupil that re-turned to baseline size within 20 minutes of heat-ing. The premise that low-temperature heatingcan produce reversible lesions in the brain isbased on these studies. It is now recognizedthat low-temperature heating can cause thermalinjury depending on the duration of exposuresuch that tissue ablation even occurs at approxi-mately 43�C when exposed for a duration of240 minutes.17

Ultrasound Neuromodulation

Interestingly, even before the publication of cryo-thalamotomy and radiofrequency lesioning in thebasal ganglia, Fry and colleagues18,19 reportedthe use of high-intensity ultrasound to createdestructive lesions of the internal capsule in cats.The goal of their research was to provide neuro-surgeons with a tool to perform functional

neurosurgery in the treatment of movement disor-ders. They sonicated the feline lateral geniculatenucleus with lower doses of acoustic energy andtemporarily suppressed visual evoked responsesrecorded at the cortex.20 These experimentsnecessitated craniotomy because the skull re-flected and absorbed the ultrasound waves. Therecent decade has led to advances in ultrasoundtransducer design so that transcranial delivery ofhigh-intensity ultrasound is possible and precisein humans.21,22 Our group observed neuromodula-tion of the sensory, ventrolateral thalamus in 5 of15 patients with ET undergoing focused ultra-sound thalamotomy although likely from thermalmechanisms.23 In the laboratory, ultrasound neu-romodulation has been demonstrated in vivo in ro-dents with low-intensity, pulsed parameters andwithout heating.24,25

Magnetic Neuromodulation

Transcranial magnetic stimulation (TMS) is anoninvasive technique used for measuring andmodulating cortical plasticity introduced by Barkerand colleagues26 in 1985. TMS is delivered viaan electrical coil placed on the scalp, which ge-nerates a magnetic field that traverses thecranium and induces an electrical field in the cor-tex. This electrical field depolarizes neurons andhas been used extensively to measure corticalplasticity in a variety of neurologic disorders. Thiscontrasts with transcranial electrical stimulationwhere current flow is achieved directly throughthe skull via leads injected into the scalp. Repeti-tive pulsing of TMS, known as repetitive transcra-nial magnetic stimulation (rTMS), has been used inthe past 2 decades to modulate cortical excit-ability in ways that treat neurologic and psychiatricdisease. rTMS is currently approved for use inmedication-refractory depression in the UnitedStates and Canada. It has been studied in neuro-logic diseases such as PD, tremor, dystonia, tics,spasticity, and epilepsy.27 High-frequency rTMS(>1 Hz) increases cortical excitability28 and low-frequency rTMS (<1 Hz) reduces cortical excit-ability.29 Paradigms of stimulation based on theseobservations have driven the design of studiesinvestigating rTMS in movement disorders.rTMS has been studied extensively for PD motor

features with the hypothesis that high-frequency,cortically excitatory stimulation can overcome de-creased output from the basal ganglia via thethalamus. Elahi and colleagues30 performeda meta-analysis of studies with high-frequency andlow-frequency rTMS to the motor cortex on PDmo-tor scores. All of the studies had sham-controlledarms and compared the sham group with active

Neuromodulation for Movement Disorders 51

groups (either low-frequency or high-frequencyrTMS). In the pooled effect, they found a significantreduction in theUPDRSpart III (motor) of 6.68points(95% confidence interval 5 –9.66 to –3.69) in thehigh-frequency studies and no significant changeon UPDRS part III in the low-frequency studies. Itshould be noted that the power of the analysis inboth paradigms was low. Recent studies havelooked at intermittent bursts of very high frequencystimulation to the motor cortex,31 stimulation of thesupplementary motor area,32 and of the cere-bellum33 and have shown promising results. This istempered, however, by other studies showing nosignificant motor benefit of high-frequency stimula-tion of the motor cortex.34,35 Further studies areneeded to identify the paradigms and sites of stimu-lation thatmaybeeffective in treatingmotor featuresof PD.

Levodopa-induced dyskinesia is a common,disabling feature of PD characterized by ex-cessive, often uncontrollable, movements in themedicated PD state. Use of low-frequency andhigh-frequency rTMS over the motor cortex, sup-plemental motor area, and cerebellum have de-monstrated mixed results on dyskinesia andUPDRS motor scores.36–39

In essential tremor, the role of excitation of themotor cortex seems promising. Studies haveshown that DBS to the Vim increases motor cortexexcitability40 and subdural motor cortex stimula-tion has shown benefit in ET.40 Hellriegel and col-leagues41 investigated very high frequency rTMS(50 Hz) over the motor cortex in ET and foundsignificant reduction in tremor as measured by ac-celerometry. However, this benefit was not appre-ciated by the study subjects and patient ratings ofchange were no different between active andsham stimulation. The role of the cerebellum aspart of the cerebello-thalamo-cortical pathway inessential tremor has been explored via cerebellarrTMS. Popa and colleagues42 used 1-Hz bilateralcerebellar stimulation and found significantimprovement in tremor amplitude and functionaldisability due to tremor that was persistent for3 weeks.

Electrical Neuromodulation: DBS

Shortly after the development of a stereotacticframe applicable to the human skull by Spiegeland Wycis43–46 in 1947, many teams of neurosur-geons and neurophysiologists began electrical re-cordings and stimulation of subcortical structuresin the human brain. The principal investigations inthese studies were patients with psychiatric dis-ease; however, they quickly moved to movementdisorders. Spiegel and Wycis43–46 published

reports using stereotactic surgery to treat Hun-tington disease, choreoathetosis, and PD shortlyafter their description of the stereoencephatome.In these operations, electrical stimulation wasused to ensure the electrode was not in aneloquent structure, such as the internal capsule.During these operations, the surgical conditionsmade it difficult to assess symptoms; however,subsequent surgeries used electrical stimulationof the target to monitor clinical symptoms. Itwas noted that electrical stimulation of the targetcould mimic the effects of a lesion. In 1961, Albertsand colleagues47 found that stimulation of theventrolateral thalamus or internal segment of theglobus pallidus at 60 Hz could evoke or abatetremor. Chronic electrical stimulation of the thal-amus and pallidum was also described to locatetargets for subsequent lesioning. In 1965, Sem-Ja-cobsen48 reported chronic stimulation of the thal-amus with multiple implanted electrodes todetermine the optimal target for lesioning. In hisdescription, he noted that electrodes could bekept in place for months without complication. In1972, Bechtereva and colleagues49 reportedchronic electrode placement in the ventrolateralthalamus with intermittent high-frequency stimu-lation, the results of which were used for laterablative procedures. These and many otherstudies set the stage for modern DBS. In 1987, Be-nabid and colleagues50 published their results ofunilateral Vim thalamotomy and unilateral contin-uous, high frequency Vim stimulation with animplanted electrode in patients with PD. The prin-cipal benefits of stimulation compared with lesionare well noted, but include the ability for neuromo-dulation. These studies demonstrated that tremorwas optimally suppressed with higher frequency(>130 Hz) stimulation, and that this suppressioncould be maintained chronically with implantedneurostimulator devices.50,51 This opened thedoor to electrical neuromodulation of severaldifferent subcortical structures previously targetedby lesioning for the treatment of movementdisorders.

ACUTE ELECTRICAL NEUROMODULATIONFOR STEREOTACTIC TARGET LOCALIZATIONDURING SURGERYTechnique

Stereotactic technique is used for both ablativeand DBS surgeries in the treatment of movementdisorders. Modern frame-based, and morerecently skull-mounted devices, are typically pre-cise for electrode insertion to approximately1 mm.52–54 Almost all preoperative planning relieson magnetic resonance imaging (MRI) sequences

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uploaded to a computer-based neuronavigationplatform so that coordinates can be determinedby either direct visualization of the target structureor by indirect methods by using calculations fromthe midcommissural point. Anatomic software isavailable for most of these navigation programsso that stereotactic brain atlases can be overlainon the patient’s MRI or computed tomographyimages.Regardless of whether the surgical procedure

involves lesioning or stimulation, it is imperativeto localize and confirm the target before the ther-apeutic treatment. Microelectrode recordingsthrough small, higher-impedance electrodes inthe extracellular space can identify dischargesfrom a single or small group of neurons along theplanned trajectory. Neurons of the striatum, pal-lidum, and ventrolateral thalamus have character-istic firing patterns that can be recognized andused to determine electrode location. These mi-croelectrodes with exposed tips of approximately5 mm can also be used for microstimulation withamplitudes ranging from 0 to 100 mA althoughhigh-stimulation currents will subsequently affectthe impedance of the electrode.55

Although the use of microelectrode recordingsfor target localization remains debated, electricalstimulation is always applied through amacroelec-trode (typical diameter�1mm) such as those usedfor lesioning or for DBS. Macrostimulation appliesrepetitive low-amplitude voltage or currents at theelectrode tip to elicit a clinical response, thus map-ping the region for efficacious treatment or theidentification of critical surrounding structuresthat should be avoided. High-frequency (1001Hz) stimulation is used to simulate the chronictherapy that is typically used in the outpatient clinicsetting. Low frequencies (2–10 Hz) can be used topreferentially activate large, myelinated axons likethose of the pyramidal tract encountered in theposterior limb of internal capsule. As a compari-son, cortical stimulation during awake craniotomysurgery typically uses 50-Hz to 60-Hz stimulation,which is ideal for mapping cortex and subcorticaltracts.

Vim Thalamus

The ventral intermediate nucleus of the thalamus isthe preferred of target to treat tremors. This nu-cleus receives projections from the spinal cordand deep cerebellar nuclei and has reciprocal con-nections with the cerebral cortex. Anatomically, itis “intermediately” positioned between the motor(ventral oral) and sensory (ventral caudal) thalamusand medially adjacent to the posterior limb of theinternal capsule. The Vim nucleus is not readily

discernable from the adjacent thalamic nuclei byMRI likely due to its small size and relatively hypo-cellular composition,56 and so electrophysiologicor clinical testing is even more important for targetconfirmation. Because stimulation of Vim thal-amus suppresses tremor immediately, intraopera-tive localization ultimately relies on thedemonstration of tremor suppression with high(>100 Hz) stimulation, typically through a macroe-lectrode in the awake patient. Capsular stimulationfrom a laterally positioned electrode will activatedescending corticobulbar or corticospinal tracts,thus eliciting tonic motor contractions of the faceor upper extremity. Electrodes positioned poste-rior of Vim will stimulate sensory thalamus leadingto localized and persistent paresthesias of the faceor upper or lower extremities. Medial or anteriorlyplaced electrodes will often be ineffective inrelieving tremor. Microstimulation mapping ismore precise than macrostimulation for identifyingthe exact border between Vim and Vc.57 Either ofthese methods can be used to confirm target loca-tion before lesioning or final placement of chronicstimulating electrodes.

GPi, Internal Segment

The GPi is a common target for the surgical treat-ment of dystonias and the medication-refractory,motor symptoms of PD. This disc-shaped nucleushas a volume of approximately 500 mm3, and rep-resents the primary outflow of basal ganglia. Incontrast to stimulation of the Vim nucleus, acutestimulation of the GPi through a macroelectroderequires several minutes before clinical improve-ment in parkinsonism can be observed. Therefore,macroelectrode stimulation during GPi targetingfocuses on avoiding the critical surrounding struc-tures, namely the internal capsule medially and op-tic tract inferiorly. Most commonly, the posteriorventrolateral portion of the nucleus, the somato-sensory region, is targeted for therapy towardthe junction of the optic tract and internal capsule.Low-frequency (2 Hz) stimulation of corticobulbarin the 2-V to 4-V range can aid in finding the appro-priate distance of GPi from the internal capsule. Ina dark room, phosphenes and other visual phe-nomena in the contralateral visual field can be eli-cited with optic tract stimulation at high (1301 Hz)stimulation.

STN

The STN is commonly targeted for the treatmentof PD. As part of the intrinsic circuitry of thebasal ganglia, it provides excitatory, glutamatergicoutput to the GPi. Macroelectrode stimulation isquite valuable in determining electrode placement

Neuromodulation for Movement Disorders 53

in the STN and frequently results in transient par-esthesias of the distal extremities. Stimulation ofthe STN will produce immediate tremor arrestand reduced rigidity that returns when stimulationis stopped. Bradykinesia can be more difficult toassess and is often susceptible to lesional effectsfrom macroelectrode insertion and repetitive high-frequency stimulation testing. Placement of anelectrode in the anterolateral direction will resultin stimulation of the cerebral peduncle, resultingin contralateral facial or hand contractions. Poste-riorly placed electrodes near the medial leminiscusresult in persistent or hemibody paresthesias.Medially placed electrodes will stimulate the rednucleus or the oculomotor nerve, resulting inunilateral eye deviation and/or diplopia. Identifica-tion of symptoms related to these structures guidesubsequent electrode placement. Stimulation-induced dyskinesia is perceived as a favorableprognosis for a favorable outcome.

CLINICAL OUTCOMES OF CHRONICELECTRICAL NEUROMODULATION FORMOVEMENT DISORDERSDBS for Essential Tremor

Numerous studies of Vim ablation and stimulationhave demonstrated dramatic improvements ofappendicular tremors in ET. In one of the firstreports of thalamotomy for PD, Speakman58

treated 73 patients with 4-year follow-up andfound that 56 patients were improved. Akbostanciand colleagues59 reported the results of 37 pa-tients treated with Vim thalamotomy for ET. Atfollow-up, 60.5% of patients had no tremor andan additional 13.9% of patients had mild tremorthat did not interfere with activities of daily living.

There are several studies that demonstrate theefficacy of Vim DBS for essential tremor.60–64 Asystematic review of the literature published in2009 found 17 studies that evaluated patientstreated with Vim DBS for essential tremor.65 Allstudies were retrospective case series and pro-vide class IV evidence showing a reduction intremor scores compared before or after surgeryor with DBS turned off or on. Collectively, thesestudies suggest that Vim DBS improves tremorby 70% to 90%.

The durability of thalamic ablation and stimula-tion on tremor has been reported in long-termretrospective series.66,67 Improvements in tremorseverity are significant for as long as 7 years. How-ever, with radiofrequency-thalamotomy, up to20% of patients experienced tremor recurrence.Similarly, with thalamic DBS, tolerance to stimula-tion develops in up to 30% of patients; however,this can be improved by adjusting DBS settings.68

DBS for PD

In 1994, DBS was applied to the pallidum for treat-ment of PD.69 The efficacy of chronic bilateral pal-lidal DBS was observed as comparable to pallidallesioning.70,71 Most studies report 30% to 50%improvement in motor symptoms with bilateralpallidal stimulation. Tremor is reduced by approx-imately 80%, and rigidity and akinesia improves byapproximately 60%. The effects were reversiblewhen stimulation was stopped, and parameterscould be titrated to maximize therapeutic effectswhile minimizing negative size effects with bilateralimplants.70,72

Like the GPi, the STN was recognized in exper-imental models of PD to be hyperactive.73,74 STNlesions in nonhuman 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine primates alleviated parkinso-nian signs, thus paving the way to explore thesubthalamus as a potential stereotactic targetfor PD.

Subthalamotomy has never been widelyaccepted because of concerns for hemiballismus,primarily due to observations in humans withstroke in the region of the subthalamus and bythe confirmation in the 1940s by Whittier and Met-tler,75,76 who were able to experimentally repro-duce this by subthalamic lesions in primates.Unilateral subthalamotomy for medication refrac-tory PD has proven beneficial in the alleviation ofcontralateral off-medication motor symptoms ina large series of 21 patients77 and another seriesof 89 patients followed for up to 36 months.78 Inthe former study, significant improvementswere noted on UPDRS ratings with bradykinesia,rigidity, and tremor. Improvements remained at2 years and were most pronounced for tremor.With regard to the “on” state, contralateral dyski-nesia was reduced during the 2-year study andthe mean dose of levodopa was decreasedby 34% to 47% while the total on time withoutdyskinesia increased fourfold. In the study by Al-varez and colleagues,79 significant reductionsin part 3 of the off-medication UPDRS werenoted at 12 (50%), 24 (30%), and 36 months(18%) following unilateral subthalamotomy.

There are several reported case series andlarge, multicenter trials that demonstrate the effi-cacy of STN-DBS.80–87 These studies uniformlydemonstrate improvement (reduction) in theduration of “off” medication time and a 48% to58% improvement in motor function in patientswho underwent bilateral STN-DBS comparedwith preoperative baselines.

Two multicenter, prospective, randomized con-trol trials compared STN-DBS to best medicaltherapy.88,89 In these studies, the primary

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outcomes were quality of life and motor function.As in previous studies, participants were evaluatedwith the PDQ and UPDRS. At 6-month follow-upevaluation, patients treated with STN-DBS hadsignificant improvements in motor function, whilenot taking medications in both studies comparedwith best medical treatment. Further, quality-of-life measurements based on the PDQ demon-strated improvement in several categories,including activities of daily living and mobility.These studies concluded that STN-DBS wasmore effective at controlling severe motor compli-cations in PD than medical management.Long-term data regarding the efficacy STN-DBS

have now been published. Several case seriesdemonstrate the long-term durability of the effectsof STN-DBS with 5-year and 10-year follow-up.90–92 These studies show continued improvedfunction in motor scores and activities of dailyliving compared with baseline preoperative func-tion. In general, PD medication dosages weredecreased by approximately 50%, as weremedication-related dyskinesias. However, somestudies reported worsening of postural stability,gait, axial DOPA-unresponsive symptoms, andcognitive neurologic decline. From these studies,it is unclear whether the decline in some symp-toms was a factor of untreated disease progres-sion in these patients or whether STN-DBS wasa contributing factor.Rigorous trials of STN versus GPi DBS include 3

randomized, double-blind, controlled trials docu-menting similar motor improvements as testedusing UPDRS in the nonmedicated state.93–95 Theonly consistent difference between targeting theSTN and GPi-DBS are that there are significant re-ductions in levodopamedications andmore cogni-tive and psychological sequelae with STN-DBS.

COMPARING NEUROMODULATIONMODALITIES

There is no perfect technique for neuromodulation.Ideally, a combination of neuromodulation tech-niques could be used for both stereotactic locali-zation in surgery and therapeutic uses in achronic setting. Each of the modalities has itsmerits and limitations.Chemical infusions theoretically have the poten-

tial for neuromodulation in a very selective fashionsuch that nuclear groups as well as axonal tractscould be manipulated independently. Most impor-tantly, various neurotransmitter systems could betargeted for investigation and treatment. Unfortu-nately, chemical neuromodulation is relegated asa research tool today. If it becomes further devel-oped, chemical infusions would likely be delivered

with convective properties and image guidancefor monitoring with a surrogate imaging tracer.Modern implanted infusion pumps are quite pre-cise and reliable, although expensive. A more tem-porary infusion system can be implemented in theoperating room environment, but semichronic in-fusions require externalized pump systems thatare cumbersome with the risk of infection.Cryogenic neuromodulation has been minimally

used since the 1950s. There are currently no com-mercial systems available to implement this in theoperating room. Importantly, the safety of neuronalcooling is poorly understood, and requires furtherinvestigation.There is a long tradition of using thermal neuro-

modulation at subthreshold temperatures beforepermanent therapeutic ablation. Thermal modula-tion can now be implemented without surgerywith the advent of contemporary transcranial-focused ultrasound devices. Importantly, theconcept of a reversible thermal lesion should bequestioned, as thermal dose occurs on a contin-uum proportional to the risk of neuronal damage.Safety considerations with rTMS include

possible induction of seizures, particularly withhigh-frequency paradigms.96,97 Caution must beexercised, particularly in patients with a history ofseizures and those who may be on medicationsthat can reduce seizure threshold. Other reportedadverse effects include temporary hearing lossand tinnitus associated with sound emitted bythe TMS coil, local pain and cephalgia, andsyncope.27

Contemporary transcranial-focused ultrasoundsystems can deliver acoustic energy through theintact scalp and cranium. Additionally, thesetreatments can be monitored in real time withMRI and MR thermometry. Because the tech-nique is independent of an implanted stereotacticdevice, adjustments can be made in any dimen-sion without invasive intracerebral penetrations.On the other hand, current ultrasound neuromo-dulation in humans depends on high-intensitywave forms. These are the ultrasound perimetersused for tissue ablation, and so thermal mecha-nisms analogous to radiofrequency energy areresponsible for neuronal manipulation. Futuresystems may use low-intensity pulsed ultra-sound, which does not result in heating. Ultra-sound neuromodulation can be used today onlyfor acute intraprocedural localization of a stereo-tactic target, as there is no current device avail-able for chronic use.Electrical neuromodulation is time tested, as

more than 100,000 patients have been treatedwith DBS. The major advantage of electrical neu-romodulation relates to its safety and reversibility.

Neuromodulation for Movement Disorders 55

Electrode configurations and stimulation parame-ters can be altered such that the electrical field isadjustable as well. Obviously, electrical neuromo-dulation relies on a surgically implanted electrodewith some small risk of a hemorrhagic complica-tion. Chronic neurostimulation devices are expen-sive and associated with inherent hardwarecomplications, such as lead fracture, lead migra-tion, scalp erosion, and device infection. Thesesystems are expensive to implant and maintainwith battery replacements. There is some selec-tivity of electrical stimulation, although this re-mains unknown. The electrical field likely affectsneurons of all types, as well as traversing axonalpathways.

SUMMARY

Neuromodulation has been used extensively inmovement disorder surgery for ET and PD. Acuteand chronic electrical neuromodulation arecurrently the only modalities that are commonlyused clinically. Chemical neuromodulation hasbeen used in the past and experimentally in move-ment disorder surgery. This modality is a prom-ising experimental tool for understanding thesubcortical circuitry that underlies movementdisorders. Transcranial magnetic stimulation andfocused ultrasound neuromodulation are emer-ging, noninvasive modalities that are likely tohave a large impact on therapy for movementdisorders.

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