R E V I E W

Tremor Habituation to Deep Brain Stimulation: UnderlyingMechanisms and Solutions

Alfonso Fasano, MD, PhD,1,2,3* and Rick C. Helmich, MD, PhD4

1Edmond J. Safra Program in Parkinson’s Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto WesternHospital, UHN, Toronto, Ontario, Canada; Division of Neurology, University of Toronto, Toronto, Ontario, Canada

2Krembil Brain Institute, Toronto, Ontario, Canada3CenteR for Advancing Neurotechnological Innovation to Application (CRANIA), Toronto, Ontario, Canada

4Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Department of Neurology,Nijmegen, The Netherlands

ABSTRACT: DBS of the ventral intermediate nucleus isan extremely effective treatment for essential tremor,although a waning benefit is observed after a variable timein a variable proportion of patients (ranging from 0% to73%), a concept historically defined as “tolerance.” Toler-ance is currently an established concept in the medicalcommunity, although there is debate on its real existence.In fact, very few publications have actually addressed theproblem, thus making tolerance a typical example of sci-ence based on “eminence rather than evidence.” Theunderpinnings of the phenomena associated with the pro-gressive loss of DBS benefit are not fully elucidated,although the interplay of different—not mutually exclusive—factors has been advocated. In this viewpoint, we gatheredthe evidence explaining the progressive loss of benefitobserved after DBS. We grouped these factors in three

categories: disease-related factors (tremor etiology and pro-gression); surgery-related factors (electrode location, micro-lesional effect and placebo); and stimulation-related factors(not optimized stimulation, stimulation-induced side effects,habituation, and tremor rebound). We also propose possiblepathophysiological explanations for the phenomenon anddefine a nomenclature of the associated features: early ver-sus late DBS failure; tremor rebound versus habituation(to be preferred over tolerance). Finally, we provide a practi-cal approach for preventing and treating this loss of DBSbenefit, and we draft a possible roadmap for the researchto come. © 2019 International Parkinson and MovementDisorder Society

Key Words: deep brain stimulation; habituation; sur-gery; tolerance; tremor

Tremor is defined as “an involuntary, rhythmic, oscilla-tory movement of a body part.”1,2 Essential tremor(ET) has been historically considered the most commonmovement disorder in adults, with an estimated prevalence

of 0.5% to 5%3; however, it has been the subject of sev-eral debates in recent years, particularly in light of itsphenomeno- and pathophysiological heterogeneity.4,5

Accordingly, ET definition has changed considerably overthe years and current criteria are rather strict, defining it asan isolated tremor syndrome of bilateral upper limb actiontremor for at least 3 years’ duration, with or withouttremor in other locations and in absence of other neuro-logical signs, such as dystonia, ataxia, or parkinsonism.2

DBS is the most common surgical procedure formedication-refractory ET since the first report confirmingsustained improvement in 6 ET patients in 1991.6 Theventral intermediate nucleus (Vim) of the thalamus is thetraditional target for DBS in ET and also the target of abla-tive procedures (thalamotomies), which can be performedwith invasive (radiofrequency; RF) or “minimally inva-sive” (either gamma-knife radiosurgery [GKRF] or MRI-guided focused ultrasound [MRIgFUS]) procedures.7-9

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -*Correspondence to: Dr. Alfonso Fasano, Movement Disorders Centre,Toronto Western Hospital, 399 Bathurst Street, 7McL412, Toronto, ON,Canada, M5T 2S8; E-mail: alfonso.fasano@uhn.ca

Funding agencies: R.H. received funding from the Dutch BrainFoundation.

Relevant conflicts of interest/financial disclosures: A.F. receivedhonoraria and research funding from Medtronic and Boston Scientific.R.H. received honoraria from AbbVie.

Full financial disclosures and author roles may be found in the onlineversion of this article.

Received: 9 March 2019; Revised: 1 July 2019; Accepted: 18July 2019

Published online 00 Month 2019 in Wiley Online Library(wileyonlinelibrary.com). DOI: 10.1002/mds.27821

Movement Disorders, 2019 1

Vim DBS is an extremely effective treatment for ET,although a waning benefit is observed after a variabletime. Benabid and colleagues first introduced the conceptof “tolerance” as they observed that thalamic stimulationwas less effective over time in ET.10 It is now known thatin a variable proportion of patients—ranging from 011 to73%12

—no benefit is perceived anymore, and this raisesthe question of whether this is attributed to disease pro-gression, tolerance, or other factors.In this viewpoint, we gather all the available evidence

explaining the waning effect of DBS in ET patients over timeand propose possible pathophysiological explanations forthe phenomenon. Furthermore, we propose a practicalapproach for preventing and treating this loss ofDBS benefit,andwe draft a possible roadmap for the research to come.

Nomenclature

Over time, the loss of DBS benefit has been linked to avariety of phenomena, such as tremor rebound or toler-ance.13-16 For this review, we propose the following defini-tions, which will be consistently used in the text below:Early and late DBS failure are defined as the loss of benefitoccurring within or after 1 year of satisfactory tremor sup-pression with DBS, respectively, when comparing pre-DBStremor severity with the post-DBS on state (Fig. 1A,B).Tremor rebound is defined as a temporary increase oftremor intensity over the preoperative state occurring upto 1 hour after switching DBS off. A longer evaluationwithout stimulation (up to 3 days17) has been proposed,but this is not practical outside of a research context, anda recent study found objective evidence that reboundtremor ends within 30 to 60 minutes from stimulation dis-continuation.18 Finally, habituation is defined as the lossof sustained tremor control, which can become visibledays to weeks after DBS programming. For the purpose ofthe review, we viewed habituation and tolerance as twonames describing the same phenomenon.

DBS for ET: Short- and Long-TermOutcomes

Several studies have shown that unilateral Vim DBS sig-nificantly reduces overall tremor in the short term.9 Fewerlong-term studies are available (Table 1), overall con-firming a persistent improvement of tremor in most sub-jects when compared to baseline, even though with areduction of magnitude of the delta off versus onDBS.9,19,20 The longest available follow-up of ET patientsup to 18 years after surgery reported that the meanimprovement decreased from 66% at 1 year to 48% at lat-est follow-up, although in a subgroup analysis this reduc-tion of efficacy was not significant.11 Finally, bilateral VimDBS leads to an even greater overall tremor reductiongiven that both sides of the body are treated.11,21-25 There

are reports of up to 75% improvement in head tremor and60% in voice tremor 5 years after DBS implantation.26

Other TargetsThe posterior subthalamic area (PSA)/caudal zona

incerta (cZI) represents the white matter underneath thethalamus, where the cerebellothalamic tract (CTT)—alsoknown as dentato-rubro-thalamic tract—runs.27,28 Giventhat CTT is thought to play an important role in tremorpathophysiology, the PSA/cZI has been also targeted byDBS in ET. Uni- and bilateral PSA/cZI DBS have excellentshort-term outcomes.29-31 Within the first 5 years afterimplantation, a reduction in efficacy has been demon-strated in unilateral32,33 and bilateral cases.34 Otherreported targets for ET patients are ventralis oralis

FIG. 1. (A) According to Paschen and colleagues,18 comparing tremorseverity in the OFF condition at two time points should reflect only dis-ease progression whereas tremor severity in the ON condition is deter-mined by both progression and the effect of stimulation, including apossible habituation. In order to avoid the bias of rebound tremor, wepropose the definition of “escapers” because those tremor patients inwhom DBS had reduced tremor severity initially and who have subse-quently reached the same pre-DBS tremor while ON stimulation.(B) Early and late DBS failure occurs when for an escaper within or afterthe arbitrary cutoff of 1 year of satisfactory tremor suppression withDBS, respectively. (C) DBS failure is not a uniform phenomenon, andthe time elapsed between surgery and decay of benefit should supportthe interplay of different—not mutually exclusive—factors, which wegrouped in three main domains: disease-, surgery-, and stimulation-related factors. [Color figure can be viewed at wileyonlinelibrary.com]

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posterior (Vop) and anterior nuclei of the thalamus andSTN.35,36 Efficacy and safety are overall good, althoughthe experience is limited to few reported patients, forwhich a publication bias may also apply.

The Mechanisms Explainingthe Loss of DBS Benefit

The underpinnings of the phenomena associated withthe progressive loss of DBS benefit are not fully elucidated,

although the interplay of different—not mutuallyexclusive—factors has been advocated, as grouped belowin three main domains: disease-, surgery-, and stimulation-related factors (Fig. 1C).

Disease-Related Factors(Tremor Etiology and Progression)

The natural progression of ET has been considered by sev-eral researchers as a cause of loss of DBS benefit,15,22,37,38

although the natural history of ET is a matter of debate initself. The average annual increase in severity of ET from

TABLE 1. Clinical efficacy and safety of DBS for ET in the available long-term studies (over 3 years)

Reference N*FU Duration

(Years) Effect Escapers

50 25 3.3 50.0% vs. baseline45.5 vs. OFF

5 of the initial cohort of 49 patients: after 3 months (2 patients),6 months (1 patient), 12 months (2 patients), and 24 months(1 patient already reimplanted 3 months after DBS). Inaddition, incomplete benefit in 1 patient and lead migrationin another patient (causing loss of benefit)

19 13 (1) 6.5 � 0.3 47.1% vs. baselinea

47.1% vs. OFFa0

26c 19 (7) 6.5 � 0.6 56.6% vs. baselined

45.9% vs. OFFd0 (worsened tremor control)

125 13 (NA) 3 88.4% vs. baseline86.2% vs. OFF

8 of 75 leads (52 patients of the original cohort) requiredrepositioning because of “loss of effect”

21 26 (8) 5 49.6% vs. baselinee

50.7% vs. OFFe2

126 19 (0) 7.2 � 0.75 44.1% vs. baselinea

44.4% vs. OFFa2 excluded from the initial cohort because of diagnostic revision

(dystonic and cerebellar tremor)57 6 5 Tremor suppression at 6 months,

reoccurrence of mild ormoderate tremor in 3 patients

0 of 6 ET patients, 0 of 19 PD patients, and 3 of 5 MS patientsincluded in the same series

127 12 (UK) 7.6 67.7%b Of the initial cohort, 2 ceased to use DBS because ofside effects

114 18 (2) 4.0 � 0.8 52.4% vs. baseline51.4 vs. OFF

0 (target is cZi)

24 22 7 to 12 31.2% vs. baseline Leads were revised because of loss of benefit in 2 of 42patients (2–7 years after DBS) and in 3 of 22 patients(7–12 years after DBS).

12 45 (21) 4.7 � 2.9 UK 33 (3 more excluded from the initial cohort because ofdiagnostic revision of cerebellar ataxia)

20 13 (7) 11.0 � 1.3 44.1% vs. OFF (open)a

44.4% vs. OFF (blind)a1

128 36 6.0 VAS: 8.5 (after DBS), 7.4 (latest FU)f UK56 14 (11) 7.7 � 3.8 50.1% vs. baselinee 2 excluded from initial cohort attributed to early failure

because of electrodes misplacement11 12 13.2 � 2.8 33.5% (vs. baseline)

48% (vs. OFF)0

115 47 (6) 4 VIM: 68-92% vs. baselinea

cZI: 33-76% vs. baselinea0

38 31 (3) 3.3 � 2.7 44.2% vs. baselinea 10 (2 early)18 20 (20) 5.9 � 0.6 22.0% vs. 1 year after DBSe

42.6.% vs. OFFe0

*Number of bilateral cases into brackets.aItemized A and B of stimulated side.bSelected items of A + B.cFU of an earlier work.129dItemized part A.eTotal TRS.fQuestionnaire-based, side effects based on 26 pts.FU, follow-up; UK, unknown; VAS, visual analogue scale.

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baseline ranged from 3.1% to 5.3% in epidemiological stud-ies on the natural progression of ET.37,39 Very recently,Paschen and colleagues blindly evaluated 20 ET patientsfollowed up to 10 years after surgery and found that theeffect of DBS on tremor decreased with time; this effect waspresent both during the stimulation OFF and ON condi-tions, suggesting that most of the benefit decay (87%according to the researchers) was caused by disease progres-sion.18 The idea of a disease progressing to a point whenDBS is no longer able to suppress the pathological neuronaloscillation of ET contrasts with the good long-term outcomeof Parkinson’s disease (PD) tremor.10,40 In fact, loss of bene-fit has been rarely reported in PD-related tremor,13 ashighlighted since the initial reports of this problem,10 andalso recently confirmed by another study.38 On the otherhand, tremor is an early sign of PD that can spontaneouslyimprove with disease progression—unlike ET.41

The variable post-DBS outcome might reflect the fact thatET is a heterogeneous condition, often heralding a progres-sive cerebellar disease (Video 1).5,38,42 This leads to thehypothesis that greater cerebellar dysfunction may beneeded to see DBS failure. With few exceptions,43 the vastmajority of DBS studies in cerebellar tremor are retrospec-tive and small case series, most commonly describing fragileX–associated tremor/ataxia syndrome, Holmes tremor, andtremor associated with multiple sclerosis (MS).44 Notewor-thy, DBS failure has been reported also in patients sufferingfrom tremor associated with demyelinating neuropathy.16

The occurrence of tremor in demyelinating neuropathieshas been linked to cerebellar dysfunction: Classical eyeblink conditioning, which depends on an intact cerebellarcircuitry, was found to be impaired only in neuropathicpatients with tremor.45 In keeping with these concepts, arecent study found that the objective measure of ataxia (spi-ral width variability index), rather than tremor severity, pre-dicts the development of early failure after Vim DBS inpatients with a clinical diagnosis of ET.46

Surgery-Related Factors (Electrode Location,Microlesional Effect, and Placebo)

The most relevant surgery-factor is the location of theelectrode. In DBS literature, it is well established that a per-fectly placed electrode does not need high stimulating cur-rent, which in turn means minimal stimulation-induced sideeffects (see below). Although patients with and withoutDBS failure frequently do not differ in terms of lead locationcoordinates,12 it has been found that the distance betweenthe active electrode contact and CTT is longer in ETpatients with DBS failure than patients without it.47 Like-wise, stronger intraoperative beta oscillation—also linkedto the afferent areas of CTT (i.e., Vim48)—has been hypoth-esized to predict the long-term benefit of DBS.38 In MStremor, implantation of an additional lead adjacent to Vim(e.g., in Vop) has been shown to be superior to single-leadDBS, possibly because a larger thalamic volume is

stimulated.43 Interestingly, this approach has also been suc-cessfully tried in ET patients who had experienced benefitdecay, particularly when a current flow from one electrodeto the other was induced.49

A second surgery-related factor is the thalamic micro-lesion (microthalamotomy) made during lead placement,which can have a beneficial, but transient, effect ontremor. Specifically, often patients need stimulationincrease within a few weeks after the initial DBS pro-gramming. According to our definition, this is probablynot be related to habituation, but rather to the decliningeffect of microthalamotomy. Clinicians have argued thatthis effect is too transient to explain most cases of DBSfailure, particularly the late ones. However, it should benoted that the microlesional effect is highly variableacross subjects. For example, 1 ET patient was explantedafter 1 year because of a persistent thalamotomy effectbecause of which the stimulator was never used.50

Besides the possibility of a microlesion, lead placementalso induces a number of immediate and delayed localeffects, such as gliosis around the electrodes in brain tis-sue over time.51-53 These factors play a role in the imped-ance drift, which mainly occurs in the first 6 monthsafter lead implantation. Interestingly, long-term fluctua-tions in impedance and lack of downward trends seemto be more common in Vim implants,54 although nostudy has specifically correlated these phenomena withthe duration of DBS benefit.Third, surgery has a strong placebo effect,55 although its

role in tremor patients has never been explored. However,placebo-related improvements are short-lived and variableacross patients (depending on expectations), features alsoshared by tremor patients manifesting habituation.

Stimulation-Related Factors (SuboptimalStimulation, Stimulation-Induced Side Effects,

Habituation, and Tremor Rebound)There is evidence suggesting that initial benefit

achieved by DBS is reduced relatively soon after initialDBS programming, possibly attributed to the factorsoutlined above.14 In these circumstances, DBS devicescan be reprogrammed to further control tremor. A pro-spective study found a significant positive correlationbetween tremor scores and total electrical energy deliv-ered, which increased exponentially over the first 4 yearsof Vim DBS, plateaued for 3 more years, and subse-quently raised again.56 As such, loss of DBS benefit maybe compensated by optimizing stimulation parameters.In some patients, however, the occurrence of

stimulation-induced side effects limits the possibility tofurther increase stimulation.38,57,58 Paresthesia and painare among the most common limiting side effects andare caused by the current spreading toward the ventralcaudal thalamic nucleus, posterior to Vim. In keepingwith this notion, a more anterior electrode placement

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within the Vim is associated with sustained long-termbenefit.38 This is further confirmed by a recent report ofbetter tremor control attributed to an expansion of thetherapeutic window by using short pulse width, a way toreduce the engagement of nonintended targets.59 Ataxia isone of the most common neurological side effects of tha-lamic DBS, occurring more often in bilateral thalamic DBS(56–85.7%) than unilateral DBS (9.1–16.7%).60,61 Theoccurrence of ataxia may be explained by antidromic DBSeffects onto the cerebellum, by an interference with cere-bellar efferents to the thalamus, or both. Furthermore, acompelling hypothesis proposes that chronic high-intensity stimulation might induce detrimental plasticchanges in the cerebellar circuit, and that tremor worsen-ing over time may thus represent a reversible cerebellartremor.17 The early reports62,63 of improved tremor con-trol after stimulation is turned off for hours, days, orweeks are possibly related to a stimulation-induced ataxiasuperimposed on tremor. Nevertheless, this hypothesisprobably does not apply to most patients with DBS failure,given that a disabling tremor is observed even when DBS-induced ataxia subsides. Finally, whereas excessive stimu-lation induces ataxia, lower amplitudes are also found toimprove the mild subclinical signs derived from the cere-bellar involvement (Table 2),64-66 which again arguesagainst the hypothesis that chronic DBS might worsentremor if the right parameters are used.Whether or not habituation of neurons or circuits can

occur after DBS is a topic of debate. Very recently, Paschenand colleagues reported that the long-term worsening of thetremor scores is more profound when comparing ON ver-sus OFF stimulation conditions over time, thus indicatinghabituation to stimulation.18 In particular, these researchersfound that the difference in tremor progression was largerON than OFF stimulation (i.e., delta of 0.05 TRS point-s/month, which constituted 13% of the total loss of benefit)and attributed this fraction to habituation.18 According toBenabid and coworkers, habituation (or tolerance) mightbe attributed to an adaptation of the biological response ofthe stimulated neuronal network.10,62 DBS may reducetremor severity in ET by masking burst-driver inputs to the

thalamus through the cerebellum,67 suggesting that tremorhabituation in ET results from restoring of the pathologicaloscillatory frequency of thalamic neurons.68 Accordingly, apostmortem study found differences in cerebellar climbingfiber pathology in ET patients with DBS as compared topatients without DBS.69

To understand the concept of habituation, a distinctionbetween when it happens has to be made. Barbe and col-legaues described habituation of tremor suppression as sub-stantial loss of acute benefit from electrode reprogrammingafter 10 weeks, observed prospectively in 54% of Vim elec-trodes implanted for ET.14 Such occurrence is relativelycommon in DBS (also in other targets and for other indica-tions), especially in case of suboptimal DBS lead location.70

Noteworthy, early tremor reoccurrence is also described inthalamotomies, likely attributed to too small lesions, andcan be treated repeating the same procedure, either RFthalamotomy71 or MRIgFUS thalamotomy.72 More com-plex is the issue of habituation observed years after DBSimplant, which probably also reflects the factors alreadydescribed. Here, simply increasing the electrical field is notenough (and also detrimental) because these patients wouldtypically obtain an immediate near-complete control of thetremor; however, the effect would consistently wear off afew days later (Videos 2 and 3).There are several strategies for preventing or mini-

mizing habituation, for example, using DBS only whenneeded (“on-demand DBS”),73 or turning the deviceoff for a few days (“DBS holidays”).63 The bestknown strategy to prevent habituation is to switchDBS off at night,13 although the effectiveness of thisapproach has never been proven in a controlled studyand individual patients might anecdotally report sometransient benefit soon after switching the implantablepulse generator (IPG) back on. Also, these procedurescan be difficult and distressing for patients with severetremor.16 This is why switching between two equiva-lent, but slightly different, stimulation settings hasbeen proposed as an alternative, which may indeedresult in a more enduring effect of chronic DBS overtime.74 This approach has been recently successfullytested in a 12-week, randomized, placebo-controlledtrial where 16 ET patients were randomized, on aweekly basis, to either alternating stimulation settingsor to standard continuous stimulation.75

Finally, the relationship between habituation, which pre-sumably involves more sustained mechanisms—and tremorrebound—which likely involves short-term mechanisms, ispresently unknown. Objective tremor recordings (at baselineand 2, 10, 20, 30, and 60 minutes after switching OFF thestimulator) disclosed that only 7 of the 17 ET patients(~41%) showed a rebound effect in a recent study investigat-ing long-term habituation to DBS, with no clear correlationwith tremor outcome.18Other studies confirmed that tremorrebound can be observed in a subgroup (10–30%) ofpatients,13,16,63 whereas others reported no evidence of such

TABLE 2. Effect of thalamic DBS on the subclinical signs ofcerebellar involvement displayed by ET patients

Function Effect Reference

Eyeblink conditioning + 130Sense of smell – 131Adaptive motor control (reaching) – 132Upper limb ataxia (agonist-antagonistcoupling)

= 133

Upper limb ataxia (dysmetria) + 64Lower limb ataxia + 65,66Gait + 65,66Balance –/+ 134

–, worsening; +, improvement; –/+, variable; =, no change.

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phenomenon.73,76 Although a recent article showed a stron-ger rebound effect only for a subgroup of patients whodeveloped ataxia as a side effect,17 the neurobiologicalunderpinning of tremor rebound remains unknown.

Explaining Loss of DBSBenefit From A Pathophysiological

Standpoint

The pathophysiology of ET has been linked to abnor-mal oscillatory activity in a cerebral network consistingof motor cortex, cerebellum, thalamus, and possibly thebrainstem.77 More specifically, electrophysiologicalstudies have shown corticomuscular coherence in motorcortex,78 cerebellum,79 thalamus,80 and brainstem.77,81

Furthermore, direct thalamic recordings (during DBS)have shown coherence between thalamic activity andtremor bursts.82 Finally, combined electromyography(EMG) functional MRI (fMRI) studies have foundincreased tremor-related activity in the cerebellum83

and resting-state fMRI studies have found increasedfunctional connectivity between thalamus and cortex,84

reduced functional connectivity between cerebellar cor-tex and dentate,85 and increased effective connectivitybetween cerebellum and thalamus.86 Anatomically,these regions encompass two anatomical circuits thatinteract in the cerebellum: the cortico-ponto-cerebello-thalamo-cortical loop and the dentato-rubro-olivo-cere-bello-dentate loop (Gullain-Mollaret triangle).87 It isunclear whether oscillatory activity in this circuit is cau-sed by a single pacemaker, multiple pacemakers, oraltered network dynamics (such as unstable feedbackloops). An intriguing finding is that corticomuscularcoherence is intermittent in ET despite ongoingtremor.78,88 This suggests that there are multiple oscil-lators involved.A key node is without doubt the cerebellum: Post-

mortem studies have shown pathological changes in thecerebellar cortex (Purkinje cell dysfunction)89 andreduced gamma-aminobutyric acid levels in the dentatenucleus90—which has been confirmed by nuclear imag-ing.91 Cerebellar Purkinje cell dysfunction may lead toimpaired inhibition of cerebellar output nuclei, causingpacemaker activity in these nuclei.86,92 Cerebellar dys-function may also introduce instabilities in thecerebello-thalamo-cortical circuit, given the feedbackloops between cerebellum and motor cortex. Evidencefor this idea comes from EMG studies showing abnor-mal ballistic movements in ET. Specifically, the onset ofantagonist activity—which normally breaks the agonistmovement—and the second activity of the agonist wasfound to be delayed in ET, and the duration of thedelay correlated with tremor period.93,94 This suggeststhat instabilities in the motor network make it prone tooscillations, although it is not clear whether the altered

triphasic response is cause or consequence of thetremor.95 Patients with more cerebellar dysfunction atbaseline are more prone to developing habituation afterDBS,46 and DBS can lead to cerebellar changes in ET.69

This suggests that the cerebellum plays a key role in thedevelopment of habituation to DBS.Vim DBS is thought to interfere with oscillatory

activity in this circuit by inhibiting rhythmic activity inthe thalamus. The mechanism underlying this inhibitionis likely synaptic fatiguing of glutamatergic afferents tothe Vim.96 The Vim receives glutamatergic afferentsfrom the cerebellar output nuclei and from the cortex.Thalamic inhibition uncouples thalamocortical fromcorticospinal reflex loops, leading to reduced tremor. Itis unclear exactly how synaptic inhibition is achieved:possibly by inactivation of T-type calcium channels orincreased levels of adenosine.97 As stated already, thedistance of the DBS electrode to CTT seems to correlatewith tremor suppression.38,47,48,98 With disease pro-gression, a larger number of cerebellothalamic neuronsmay become entrained in tremor. This could make itmore difficult to achieve synaptic depression in all thesefibers, especially if the distance from the DBS electrodeto the CTT is large. There may also be other circuit-level factors that contribute to the loss of benefit ofDBS. For example, it has been argued that the supple-mentary motor area (SMA) compensates for cerebellardysfunction in ET, as evidenced by increased structuralconnectivity from SMA to the corticospinal tract.85 Afailure of compensatory mechanisms later in the diseasemay worsen instabilities in the cerebello-thalamo-cortical circuit, reducing the efficacy of DBS.

Discussion

We gathered evidence explaining the progressive loss ofbenefit observed in a variable proportion of ET patientsafter Vim DBS. Tolerance is currently an established con-cept in the medical community, although there is debateon its real existence.15 In fact, very few publications haveactually addressed the problem, thus making tolerance atypical example of science based on “eminence rather thanevidence.” Nevertheless, this important topic raises thequestion to what extent patients and families should beinformed about a possible lack of efficacy after surgery.12

A number of issues need clarifications, as detailed below.

ET Is Not a Single EntityThe Task Force on Tremor of the International

Parkinson and Movement Disorder Society (MDS) hasrecently defined tremor according to a two-axis classifi-cation: clinical features (axis 1) and etiology (axis 2).2

Most tremor disorders are only classified in terms ofaxis 1, which is probably enough for the selection ofsurgical candidate. The recent IPMDS classification

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introduced the construct of ET-plus (ET patients withother “soft” signs, such as parkinsonism, ataxia, ordystonia), thus making the “pure” ET much rarer thanin the past.99 It is presently unknown whether loss ofDBS benefit is more common in ET-plus, but our pre-diction is that it is a feature of ET patients already pre-senting subtle signs of ataxia at baseline, in keepingwith a recent study.46 Object of debate is the relation-ship between dystonia, ET, and ET-plus with dystonicfeatures attributed to the lack of reliable biomarkersand complexity of clinical diagnosis when it comes tosoft signs.100 At the moment, it is hard to predictwhether the presence of dystonia is associated with theloss of DBS benefit over time.

Early and Late DBS FailureShih and coworkers found that 33 of 45 patients

(73.3%) reported waning benefit at a mean time of18.8 � 15.1 months (range, 3–75) following lead implan-tation.12 Such a time window clearly indicates that DBSfailure is not a uniform phenomenon and the time elapsedbetween surgery and decay of benefit should inform ourunderstanding of its pathophysiology (Fig. 1C). Forinstance, Sandoe and coworkers found that early failure isobserved in patients with a variety of cerebellar tremorwhereas late failure is less common and observed in ET.38

As detailed in the section Nomenclature, we arbitrarilydefine a cutoff of 1 year after DBS to differentiate earlyfrom late failure (Fig. 1B).

Definition of Tolerance Versus HabituationTolerance is a concept coming from pharmacology and

it is defined as “the capacity of the body to endure orbecome less responsive to a substance (as a drug) or aphysiological insult especially with repeated use or expo-sure.”101 Indeed, tolerance was brought up in early litera-ture on the pharmacological treatment of ET.13,102 It isprobably better to abandon the term tolerance and usehabituation to indicate the rapid vanishing of DBS effi-cacy after programming and escapers to indicate patientswith early or late DBS failure.

How to define EscapersCurrently, there does not seem to be any clear consensus

with regard to the definition of escapers. The definitionsused in articles addressing the problem generally refer tothe loss of perceived benefit,12,38 or a worsening on tremorscales,15 although it can be difficult to discern its clinicalmeaningfulness. While waiting for future research, we pro-pose this definition: “escapers are tremor patients in whomDBS had reduced tremor severity by at least 50% for atleast 6 months and who have subsequently reached thesame pre-DBS tremor severity within 1 year (earlyescapers) or later (late escapers) while on stimulation”(Fig. 1A). The construct of this definition, which is based

on tremor severity with DBS turned on, has three mainreasons: (1) It is ecological, given that patients’ daily func-tion is based on the effectiveness of DBS; (2) it is practical,given that patients are seen in the clinic with their stimula-tion turned on; and (3) it is scientifically more solid, giventhat tremor rebound does not bias the assessment.

Strategy to Treat EscapersDisentangling the real cause of a refractory tremor in a

DBS patient is crucial in order to identify the strategywith the highest chances of success. In fact, refractorytremor can be caused by DBS-induced cerebellar tremor,suboptimal DBS parameters, or DBS failure (Fig. 2).

Reprogramming

The first step is ruling out the occurrence of a cerebellartremor caused by excessive stimulation: Reducing the pulsewidth—if possible—should be followed by the reduction ofamplitude.58 Turning the DBS off might be useful, althoughthis requires prolonged observation to rule out the occur-rence of a rebound tremor. Once an iatrogenic cerebellartremor is ruled out, higher frequency should be triedfollowed by higher amplitudes.58 The impact of ultra-high-frequency DBS at 10,000 Hz is unknown in these patients,but certainly a possibility in the future.103 Increasing thestimulation strength might improve tremor in case of notoptimized settings; however, the possibility of inducingataxia should be taken into account and patients need to beevaluated after a few weeks. Increasing DBS settings mightalso cause other side effects (e.g., paresthesia or dysarthria):In some cases, the use of a bipolar lead configuration,58

reversing the polarity of an existing bipolar setting,104 inter-leaved stimulation,105 directional leads,106,107 or short pulsewidths59 expand the therapeutic window and allow higheramplitudes. Rarely, adding another contact for stimulationis beneficial, but it should be attempted, particularly activat-ing the closest to the thalamic boarder.64 Some escapers willmanifest habituation to reprogramming. As stated before,alternating parameter settings,74,75 on-demand DBS,73 orDBS holidays63 have been proposed, but the real efficacyand feasibility of this “varying DBS” is unknown.

Surgical Approaches

In case of unsuccessful management with conserva-tive measures, more-invasive strategies are justifiablefor disabling tremor in the absence of contraindica-tions. These approaches include an upgrade of theIPG,59 repositioning of the DBS lead,50 or insertion ofan additional electrode in the Vop or PSA/cZI.43,49

Neurosurgical treatments alternative to DBS can beconsidered, although there is no evidence that they cantreat escapers. Recently, the application of theta-burststimulation of the primary motor cortex (M1) has beenreported to be more effective in 1 ET patient who haddeveloped habituation to M1 stimulation.108,109

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Strategy to Prevent EscapersIntraoperative Vim targeting might be improved by

measuring beta oscillations38 or measuring cortical activityin response to thalamic stimulation,110 although the realusefulness of these approaches is not proven. Diffusiontensor imaging fiber-tractography–assisted DBS has beenproposed to identify and target individual tremor anatomyas well as to improve surgical outcome.27,111-113 Thisraises the question of whether DBS targeting CTT (as incZi/PSA) is less prone to habituation. No tolerance hasbeen reported with cZi/PSA,34,114 suggesting that toler-ance is property of the Vim itself. These notions need fur-ther research given that the number of cZI/PSAprocedures is much smaller than Vim. Nevertheless, thelong-lasting effects in cZi/PSA DBS series are achieved at alow stimulation strength (because the axons located in this

area are very sensitive to stimulation). In contrast, in arecent study where 47 ET patients were retrospectivelydivided into Vim or cZI stimulation groups according tothe location of the activated contact, a significant superior-ity of the former at 4 years’ follow-up in both OFF stimu-lation and ON stimulation was found.115 This study is tobe interpreted with caution in light of its retrospectivenature, the fact that cZI was not specifically targeted, andthe unusually higher stimulation strength in the cZI group.

Is There Any Habituation to Thalamotomy?We are witnessing a renaissance of lesioning proce-

dures using minimally invasive approaches (GKRF orMRgFUS).116 More recently, some researchers haveargued that habituation is only observed after DBS andablation might be preferred for this reason.17 This

FIG. 2. Strategies to treat refractory tremor in DBS patients. *Presently available with leads manufactured by Boston Scientific (Marlborough, MA) andAbbott (Chicago, IL); **IPG upgrade might be needed given that it is presently available only with IPGs manufactured by Boston Scientific and—uponspecial permission to unlock some features—by Medtronic (Dublin, Ireland). CT, cerebellar tremor; PW, pulse width; stim., stimulation; TEED, total elec-trical energy delivered. [Color figure can be viewed at wileyonlinelibrary.com]

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should be weighed against studies showing that patientswho underwent RF thalamotomy had an increased rateof early surgical complications and permanent neuro-logical side effects.57,117,118

Comparisons between DBS and non-DBS populationsare difficult, especially with retrospective studies, andbecause these patients will likely differ in other respectsthan the chosen surgical treatment (e.g., some medicalcomorbidities are a contraindication for DBS). Also,long-term outcome of RF thalamotomy is seldom publi-shed (Table 3), and most of these studies were performedmany years ago, often lacking a rigorous and objectiveassessment of the outcomes. Finally, as for MRgFUS, theworldwide experience is limited, although mid-termresults indicate a decline of benefit faster than initiallypredicted.119 The highest level of evidence comes fromthe follow-up of patients randomized to thalamic stimula-tion versus RF thalamotomy: Better long-term outcomehas been reported in ET patients who received DBS,although the few MS patients observed at last follow-upseemed to respond more favorably to thalamotomy.57,118

In conclusion, presently there is no reason to believethat loss of benefit is specific to DBS.

Roadmap for Future ResearchDBS treatment is currently based on an open-loop sys-

tem where continuous stimulation is applied to a targetarea in the brain. Adaptive DBS (aDBS) is a closed-loopsystem fed by relevant biomarkers, such as local fieldpotential activity in the brain or inertial tremor data.120,121

Theoretically, aDBS has many advantages, particularly thelower battery consumption, better safety profile,17 and pos-sibly higher effectiveness on tremor (when it can be appliedin a phase-locked manner).69,122,123 Finally, patternedstimulation (as in coordinated reset neuromodulation) iscertainly an attractive option, although it has been mainlyexplored in PD.124 Intriguingly, if proven effective, bothoptions will be easily implemented for current escapers byupgrading the IPG. Finally, an outstanding clinical ques-tion is whether detailed genetic testing (to exclude certain

axis 2 diagnoses) can and should be used in the surgicalselection of ET patients.5,42

From a pathophysiological perspective, there are dif-ferent testable predictions linking the pathophysiologyof ET to the development of habituation. First, we sug-gest that it is worth testing the hypothesis that the dis-tance from the DBS electrode to the CTT and/orcerebellar dysfunction (assessed with structural MRI orwith task-based fMRI) predicts habituation in a pro-spective study. Second, it would be interesting to testwhether a failure of compensatory mechanisms (e.g., bythe SMA85) is associated with a failure of DBS to ade-quately control tremor. Finally, to test the hypothesisthat plasticity within the tremor circuit is associatedwith habituation, the topography of tremor-relatedactivity could be prospectively measured after DBS, forexample using electrophysiology or neuroimaging.

Conclusions

The loss of DBS benefit in ET patients is probablyunder-reported, poorly defined, and largely unstudied. Wediscourage the use of the word tolerance to define thesepatients, which should also be characterized as early (6–12months after DBS) and late escapers. Some of theseescapers can indeed show habituation to DBS adjustments,a phenomenon poorly studied also in other indicationsand targets. Vim DBS still benefits most patients even inthe long term, as shown by studies comparing OFF versusON DBS.11,15,18 As such, DBS should still be seen as thetreatment of choice for patients who are severely affectedby a medication-refractory tremor with a favorable surgi-cal risk to benefit ratio even in the long term. The progres-sive loss of benefit that is observed in some ET patientsmay be explained by the interplay of several factors, suchas disease progression, placement of the electrode withrespect to the CTT, or plastic changes in the tremor cir-cuitry. We hope that new ways of identifying these factors(in individual patients) may help reduce habituation toDBS in the future.

TABLE 3. Clinical efficacy and safety of thalamotomy for non-PD tremor disorders in the available long-term studies(over 3 years)

Reference Technique Disease N Longest FU Duration (Years) Escapers

135 RF ET 21 (5) 4.7 � 3.0 0136 RF ET/MS/CT 21 (3)/33/21 ET: 1 to 7 in 5 patients,

over 7 in 5MS: 2 to 4 in 4 patientsCT: 1 to 5 in 11 patients

Partial loss of benefit in 9 ET (42.8%),15 MS (45.4%), 10 CT (47.6%) patients

137 GKRS ET 31 3 (median) 057 RF ET/MS 4/4 5 0138 GKRS ET 28 4.5 (median) “Some reoccurrence of tremor” in 3 patients139 MRgFUS ET 12 4 0

Number of bilateral cases into brackets.CT, cerebellar tremor other than MS; FU, follow-up.

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Legends of the VideosVideo 1. Familiar ET patient without DBS showing

clear gait ataxia almost 50 years after disease onset. Inthe first segment (in 2005), the patient has a typicalaction tremor in absence of cerebellar signs (notvideotaped). In the second segment (10 years later),action tremor has not significantly progressed, but thepatient features a wide-based gait. In the last segment(in 2018), a clear ataxia syndrome is manifested withappendicular and axial involvement (including titubationand inability to walk unassisted).Video 2. ET patient with long-term Vim DBS showing

late DBS failure and tolerance to DBS adjustments. Insegment 1, the patient is on high stimulation settings(0 + 1-2-, 3.8 V, 150 μsec, 250 Hz), tremor is not con-trolled, and appendicular ataxia is also visible. In segment2, DBS is off and ataxia has improved.Video 3. Same patient seen in Video 2 three days

after implementation of a new setting with lower stimu-lation (0 + 1-2-, 3.0 V, 60 μsec, 250 Hz), which acutelyimproved tremor and ataxia: Tremor and ataxia haveworsened again. In segment 2, the patient’s tremor isbetter controlled now that she is back to the high stimu-lation used before (0 + 1-2-, 3.8 V, 150 μsec, 250 Hz).

Acknowledgments: We thank Prof. Guenther Deuschl (Kiel, Germany)and the other anonymous reviewers for their valuable insights.

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