REVIEW

Tremor Habituation to Deep Brain Stimulation: Underlying

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

1
Edmond J. Safra Program in Parkinson’s Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western
Hospital, UHN, Toronto, Ontario, Canada; Division of Neurology, University of Toronto, Toronto, Ontario, Canada
2
Krembil Brain Institute, Toronto, Ontario, Canada
3
CenteR for Advancing Neurotechnological Innovation to Application (CRANIA), Toronto, Ontario, Canada
4
Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Department of Neurology,
Nijmegen, The Netherlands

A B S T R A C T : DBS of the ventral intermediate nucleus is
an extremely effective treatment for essential tremor,
although a waning benefit is observed after a variable time
in a variable proportion of patients (ranging from 0% to
73%), a concept historically defined as “tolerance.” Toler-
ance is currently an established concept in the medical
community, although there is debate on its real existence.
In fact, very few publications have actually addressed the
problem, thus making tolerance a typical example of sci-
ence based on “eminence rather than evidence.” The
underpinnings 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 gathered
the evidence explaining the progressive loss of benefit
observed 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 possible
pathophysiological explanations for the phenomenon and
define 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 DBS
benefit, and we draft a possible roadmap for the research
to come. © 2019 International Parkinson and Movement
Disorder Society
Key Words: deep brain stimulation; habituation; sur-
gery; tolerance; tremor

Tremor is defined as “an involuntary, rhythmic, oscilla- of 0.5% to 5%3; however, it has been the subject of sev-
tory movement of a body part.”1,2 Essential tremor eral debates in recent years, particularly in light of its
(ET) has been historically considered the most common phenomeno- and pathophysiological heterogeneity.4,5
movement disorder in adults, with an estimated prevalence Accordingly, ET definition has changed considerably over
the years and current criteria are rather strict, defining it as
-*Correspondence
- - - - - - - - - - - - - - -to:- - Dr.
- - - Alfonso
- - - - - - -Fasano,
- - - - - - Movement
- - - - - - - - -Disorders
- - - - - - - -Centre,
------ an isolated tremor syndrome of bilateral upper limb action
Toronto Western Hospital, 399 Bathurst Street, 7McL412, Toronto, ON, tremor for at least 3 years’ duration, with or without
Canada, M5T 2S8; E-mail: alfonso.fasano@uhn.ca tremor in other locations and in absence of other neuro-
Funding agencies: R.H. received funding from the Dutch Brain logical signs, such as dystonia, ataxia, or parkinsonism.2
Foundation. DBS is the most common surgical procedure for
Relevant conflicts of interest/financial disclosures: A.F. received medication-refractory ET since the first report confirming
honoraria and research funding from Medtronic and Boston Scientific.
R.H. received honoraria from AbbVie. sustained improvement in 6 ET patients in 1991.6 The
Full financial disclosures and author roles may be found in the online
ventral intermediate nucleus (Vim) of the thalamus is the
version of this article. traditional target for DBS in ET and also the target of abla-
Received: 9 March 2019; Revised: 1 July 2019; Accepted: 18 tive procedures (thalamotomies), which can be performed
July 2019 with invasive (radiofrequency; RF) or “minimally inva-
Published online 00 Month 2019 in Wiley Online Library
sive” (either gamma-knife radiosurgery [GKRF] or MRI-
(wileyonlinelibrary.com). DOI: 10.1002/mds.27821 guided focused ultrasound [MRIgFUS]) procedures.7-9

Movement Disorders, 2019 1

F A S A N O A N D H E L M I C H

Vim DBS is an extremely effective treatment for ET,

although a waning benefit is observed after a variable
time. Benabid and colleagues first introduced the concept
of “tolerance” as they observed that thalamic stimulation
was less effective over time in ET.10 It is now known that
in a variable proportion of patients—ranging from 011 to
73%12—no benefit is perceived anymore, and this raises
the 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 time
and propose possible pathophysiological explanations for
the phenomenon. Furthermore, we propose a practical
approach for preventing and treating this loss of DBS benefit,
and we draft a possible roadmap for the research to come.

Nomenclature
Over time, the loss of DBS benefit has been linked to a
variety 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 benefit
occurring within or after 1 year of satisfactory tremor sup-
pression with DBS, respectively, when comparing pre-DBS
tremor severity with the post-DBS on state (Fig. 1A,B).
Tremor rebound is defined as a temporary increase of
tremor intensity over the preoperative state occurring up
to 1 hour after switching DBS off. A longer evaluation
without stimulation (up to 3 days17) has been proposed,
but this is not practical outside of a research context, and
a recent study found objective evidence that rebound
tremor ends within 30 to 60 minutes from stimulation dis-
continuation.18 Finally, habituation is defined as the loss
of sustained tremor control, which can become visible
days to weeks after DBS programming. For the purpose of
the review, we viewed habituation and tolerance as two
names describing the same phenomenon.
FIG. 1. (A) According to Paschen and colleagues,18 comparing tremor
severity 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 a
possible habituation. In order to avoid the bias of rebound tremor, we
propose the definition of “escapers” because those tremor patients in
whom 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 after
the arbitrary cutoff of 1 year of satisfactory tremor suppression with
DBS, respectively. (C) DBS failure is not a uniform phenomenon, and
the time elapsed between surgery and decay of benefit should support
the interplay of different—not mutually exclusive—factors, which we
grouped in three main domains: disease-, surgery-, and stimulation-
related factors. [Color figure can be viewed at wileyonlinelibrary.com]

DBS for ET: Short- and Long-Term

Outcomes
Several studies have shown that unilateral Vim DBS sig-
nificantly reduces overall tremor in the short term.9 Fewer
long-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 a
reduction of magnitude of the delta off versus on
DBS.9,19,20 The longest available follow-up of ET patients
up to 18 years after surgery reported that the mean
improvement 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 Vim
DBS leads to an even greater overall tremor reduction
given that both sides of the body are treated.11,21-25 There
are reports of up to 75% improvement in head tremor and
60% in voice tremor 5 years after DBS implantation.26
Other Targets
The posterior subthalamic area (PSA)/caudal zona
incerta (cZI) represents the white matter underneath the
thalamus, where the cerebellothalamic tract (CTT)—also
known as dentato-rubro-thalamic tract—runs.27,28 Given
that CTT is thought to play an important role in tremor
pathophysiology, the PSA/cZI has been also targeted by
DBS in ET. Uni- and bilateral PSA/cZI DBS have excellent
short-term outcomes.29-31 Within the first 5 years after
implantation, a reduction in efficacy has been demon-
strated in unilateral32,33 and bilateral cases.34 Other
reported targets for ET patients are ventralis oralis

2 Movement Disorders, 2019

 T R E M O R H A B I T U A T I O N T O D B S

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

FU Duration
Reference N* (Years) Effect Escapers

50 25 3.3 50.0% vs. baseline 5 of the initial cohort of 49 patients: after 3 months (2 patients),
45.5 vs. OFF 6 months (1 patient), 12 months (2 patients), and 24 months
(1 patient already reimplanted 3 months after DBS). In
addition, incomplete benefit in 1 patient and lead migration
in another patient (causing loss of benefit)
19 13 (1) 6.5  0.3 47.1% vs. baselinea 0
47.1% vs. OFFa
26c 19 (7) 6.5  0.6 56.6% vs. baselined 0 (worsened tremor control)
45.9% vs. OFFd
125 13 (NA) 3 88.4% vs. baseline 8 of 75 leads (52 patients of the original cohort) required
86.2% vs. OFF repositioning because of “loss of effect”
21 26 (8) 5 49.6% vs. baselinee 2
50.7% vs. OFFe
126 19 (0) 7.2  0.75 44.1% vs. baselinea 2 excluded from the initial cohort because of diagnostic revision
44.4% vs. OFFa (dystonic and cerebellar tremor)
57 6 5 Tremor suppression at 6 months, 0 of 6 ET patients, 0 of 19 PD patients, and 3 of 5 MS patients
reoccurrence of mild or included in the same series
moderate tremor in 3 patients
127 12 (UK) 7.6 67.7%b Of the initial cohort, 2 ceased to use DBS because of
side effects
114 18 (2) 4.0  0.8 52.4% vs. baseline 0 (target is cZi)
51.4 vs. OFF
24 22 7 to 12 31.2% vs. baseline Leads were revised because of loss of benefit in 2 of 42
patients (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 of
diagnostic revision of cerebellar ataxia)
20 13 (7) 11.0  1.3 44.1% vs. OFF (open)a 1
44.4% vs. OFF (blind)a
128 36 6.0 VAS: 8.5 (after DBS), 7.4 (latest FU)f UK
56 14 (11) 7.7  3.8 50.1% vs. baselinee 2 excluded from initial cohort attributed to early failure
because of electrodes misplacement
11 12 13.2  2.8 33.5% (vs. baseline) 0
48% (vs. OFF)
115 47 (6) 4 VIM: 68-92% vs. baselinea 0
cZI: 33-76% vs. baselinea
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 0
42.6.% vs. OFFe

*Number of bilateral cases into brackets.

a
Itemized A and B of stimulated side.
b
Selected items of A + B.
c
FU of an earlier work.129
d
Itemized part A.
e
Total TRS.
f
Questionnaire-based, side effects based on 26 pts.
FU, follow-up; UK, unknown; VAS, visual analogue scale.

posterior (Vop) and anterior nuclei of the thalamus and although the interplay of different—not mutually
STN.35,36 Efficacy and safety are overall good, although exclusive—factors has been advocated, as grouped below
the experience is limited to few reported patients, for in three main domains: disease-, surgery-, and stimulation-
which a publication bias may also apply. related factors (Fig. 1C).

Disease-Related Factors
The Mechanisms Explaining (Tremor Etiology and Progression)
the Loss of DBS Benefit The natural progression of ET has been considered by sev-
eral researchers as a cause of loss of DBS benefit,15,22,37,38
The underpinnings of the phenomena associated with although the natural history of ET is a matter of debate in
the progressive loss of DBS benefit are not fully elucidated, itself. The average annual increase in severity of ET from

Movement Disorders, 2019 3

F A S A N O A N D H E L M I C H
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 patients
followed up to 10 years after surgery and found that the
effect of DBS on tremor decreased with time; this effect was
present 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 when
DBS is no longer able to suppress the pathological neuronal
oscillation of ET contrasts with the good long-term outcome
of Parkinson’s disease (PD) tremor.10,40 In fact, loss of bene-
fit has been rarely reported in PD-related tremor,13 as
highlighted since the initial reports of this problem,10 and
also recently confirmed by another study.38 On the other
hand, tremor is an early sign of PD that can spontaneously
improve with disease progression—unlike ET.41
The variable post-DBS outcome might reflect the fact that
ET is a heterogeneous condition, often heralding a progres-
sive cerebellar disease (Video 1).5,38,42 This leads to the
hypothesis that greater cerebellar dysfunction may be
needed to see DBS failure. With few exceptions,43 the vast
majority of DBS studies in cerebellar tremor are retrospec-
tive and small case series, most commonly describing fragile
X–associated tremor/ataxia syndrome, Holmes tremor, and
tremor associated with multiple sclerosis (MS).44 Notewor-
thy, DBS failure has been reported also in patients suffering
from tremor associated with demyelinating neuropathy.16
The occurrence of tremor in demyelinating neuropathies
has been linked to cerebellar dysfunction: Classical eye
blink conditioning, which depends on an intact cerebellar
circuitry, was found to be impaired only in neuropathic
patients with tremor.45 In keeping with these concepts, a
recent 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 in
patients 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 the
electrode. 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 side
effects (see below). Although patients with and without
DBS failure frequently do not differ in terms of lead location
coordinates,12 it has been found that the distance between
the active electrode contact and CTT is longer in ET
patients with DBS failure than patients without it.47 Like-
wise, stronger intraoperative beta oscillation—also linked
to the afferent areas of CTT (i.e., Vim48)—has been hypoth-
esized to predict the long-term benefit of DBS.38 In MS
tremor, implantation of an additional lead adjacent to Vim
(e.g., in Vop) has been shown to be superior to single-lead
DBS, possibly because a larger thalamic volume is
4 Movement Disorders, 2019
stimulated.43 Interestingly, this approach has also been suc-
cessfully tried in ET patients who had experienced benefit
decay, particularly when a current flow from one electrode
to 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 on
tremor. Specifically, often patients need stimulation
increase within a few weeks after the initial DBS pro-
gramming. According to our definition, this is probably
not be related to habituation, but rather to the declining
effect of microthalamotomy. Clinicians have argued that
this effect is too transient to explain most cases of DBS
failure, particularly the late ones. However, it should be
noted that the microlesional effect is highly variable
across subjects. For example, 1 ET patient was explanted
after 1 year because of a persistent thalamotomy effect
because of which the stimulator was never used.50
Besides the possibility of a microlesion, lead placement
also induces a number of immediate and delayed local
effects, 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 months
after lead implantation. Interestingly, long-term fluctua-
tions in impedance and lack of downward trends seem
to be more common in Vim implants,54 although no
study has specifically correlated these phenomena with
the 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 variable
across patients (depending on expectations), features also
shared by tremor patients manifesting habituation.
Stimulation-Related Factors (Suboptimal
Stimulation, Stimulation-Induced Side Effects,
Habituation, and Tremor Rebound)
There is evidence suggesting that initial benefit
achieved by DBS is reduced relatively soon after initial
DBS programming, possibly attributed to the factors
outlined above.14 In these circumstances, DBS devices
can be reprogrammed to further control tremor. A pro-
spective study found a significant positive correlation
between tremor scores and total electrical energy deliv-
ered, which increased exponentially over the first 4 years
of Vim DBS, plateaued for 3 more years, and subse-
quently raised again.56 As such, loss of DBS benefit may
be compensated by optimizing stimulation parameters.
In some patients, however, the occurrence of
stimulation-induced side effects limits the possibility to
further increase stimulation.38,57,58 Paresthesia and pain
are among the most common limiting side effects and
are caused by the current spreading toward the ventral
caudal thalamic nucleus, posterior to Vim. In keeping
with this notion, a more anterior electrode placement

within the Vim is associated with sustained long-term
benefit.38 This is further confirmed by a recent report of
better tremor control attributed to an expansion of the
therapeutic window by using short pulse width, a way to
reduce the engagement of nonintended targets.59 Ataxia is
one 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 The
occurrence of ataxia may be explained by antidromic DBS
effects onto the cerebellum, by an interference with cere-
bellar efferents to the thalamus, or both. Furthermore, a
compelling hypothesis proposes that chronic high-
intensity stimulation might induce detrimental plastic
changes in the cerebellar circuit, and that tremor worsen-
ing over time may thus represent a reversible cerebellar
tremor.17 The early reports62,63 of improved tremor con-
trol after stimulation is turned off for hours, days, or
weeks are possibly related to a stimulation-induced ataxia
superimposed on tremor. Nevertheless, this hypothesis
probably 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 to
improve the mild subclinical signs derived from the cere-
bellar involvement (Table 2),64-66 which again argues
against the hypothesis that chronic DBS might worsen
tremor 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, Paschen
and colleagues reported that the long-term worsening of the
tremor scores is more profound when comparing ON ver-
sus OFF stimulation conditions over time, thus indicating
habituation to stimulation.18 In particular, these researchers
found that the difference in tremor progression was larger
ON 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 to
Benabid and coworkers, habituation (or tolerance) might
be attributed to an adaptation of the biological response of
the stimulated neuronal network.10,62 DBS may reduce
tremor severity in ET by masking burst-driver inputs to the
TABLE 2. Effect of thalamic DBS on the subclinical signs of
cerebellar involvement displayed by ET patients
Function Effect Reference
Eyeblink conditioning + 130
Sense of smell – 131
Adaptive motor control (reaching) – 132
Upper limb ataxia (agonist-antagonist = 133
coupling)
Upper limb ataxia (dysmetria) + 64
Lower limb ataxia + 65,66
Gait + 65,66
Balance –/+ 134
–, worsening; +, improvement; –/+, variable; =, no change.
T R E M O R H A B I T U A T I O N T O D B S
thalamus through the cerebellum,67 suggesting that tremor
habituation in ET results from restoring of the pathological
oscillatory frequency of thalamic neurons.68 Accordingly, a
postmortem study found differences in cerebellar climbing
fiber pathology in ET patients with DBS as compared to
patients without DBS.69
To understand the concept of habituation, a distinction
between 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 reprogramming
after 10 weeks, observed prospectively in 54% of Vim elec-
trodes implanted for ET.14 Such occurrence is relatively
common 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 in
thalamotomies, likely attributed to too small lesions, and
can be treated repeating the same procedure, either RF
thalamotomy71 or MRIgFUS thalamotomy.72 More com-
plex is the issue of habituation observed years after DBS
implant, which probably also reflects the factors already
described. Here, simply increasing the electrical field is not
enough (and also detrimental) because these patients would
typically obtain an immediate near-complete control of the
tremor; however, the effect would consistently wear off a
few days later (Videos 2 and 3).
There are several strategies for preventing or mini-
mizing habituation, for example, using DBS only when
needed (“on-demand DBS”),73 or turning the device
off for a few days (“DBS holidays”).63 The best
known strategy to prevent habituation is to switch
DBS off at night,13 although the effectiveness of this
approach has never been proven in a controlled study
and individual patients might anecdotally report some
transient benefit soon after switching the implantable
pulse generator (IPG) back on. Also, these procedures
can be difficult and distressing for patients with severe
tremor.16 This is why switching between two equiva-
lent, but slightly different, stimulation settings has
been proposed as an alternative, which may indeed
result in a more enduring effect of chronic DBS over
time.74 This approach has been recently successfully
tested in a 12-week, randomized, placebo-controlled
trial where 16 ET patients were randomized, on a
weekly basis, to either alternating stimulation settings
or to standard continuous stimulation.75
Finally, the relationship between habituation, which pre-
sumably involves more sustained mechanisms—and tremor
rebound—which likely involves short-term mechanisms, is
presently unknown. Objective tremor recordings (at baseline
and 2, 10, 20, 30, and 60 minutes after switching OFF the
stimulator) 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 correlation
with tremor outcome.18 Other studies confirmed that tremor
rebound can be observed in a subgroup (10–30%) of
patients,13,16,63 whereas others reported no evidence of such
Movement Disorders, 2019 5
F A S A N O A N D H E L M I C H
phenomenon.73,76 Although a recent article showed a stron-
ger rebound effect only for a subgroup of patients who
developed ataxia as a side effect,17 the neurobiological
underpinning of tremor rebound remains unknown.
Explaining Loss of DBS
Benefit From A Pathophysiological
Standpoint
The pathophysiology of ET has been linked to abnor-
mal oscillatory activity in a cerebral network consisting
of motor cortex, cerebellum, thalamus, and possibly the
brainstem.77 More specifically, electrophysiological
studies have shown corticomuscular coherence in motor
cortex,78 cerebellum,79 thalamus,80 and brainstem.77,81
Furthermore, direct thalamic recordings (during DBS)
have shown coherence between thalamic activity and
tremor bursts.82 Finally, combined electromyography
(EMG) functional MRI (fMRI) studies have found
increased tremor-related activity in the cerebellum83
and resting-state fMRI studies have found increased
functional connectivity between thalamus and cortex,84
reduced functional connectivity between cerebellar cor-
tex and dentate,85 and increased effective connectivity
between cerebellum and thalamus.86 Anatomically,
these regions encompass two anatomical circuits that
interact in the cerebellum: the cortico-ponto-cerebello-
thalamo-cortical loop and the dentato-rubro-olivo-cere-
bello-dentate loop (Gullain-Mollaret triangle).87 It is
unclear whether oscillatory activity in this circuit is cau-
sed by a single pacemaker, multiple pacemakers, or
altered network dynamics (such as unstable feedback
loops). An intriguing finding is that corticomuscular
coherence is intermittent in ET despite ongoing
tremor.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 the
cerebellar cortex (Purkinje cell dysfunction)89 and
reduced gamma-aminobutyric acid levels in the dentate
nucleus90—which has been confirmed by nuclear imag-
ing.91 Cerebellar Purkinje cell dysfunction may lead to
impaired inhibition of cerebellar output nuclei, causing
pacemaker activity in these nuclei.86,92 Cerebellar dys-
function may also introduce instabilities in the
cerebello-thalamo-cortical circuit, given the feedback
loops between cerebellum and motor cortex. Evidence
for this idea comes from EMG studies showing abnor-
mal ballistic movements in ET. Specifically, the onset of
antagonist activity—which normally breaks the agonist
movement—and the second activity of the agonist was
found to be delayed in ET, and the duration of the
delay correlated with tremor period.93,94 This suggests
that instabilities in the motor network make it prone to
oscillations, although it is not clear whether the altered
6 Movement Disorders, 2019
triphasic response is cause or consequence of the
tremor.95 Patients with more cerebellar dysfunction at
baseline are more prone to developing habituation after
DBS,46 and DBS can lead to cerebellar changes in ET.69
This suggests that the cerebellum plays a key role in the
development of habituation to DBS.
Vim DBS is thought to interfere with oscillatory
activity in this circuit by inhibiting rhythmic activity in
the thalamus. The mechanism underlying this inhibition
is likely synaptic fatiguing of glutamatergic afferents to
the Vim.96 The Vim receives glutamatergic afferents
from the cerebellar output nuclei and from the cortex.
Thalamic inhibition uncouples thalamocortical from
corticospinal reflex loops, leading to reduced tremor. It
is unclear exactly how synaptic inhibition is achieved:
possibly by inactivation of T-type calcium channels or
increased levels of adenosine.97 As stated already, the
distance of the DBS electrode to CTT seems to correlate
with tremor suppression.38,47,48,98 With disease pro-
gression, a larger number of cerebellothalamic neurons
may become entrained in tremor. This could make it
more difficult to achieve synaptic depression in all these
fibers, especially if the distance from the DBS electrode
to the CTT is large. There may also be other circuit-
level factors that contribute to the loss of benefit of
DBS. For example, it has been argued that the supple-
mentary motor area (SMA) compensates for cerebellar
dysfunction in ET, as evidenced by increased structural
connectivity from SMA to the corticospinal tract.85 A
failure of compensatory mechanisms later in the disease
may worsen instabilities in the cerebello-thalamo-
cortical circuit, reducing the efficacy of DBS.
Discussion
We gathered evidence explaining the progressive loss of
benefit observed in a variable proportion of ET patients
after Vim DBS. Tolerance is currently an established con-
cept in the medical community, although there is debate
on its real existence.15 In fact, very few publications have
actually addressed the problem, thus making tolerance a
typical example of science based on “eminence rather than
evidence.” Nevertheless, this important topic raises the
question to what extent patients and families should be
informed about a possible lack of efficacy after surgery.12
A number of issues need clarifications, as detailed below.
ET Is Not a Single Entity
The Task Force on Tremor of the International
Parkinson and Movement Disorder Society (MDS) has
recently 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 of
axis 1, which is probably enough for the selection of
surgical candidate. The recent IPMDS classification

introduced the construct of ET-plus (ET patients with
other “soft” signs, such as parkinsonism, ataxia, or
dystonia), thus making the “pure” ET much rarer than
in the past.99 It is presently unknown whether loss of
DBS 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 keeping
with a recent study.46 Object of debate is the relation-
ship between dystonia, ET, and ET-plus with dystonic
features attributed to the lack of reliable biomarkers
and complexity of clinical diagnosis when it comes to
soft signs.100 At the moment, it is hard to predict
whether the presence of dystonia is associated with the
loss of DBS benefit over time.
Early and Late DBS Failure
Shih and coworkers found that 33 of 45 patients
(73.3%) reported waning benefit at a mean time of
18.8  15.1 months (range, 3–75) following lead implan-
tation.12 Such a time window clearly indicates that DBS
failure is not a uniform phenomenon and the time elapsed
between surgery and decay of benefit should inform our
understanding of its pathophysiology (Fig. 1C). For
instance, Sandoe and coworkers found that early failure is
observed in patients with a variety of cerebellar tremor
whereas late failure is less common and observed in ET.38
As detailed in the section Nomenclature, we arbitrarily
define a cutoff of 1 year after DBS to differentiate early
from late failure (Fig. 1B).
Definition of Tolerance Versus Habituation
Tolerance is a concept coming from pharmacology and
it is defined as “the capacity of the body to endure or
become less responsive to a substance (as a drug) or a
physiological 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 is
probably better to abandon the term tolerance and use
habituation to indicate the rapid vanishing of DBS effi-
cacy after programming and escapers to indicate patients
with early or late DBS failure.
How to define Escapers
Currently, there does not seem to be any clear consensus
with regard to the definition of escapers. The definitions
used in articles addressing the problem generally refer to
the loss of perceived benefit,12,38 or a worsening on tremor
scales,15 although it can be difficult to discern its clinical
meaningfulness. While waiting for future research, we pro-
pose this definition: “escapers are tremor patients in whom
DBS had reduced tremor severity by at least 50% for at
least 6 months and who have subsequently reached the
same pre-DBS tremor severity within 1 year (early
escapers) or later (late escapers) while on stimulation”
(Fig. 1A). The construct of this definition, which is based
T R E M O R H A B I T U A T I O N T O D B S
on tremor severity with DBS turned on, has three main
reasons: (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, given
that tremor rebound does not bias the assessment.
Strategy to Treat Escapers
Disentangling the real cause of a refractory tremor in a
DBS patient is crucial in order to identify the strategy
with the highest chances of success. In fact, refractory
tremor 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 cerebellar
tremor caused by excessive stimulation: Reducing the pulse
width—if possible—should be followed by the reduction of
amplitude.58 Turning the DBS off might be useful, although
this requires prolonged observation to rule out the occur-
rence of a rebound tremor. Once an iatrogenic cerebellar
tremor is ruled out, higher frequency should be tried
followed 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 the
stimulation strength might improve tremor in case of not
optimized settings; however, the possibility of inducing
ataxia should be taken into account and patients need to be
evaluated after a few weeks. Increasing DBS settings might
also 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 pulse
widths59 expand the therapeutic window and allow higher
amplitudes. Rarely, adding another contact for stimulation
is beneficial, but it should be attempted, particularly activat-
ing the closest to the thalamic boarder.64 Some escapers will
manifest habituation to reprogramming. As stated before,
alternating parameter settings,74,75 on-demand DBS,73 or
DBS holidays63 have been proposed, but the real efficacy
and feasibility of this “varying DBS” is unknown.
Surgical Approaches
In case of unsuccessful management with conserva-
tive measures, more-invasive strategies are justifiable
for disabling tremor in the absence of contraindica-
tions. These approaches include an upgrade of the
IPG,59 repositioning of the DBS lead,50 or insertion of
an additional electrode in the Vop or PSA/cZI.43,49
Neurosurgical treatments alternative to DBS can be
considered, although there is no evidence that they can
treat escapers. Recently, the application of theta-burst
stimulation of the primary motor cortex (M1) has been
reported to be more effective in 1 ET patient who had
developed habituation to M1 stimulation.108,109
Movement Disorders, 2019 7
F A S A N O A N D H E L M I C H

FIG. 2. Strategies to treat refractory tremor in DBS patients. *Presently available with leads manufactured by Boston Scientific (Marlborough, MA) and
Abbott (Chicago, IL); **IPG upgrade might be needed given that it is presently available only with IPGs manufactured by Boston Scientific and—upon
special 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]

Strategy to Prevent Escapers area are very sensitive to stimulation). In contrast, in a

Intraoperative Vim targeting might be improved by
measuring beta oscillations38 or measuring cortical activity
in response to thalamic stimulation,110 although the real
usefulness of these approaches is not proven. Diffusion
tensor imaging fiber-tractography–assisted DBS has been
proposed to identify and target individual tremor anatomy
as well as to improve surgical outcome.27,111-113 This
raises the question of whether DBS targeting CTT (as in
cZi/PSA) is less prone to habituation. No tolerance has
been 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/PSA
procedures is much smaller than Vim. Nevertheless, the
long-lasting effects in cZi/PSA DBS series are achieved at a
low stimulation strength (because the axons located in this
recent study where 47 ET patients were retrospectively
divided into Vim or cZI stimulation groups according to
the 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 to
be interpreted with caution in light of its retrospective
nature, the fact that cZI was not specifically targeted, and
the 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 or
MRgFUS).116 More recently, some researchers have
argued that habituation is only observed after DBS and
ablation might be preferred for this reason.17 This

8 Movement Disorders, 2019


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)
135
RF ET 21 (5)
136
RF ET/MS/CT 21 (3)/33/21
137
GKRS ET 31
57
RF ET/MS 4/4
138
GKRS ET 28
139
MRgFUS ET 12
Number of bilateral cases into brackets.
CT, cerebellar tremor other than MS; FU, follow-up.
should be weighed against studies showing that patients
who underwent RF thalamotomy had an increased rate
of early surgical complications and permanent neuro-
logical side effects.57,117,118
Comparisons between DBS and non-DBS populations
are difficult, especially with retrospective studies, and
because these patients will likely differ in other respects
than the chosen surgical treatment (e.g., some medical
comorbidities are a contraindication for DBS). Also,
long-term outcome of RF thalamotomy is seldom publi-
shed (Table 3), and most of these studies were performed
many years ago, often lacking a rigorous and objective
assessment of the outcomes. Finally, as for MRgFUS, the
worldwide experience is limited, although mid-term
results indicate a decline of benefit faster than initially
predicted.119 The highest level of evidence comes from
the follow-up of patients randomized to thalamic stimula-
tion versus RF thalamotomy: Better long-term outcome
has been reported in ET patients who received DBS,
although the few MS patients observed at last follow-up
seemed to respond more favorably to thalamotomy.57,118
In conclusion, presently there is no reason to believe
that loss of benefit is specific to DBS.
Roadmap for Future Research
DBS treatment is currently based on an open-loop sys-
tem where continuous stimulation is applied to a target
area in the brain. Adaptive DBS (aDBS) is a closed-loop
system fed by relevant biomarkers, such as local field
potential activity in the brain or inertial tremor data.120,121
Theoretically, aDBS has many advantages, particularly the
lower battery consumption, better safety profile,17 and pos-
sibly higher effectiveness on tremor (when it can be applied
in a phase-locked manner).69,122,123 Finally, patterned
stimulation (as in coordinated reset neuromodulation) is
certainly an attractive option, although it has been mainly
explored in PD.124 Intriguingly, if proven effective, both
options will be easily implemented for current escapers by
upgrading the IPG. Finally, an outstanding clinical ques-
tion is whether detailed genetic testing (to exclude certain
T R E M O R H A B I T U A T I O N T O D B S
Escapers
4.7  3.0 0
ET: 1 to 7 in 5 patients, Partial loss of benefit in 9 ET (42.8%),
over 7 in 5 15 MS (45.4%), 10 CT (47.6%) patients
MS: 2 to 4 in 4 patients
CT: 1 to 5 in 11 patients
3 (median) 0
5 0
4.5 (median) “Some reoccurrence of tremor” in 3 patients
4 0
axis 2 diagnoses) can and should be used in the surgical
selection of ET patients.5,42
From a pathophysiological perspective, there are dif-
ferent testable predictions linking the pathophysiology
of 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/or
cerebellar dysfunction (assessed with structural MRI or
with task-based fMRI) predicts habituation in a pro-
spective study. Second, it would be interesting to test
whether a failure of compensatory mechanisms (e.g., by
the SMA85) is associated with a failure of DBS to ade-
quately control tremor. Finally, to test the hypothesis
that plasticity within the tremor circuit is associated
with habituation, the topography of tremor-related
activity could be prospectively measured after DBS, for
example using electrophysiology or neuroimaging.
Conclusions
The loss of DBS benefit in ET patients is probably
under-reported, poorly defined, and largely unstudied. We
discourage the use of the word tolerance to define these
patients, which should also be characterized as early (6–12
months after DBS) and late escapers. Some of these
escapers can indeed show habituation to DBS adjustments,
a phenomenon poorly studied also in other indications
and targets. Vim DBS still benefits most patients even in
the long term, as shown by studies comparing OFF versus
ON DBS.11,15,18 As such, DBS should still be seen as the
treatment of choice for patients who are severely affected
by 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 patients
may be explained by the interplay of several factors, such
as disease progression, placement of the electrode with
respect 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 to
DBS in the future.
Movement Disorders, 2019 9
F A S A N O A N D H E L M I C H
Legends of the Videos
Video 1. Familiar ET patient without DBS showing
clear gait ataxia almost 50 years after disease onset. In
the first segment (in 2005), the patient has a typical
action tremor in absence of cerebellar signs (not
videotaped). In the second segment (10 years later),
action tremor has not significantly progressed, but the
patient features a wide-based gait. In the last segment
(in 2018), a clear ataxia syndrome is manifested with
appendicular and axial involvement (including titubation
and inability to walk unassisted).
Video 2. ET patient with long-term Vim DBS showing
late DBS failure and tolerance to DBS adjustments. In
segment 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 segment
2, 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 acutely
improved tremor and ataxia: Tremor and ataxia have
worsened again. In segment 2, the patient’s tremor is
better 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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