The Swedish Essential Tremor (SWEET) Trial - A Multicentre Randomized Controlled Trial of Deep Brain Stimulation for Essential Tremor
Phase: NA
Conditions: Essential Tremor
Sponsor: Karolinska Institutet

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Research/trial program:  
The Swedish Essential Tremor 
 (SWEET) Trial  
– A Multicentre Randomized Controlled 
Trial of Deep Brain Stimulation for 
Essential Tremor 
 
 
 
 
 
 
 
 
 
 
 
 
2018-12-20 
 
 
 
 

2 
 
Research/trial program:  
The Swedish Essential Tremor (SWEET) Trial  
– A Multicentre Randomized Controlled Trial of Deep Brain Stimulation 
for Essential Tremor 
 
 
PURPOSE AND AIMS 
 Aim 1 - To evaluate the effect of deep brain stimulation (DBS) vs best medical treatment 
in essential tremor (ET) in a randomized, single-blinded controlled trial. 
 Aim 2 - To compare the effect of DBS in the established target in the ventrolateral (VL)-
thalamus/ nucleus ventralis intermedius thalami (Vim) and in a new target in the posterior 
subthalamic area (PSA)/caudal Zona incerta (cZi). 
 Aim 3 - To map the target area in the VL-thalamus and PSA concerning effects and side 
effects of stimulation in order to identify and delineate the optimal target. 
 Aim 4 - To evaluate the long-term effects of DBS for ET in a longitudinal non-
randomized evaluation.  
 
SURVEY OF THE FIELD 
Deep Brain Stimulation (DBS) 
In DBS, thin quadripolar electrode 
leads (with four 1.5 mm long and 
1.27 mm thick contacts, separated 
by 1.5 mm space), connected to a 
neuropacemaker are implanted 
with stereotactic technique into 
the central parts of the brain (Figure 1) where the neuronal activity is modulated with 
electrical current. DBS has 
revolutionised the treatment of 
Parkinson´s disease and other 
movement disorders, and more than 150.000 patients have so far been operated29. Currently, 
new indications and targets are emerging21.  
However, many of the brain targets subjected for DBS are not well defined, and 
one of the main problem with DBS is likely to be the high number of suboptimally placed 
electrodes with lack of effect, unacceptable side effects and costly revisions10, 31. Further, 
even though this is an invasive and highly resource demanding therapy, most clinical 
indications for DBS (asides from Parkinson´s disease and dystonia)  are not evidence based8, 
12, 13. They are considered as “established treatments” and often provided as clinical treatment 
and not within the context of trials or scientific studies.  
 
DBS for Essential Tremor 
ET is the most common adult movement disorder with a prevalence of about 5% in the 
population above 65 years of age. Of patients who seek medical care up to 50% do not 
respond adequately to drug therapy27. 
The thalamic nucleus ventralis intermedius (Vim) is the projection structure of 
the cerebello-thalamic fibres mediating tremor. Hence, Vim has been an “established” target 
for surgical treatment of ET during the thalamotomy era, and when DBS was introduced and 
replaced thalamotomy, the Vim was logically the target for DBS for tremor. However, data 
from recent years indicate that it might not be stimulation of the Vim itself, but rather, the 
stimulation was affecting the pathologic tremor oscillations mediated by the cerebello-
Figure 1. Implanted DBS system 

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thalamic-cortical projections, located in the PSA and the caudal zona incerta (cZi)3, 17, 24. 
Thus, a number of studies have demonstrated that electrode contacts that reach the PSA have 
a better effect on tremor than those located more dorsally-rostrally in the Vim. This 
subthalamic area, which is situated immediately ventral-caudal to the Vim, is particulary 
dense with cerebello-thalamic axons, dispersing into the Vim. Stimulation is thus likely to 
involve more axons in the PSA than in the Vim, since these axons in the PSA constitute so to 
speak a bottle neck of the axonal traffic mediating tremor. It is also plausible that stimulation 
of axons rather than stimulation of nuclei actually affects by antedromic and orthodromic 
propagation more neurons and therefore also alters tremor oscillations more efficiently 24. A 
number of studies directly targeting the cZi have also recently presented results comparing 
favorably with the results published for Vim DBS3, 6, 17, 19, 34.  
 
Level of evidence regarding DBS in ET: 
Neither the Vim nor the cZi are evidence based targets, and there are no evidence-based DBS 
procedures for ET (level IV evidence only)8, 12, even though this is the second most common 
indication for DBS. However, the Vim is by tradition the established target for ET and the 
procedure is recommended in the Swedish guidelines for treatment of tremor37. 
The results of Vim DBS ET have been demonstrated in a number of 
uncontrolled, mostly minor studies1, 12. A problem is that many of these studies are likely to 
contain electrodes placed blindly within the PSA36 and that the actual location of the active 
electrode contacts of the DBS lead is seldom taken into consideration. Further, many reports 
lack a preoperative baseline and the results are often reported in a heterogenous manner, 
making comparison between different studies difficult12, 18. Regarding cZi DBS, excluding 
our own studies, the results of cZi DBS in 33 patients have been presented in five small and 
non-randomized studies3. Concerning the relative merits of the two targets, we have 
previously presented a tremor reduction of 86 % following cZi, compared to only 60% in the 
Vim4, and demonstrated that the electrode contacts with the best effect in what was called 
Vim were often placed in the PSA36. There is further a scarcity of long-term data regarding 
both targets1, 18. 
 
Identifying the brain target in the individual patient 
In a recent study of 28 000 procedures, electrode revisions constituted up to one third of all 
DBS procedures35. It is likely that misplaced electrodes due to difficulties in identifying the 
target is one of the major causes explaining a poor result in DBS for movement disorders10, 38.  
There are a number of different ways in which the target can be identified. Even 
for brain targets that can be visually identified on MRI, some centres rely mostly on statistical 
coordinates of the targets based on anatomical atlases, but this may result in poorly placed 
electrodes, due to significant inter-individual differences in the anatomy25. However, 
concerning the Vim, identification of that target in relation to ventricular landmarks is a 
necessity since the Vim cannot be visualized as such in MRI. 
Currently, 60 % of the centres are relying on micro-electrode recording (MER) in order to 
identify the target in the individual patient. This is an invasive neurophysiological method 
necessitating considerable resources. It is also associated with an increased risk of 
haemorrhages, since it involves introducing several sharp cannulas and electrodes into the 
target area39. The third method is visual anatomical targeting, whereby the target is identified 
on the patients´ MRI, either directly or in relation to visible very closely related landmarks 
(Figure 2). We have over the years made significant contributions in the development of this 
last method, both concerning the pallidum26, STN22 and cZi14, 36.  Unfortunately this method 
demands a high level of dedication and relies to a high degree on personal experience. 

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Scientifically based guidelines delineating the target areas and identifying the optimal target 
do not readily exist.   
Common for all different methods is that it is normally required that the patient is awake 
during surgery in order to allow for intra-operative testing of effect/side effects, even if some 
today perform the procedure in general anaesthesia concerning some of the targets. If the 
brain targets could be identified with a high degree of certainty, and the electrode position 
within that target can be verified during surgery, then having the patients awake during 
surgery would no longer be necessary. 
 
Figure 2). Example of visual anatomical targeting. In the enlarged MRI section (B) one electrode is place in the 
STN, and one electrode more posterior in the cZi. A schematic representation (C) demonstrate the relation of the 
electrodes to the STN and red nucleus.  
 
Identifying and delineating the optimal targets 
The literature regarding optimal target point/volume for the different targets is surprisingly 
meagre. The most common target, the subthalamic nucleus (STN), is also the most studied 
regarding this issue, but the effect has been evaluated in relation to the location of the 
electrode in no more than 260 patients in a total of 13 different studies7. Interestingly, most of 
these studies have found that the best effect is not achieved in the target structure itself, but in 
another adjacent structure, the more rostral part of the Zona incerta overlying the STN7, 23, 33. 
The same is true regarding the few studies of thalamic surgery for tremor, where most have 
demonstrated that the best effect is achieved from contacts outside the thalamic target, in the 
PSA19, 24, 30, 32, 36. Concerning other targets/indications the literature is even more limited.  
The existing studies are further hampered by the heterogeneity of the methods. 
Often it is not the actual location of the electrode that is reported, but the intended one. Even 
when the actual location is reported it is most often presented according to distant landmarks, 
even if the targeting was done visually, which is a significant problem, taking into 
consideration the inter-individual variability. Further, even though the stimulation parameters 
used can differ widely and hence the electrical current affect different neighbouring 
structures, this is virtually never taken into account.  
                                                                                                                            
DBS for ET – Conclusions and aim 
DBS for ET is thus not an evidence based therapy and the same is true regarding both target 
areas used for ET. The relative merits of the different targets used have not been clearly 
demonstrated and the individual targets are not well delineated. There is thus a need to 
address these issues. 
 
  
 

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PROJECT DESCRIPTION 
 
Overview - What are we going to study? 
The effect of DBS for ET will be evaluated in a multicentre study recruiting 100 patients 
randomized to immediate surgery (group A) or best medical treatment only (as decided by the 
movement disorder neurologist, with few exceptions likely to be identical to their current 
medication) with delayed surgery at 6 months if still needed /indicated (group B). Primary 
outcome is tremor reduction as measured with Essential tremor rating scale11 (ETRS), with 
focus on items 5/6 (hand tremor) & 11-14 (hand function)18, at baseline before surgery and at 
6 months. Secondary outcome includes quality of life measured with QUEST28 and electrical 
energy consumption18. After 6 months group B is operated –as indicated-, and group A and B 
are thereafter evaluated as one single group for long-term effects and analyses of electrode 
location. The electrodes will in all patients be inserted with a trajectory developed for this 
study allowing stimulation both in the established and traditionally used target Vim as well as 
in the new target cZi. Each contact will be evaluated individually concerning location, effects 
and side effects, in relation to stimulation parameters. This is done in order to, a) compare the 
two targets, but more importantly, b) to create a map of the whole area with 
identification/delineation of the optimal target point/volume. The time necessary to gather 
100 patients is estimated to 2.5 – 3 years.  
 
Study design: 
 Step 1 is designed as a randomized controlled trial in order to compare the effect of 
DBS (Group A) and medical treatment (Group B) on ET (Aim 1). 
 In step 2 – 4 the patients in group A are operated and group A and B joined into one 
single group. 
o Step 2 -  all electrode contacts are individually analysed regarding chronic and 
acute stimulation effects in relation to their location in either the Vim or the 
cZi in order to decide which target is more effective (Aim 2). 
o Step 3 - Effects and side effects, with consideration to field of stimulation, are 
analyzed in relation to neighboring structures in order to map the whole area 
and delineate the optimal target points (Aim 3). 
o Step 4 - The long-term effect is evaluated in a non-randomized longitudinal 
study at 1, 3, 5, 10 years (Aim 4). 
o  
Sample size and power: 
In step 1, with a confidence interval of 95%, and an expected improvement of 85 % in the 
surgical group and none (or at least < 25%) in the medical group, regarding contralateral 
items 5/6 & 11-14, a power of 100 % is achieved. In step 2, with an expected improvement of 
85% in one target and 60% in the other, a power of 98% is achieved. The high number of 
patients is, however, necessary for step 3, mapping of the area,  in order to give a good cover 
of the periphery (Length of contact carrying electrode surface 7.5 mm, expected mean non-
random intended deviation from target point (as defined in the study) 1 mm, expected mean 
random deviation from intended target point 1.5 mm)40. Based on the previous experience, 
less than 5% of patients is expected to be lost during the follow up, which will have an 
insignificant effect on the power.  
 
Population 
 Inclusion criteria: Diagnosis of ET, as decided by the movement disorder specialist; 
Substantial incapacity; Duration of symptoms > 5 years; Age 18 – 75; unsatisfying 
effect from β-blockers, or be unable to tolerate the medical therapy.  

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 Exclusion criteria: Cognitive impairment; Co-morbidity or non-compliance likely to 
jeopardize the result or to confuse the evaluation; Normal surgical exclusion criteria. 
 
Endpoints 
Primary outcome measure 
 ETRS11 
Secondary outcome measures 
 Quality of life in ET (QUEST)28 
 Neuropsychological tests  
 Electric energy consumption18 
 
Chronology of assessments/investigations 
ETRS, QoL, electric energy consumption: baseline, 6, 12, 24, 36, 48, 60, 120 months. 
Neuropsychological tests: baseline, 12 months 
 
 
 
 
 
 
   DBS 
         Investigations 
      patients:          Optimized        Assessment             Baseline investigation                           
    medication       for eligibility          and randomization 
                   6 months         
                                                                                       Exclusion                              Continual 
         Investigations 
 
 
 
 
 
   optimized 
 
 
 
 
 
   medication 
 
 
                Investigations   
   Investigations                     Investigations 
                    6 months 
          12 months  
12 months                            
           DBS                      Investigations 
   Investigations                     Investigations 
 
 
Surgery 
The patients are implanted using a trajectory 
targeting both the traditional target in the Vim 
and the new target in the cZi, with electrode 
contacts in both structures. Variations in the 
anatomy of the individual patient in combination 
with random deviations from the intended target 
point, will guarantee a spread of electrode 
contacts through the area of interest (Figure 3). 
 
Evaluation of stimulation 
Tremor is measured with ETRS11 (with focus on 
items 5/6 (hand tremor) & 11-14 (hand 
function)18. ETRS is performed before surgery at 
baseline and at 6 months on/off med/stim. The 
evaluation is done blinded to the patients in the 
surgical group. The evaluation is documented on 
video (with the patient wearing a head cap) and 
segmented for blinded evaluation of two expert evaluators. In the second step all individual 
electrode contacts are evaluated in the same manner regarding tremor, but also regarding side 
effects, with standardized stimulation parameters and a gradual increase of voltage (Figure 4). 
 
Figure 3. A Sagittal view an electrode with 
contacts in both the Vim and cZi. 
demonstrating the location of the two targets.  

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Target analysis 
All individual electrode contacts are evaluated as described above (Figure 4). In all patients a 
preoperative MRI (with tractography) and a postop MRI/CT are performed under stereotactic 
conditions, allowing fusion of the images. The exact location of each contact is determined in 
relation to multiple neighbouring structures, among other structures, the anterior and posterior 
commissures, the center of the red nucleus, the posterior tip of the STN and the 
cerebellothalamic fiber bundle as identified on tractography. The analysis is performed using 
the Framelink navigation tool by two experts. The contacts are plotted on stereotactic atlases 
and 3D models created. The contacts are further classified according to their location and 
effects/side-effects. The electrical properties of the area surrounding each contact are 
analysed, and the stimulation parameters are documented in order to map the actual field of 
stimulation. Based on these data the different targets can be outlined with respect to optimal 
effects/lack of side effects and maps of the area created.  
This is done to outline the optimal target, to provide a map for preoperative 
planning of the electrode location; to provide a map for interpretation of peroperative findings 
of macrostimulation and further to develop optimal stimulation strategies. 
Further, we have within the EU FP-7 IMPACT project developed a 
computorized model with automatic segmentation of the target area based on the MRI of the 
individual patient for targeting and a stimulation model based on the location of the electrode. 
This model will in the current project be adapted to the VL-thalamus/PSA and tested against 
best clinical practice. Hopefully, this will be of help for the non-expert regarding targeting, 
and reduce the necessary time for optimization of stimulation parameters. 
 
Statistics: 
Two-tailed T-test will be used for continuous variables, Wilcoxon signed rank test for paired 
non-parametric data and Mann-Whitney U test for un-paired non-parametric data. The model 
of stimulation fields, Volumes of Neural Activation (VNAs), will be generated using 
simulations of homogeneous tissue with density compensated probabilistic stimulation 
Figure 4. Target analysis 

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maps14. Registercentrum Norr will be responsible for the statistical analyses and stimulation 
field analysis will be done by Medtronic Eindhoven Design Center for Neuromodulation. 
 
Organization 
The international experience, as well as our own, has demonstrated that a study of this size 
necessitates a large population. The study will therefore be conducted on a national scale as a 
multicenter study including all six departments performing DBS surgery in Sweden, thus 
covering a population of 10 million inhabitants.  
The work is coordinated by the Unit for Deep Brain Stimulation in Umeå, while 
strategic decisions are made by the steering group of the Swedish DBS study group:  
Umeå University Hospital – Patric Blomstedt, Professor in stereotactic functional 
neurosurgery, Marwan Hariz, Professor in functional neurosurgery. Linköping University 
Hospital - Peter Zsigmond, associate professor in neurosurgery. Sahlgrenska University 
Hospital - Thomas Skoglund, associate professor in neurosurgery. Karolinska Institutet - 
Anders Fytagoridis MD, PhD, neurosurgeon. Lund University Hospital - Anna-Lena 
Törnqvist, PhD, specialist nurse, Hjalmar Bjartmarz, neurosurgeon. Uppsala University 
Hospital - Nils Wesslén, neurosurgeon.  
An internet-based register created and run by Registercentrum Norr in 
collaboration with us has been developed to function as a national quality register regarding 
DBS and as a research register for the current project. In order to ensure conformity in 
surgical techniques and evaluations we have developed an internet-based resource with 
targeting models and examples and we are providing on-site education regarding the items of 
importance. Further, in order to ensure conformity in targeting, as well as for evaluation of 
electrode location, we have also developed a technique for sharing of operation plans – “Tele-
targeting”. 
Simulations of stimulation fields and creation of functional maps based on 
stimulation response and other information are being performed in collaboration with the 
Department of Biomedical Engineering at the University of Linköping and with the IMPACT-
network (Umeå, Cologne, Germany & Salpetriere, Paris) led by Sapiens Steering Brain 
Stimulation. 
 
PRELIMINARY RESULTS 
We have in a number of previous studies evaluated DBS for ET in both the Vim and cZi1-6, 14-
16, 18, 20, 36. These studies have analysed effects, complications, long-term outcome, quality of 
life and effects and side effects in relation to electrode location. Unfortunately, these are non-
randomized and/or small studies. However, it seems quite clear that the effect of cZi DBS is 
promising: in a recently submitted manuscript about 50 patients we could demonstrate an 
improvement of contralateral tremor and hand function by 86% after 12 months. The contact 
evaluation demonstrated that the best effect was achieved within the target area itself, and that 
this target area is clearly distinct from the Vim. We have previously demonstrated in non-
randomized longitudinal studies that the effect of cZi is superior to Vim DBS, where the 
tremor reduction in the latter target was only 60%4, and that the electrode contacts with the 
best effect in what was called Vim were actually placed below the Vim, in the cZi area36. 
 
 
 
 
ETHICAL CONSIDERATIONS 
Patients will be offered participation in this study only after the patient has been accepted for 
surgery with DBS. Thus, patients not included in this study will anyhow undergo the same 

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procedure. The surgery with combination of the two targets is an improvement of the 
procedure, which has been done since 2004 in Umeå. The evaluations performed before and 
after surgery are normal clinical practice and will not differ between patients participating in 
the study and patients not participating in the study. Minor differences in the evaluations exist 
today between the participating clinics, why minor changes of the standard clinical protocol 
will be necessary at some clinics.  
The difference between normal clinical practice and this study is the randomisation into two 
groups, with immediate/delayed surgery. However, considering that the average waiting time 
for DBS is longer than 6 months, this does in reality mean that one of the groups will have a 
normal waiting time, while the other will have a shorter waiting time than normal. The 
patients who are randomized to delayed surgery will further have one additional evaluation (6 
months after randomization) compared to a patient not participating in this study.  
 
CLINICAL SIGNIFICANCE 
The number of targets and indications for DBS is expanding rapidly. However, few 
indications and targets are evidence based. Considering that this is an invasive and lifelong 
treatment of high the cost it is desirable that all DBS procedures in clinical practice are 
evidence based.  
In the current study the “established” target in the Vim will be compared with a 
new target in the caudal Zona incerta. Our previous studies have demonstrated the latter to 
improve tremor and hand-function with 86 %, compared with 60 % in the former. Further, the 
effect is in the former stable over time and the electric energy consumption is considerably 
lower, suggesting that the implant cost can be much reduced.  
In the literature, the number of misplaced electrodes with non-optimal results 
and/or side-effects is high. Identification of the optimal target would yield better results, fewer 
stimulation programming sessions, and avoidance of expensive re-operations9, 35. 
 
OTHER GRANTS AND RELATED PROJECTS 
Grant applications are planned to Vetenskapsrådet in 2018 for “Klinisk 
behandlingsforskning” and “projektbidrag”.  
 
 
REFERENCES 
1. Blomstedt P, Hariz GM, Hariz MI, Koskinen LO (2007) Thalamic deep brain stimulation in 
the treatment of essential tremor: a long-term follow-up. Br J Neurosurg 21:504-509 
2. Blomstedt P, Lindvall P, Linder J, Olivecrona M, Forsgren L, Hariz MI (2012) Reoperation 
after failed deep brain stimulation for essential tremor. World Neurosurg 78:554 e551-555 
3. Blomstedt P, Sandvik U, Fytagoridis A, Tisch S (2009) The posterior subthalamic area in 
the treatment of movement disorders: past, present, and future. Neurosurgery 64:1029-1038 
4. Blomstedt P, Sandvik U, Hariz MI, Fytagoridis A, Forsgren L, Hariz GM, Koskinen LO 
(2011) Influence of age, gender and severity of tremor on outcome after thalamic and 
subthalamic DBS for essential tremor. Parkinsonism & related disorders 17:617-620 
5. Blomstedt P, Sandvik U, Linder J, Fredricks A, Forsgren L, Hariz MI (2011) Deep brain 
stimulation of the subthalamic nucleus versus the zona incerta in the treatment of essential 
tremor. Acta neurochirurgica 153:2329-2335 
6. Blomstedt P, Sandvik U, Tisch S (2010) Deep brain stimulation in the posterior 
subthalamic area in the treatment of essential tremor. Mov Disord 25:1350-1356 
7. Caire F, Ranoux D, Guehl D, Burbaud P, Cuny E (2013) A systematic review of studies on 
anatomical position of electrode contacts used for chronic subthalamic stimulation in 
Parkinson's disease. Acta Neurochir (Wien) 155:1647-1654 

11 
 
8. Deuschl G, Raethjen J, Hellriegel H, Elble R (2011) Treatment of patients with essential 
tremor. Lancet Neurol 10:148-161 
9. Ellis TM, Foote KD, Fernandez HH, Sudhyadhom A, Rodriguez RL, Zeilman P, Jacobson 
CE, Okun MS (2008) Reoperation for suboptimal outcomes after deep brain stimulation 
surgery. Neurosurgery 63:754-760 
10. Ellis TM, Foote KD, Fernandez HH, Sudhyadhom A, Rodriguez RL, Zeilman P, Jacobson 
CEt, Okun MS (2008) Reoperation for suboptimal outcomes after deep brain stimulation 
surgery. Neurosurgery 63:754-760 
11. Fahn S, Tolosa E, Marin C (1993) Clinical rating scale for tremor. In: Jankovic J, Tolosa 
E (eds) Parkinson´s disease and movementdisorders. Urban and Schwarzenberg Munich, pp 
271-280 
12. Flora ED, Perera CL, Cameron AL, Maddern GJ (2010) Deep brain stimulation for 
essential tremor: A systematic review. Mov Disord 25:1550-1559 
13. Fox SH, Katzenschlager R, Lim SY, Ravina B, Seppi K, Coelho M, Poewe W, Rascol O, 
Goetz CG, Sampaio C (2011) The Movement Disorder Society Evidence-Based Medicine 
Review Update: Treatments for the motor symptoms of Parkinson's disease. Mov Disord 26 
Suppl 3:S2-41 
14. Fytagoridis A, Astrom M, Wardell K, Blomstedt P (2013) Stimulation-induced side 
effects in the posterior subthalamic area: distribution, characteristics and visualization. 
Clinical neurology and neurosurgery 115:65-71 
15. Fytagoridis A, Blomstedt P (2010) Complications and Side Effects of Deep Brain 
Stimulation in the Posterior Subthalamic Area. Stereotact Funct Neurosurg 88:88-93 
16. Fytagoridis A, Sandvik U, Astrom M, Bergenheim T, Blomstedt P (2011) Long term 
follow-up of deep brain stimulation of the caudal zona incerta for essential tremor. Journal of 
neurology, neurosurgery, and psychiatry 83:258-262 
17. Fytagoridis A, Sandvik U, Astrom M, Bergenheim T, Blomstedt P (2012) Long term 
follow-up of deep brain stimulation of the caudal zona incerta for essential tremor. J Neurol 
Neurosurg Psychiatry 83:258-262 
18. Fytagoridis A, Sandvik U, Astrom M, Bergenheim T, Blomstedt P (2012) Long term 
follow-up of deep brain stimulation of the caudal zona incerta for essential tremor. Journal of 
neurology, neurosurgery, and psychiatry 83:258-262 
19. Hamel W, Herzog J, Kopper F, Pinsker M, Weinert D, Müller D, Krack P, Deuschl G, 
Mehdorn HM (2007) Deep brain stimulation in the subthalamic area is more effective than 
ventralis intermedius stimulation for bilateral intention tremor. Acta neurochirurgica 149:749-
758 
20. Hariz GM, Blomstedt P, Koskinen LO (2008) Long-term effect of deep brain stimulation 
for essential tremor on activities of daily living and health-related quality of life. Acta Neurol 
Scand 118:387-394 
21. Hariz M, Blomstedt P, Zrinzo L (2013) Future of brain stimulation: new targets, new 
indications, new technology. Mov Disord 28:1784-1792 
22. Hariz MI, Krack P, Melvill R, Jorgensen JV, Hamel W, Hirabayashi H, Lenders M, 
Wesslen N, Tengvar M, Yousry TA (2003) A quick and universal method for stereotactic 
visualization of the subthalamic nucleus before and after implantation of deep brain 
stimulation electrodes. Stereotact Funct Neurosurg 80:96-101 
23. Herzog J, Fietzek U, Hamel W, Morsnowski A, Steigerwald F, Schrader B, Weinert D, 
Pfister G, Muller D, Mehdorn HM, Deuschl G, Volkmann J (2004) Most effective stimulation 
site in subthalamic deep brain stimulation for Parkinson's disease. Mov Disord 19:1050-1054 
24. Herzog J, Hamel W, Wenzelburger R, Potter M, Pinsker MO, Bartussek J, Morsnowski A, 
Steigerwald F, Deuschl G, Volkmann J (2007) Kinematic analysis of thalamic versus 
subthalamic neurostimulation in postural and intention tremor. Brain 130:1608-1625 

12 
 
25. Hirabayashi H, Hariz MI, Fagerlund M (1998) Comparison between stereotactic CT and 
MRI coordinates of pallidal and thalamic targets using the Laitinen noninvasive stereoadapter. 
Stereotact Funct Neurosurg 71:117-130 
26. Hirabayashi H, Tengvar M, Hariz MI (2002) Stereotactic imaging of the pallidal target. 
Mov Disord 17:S130-134 
27. Louis ED, Ferreira JJ (2010) How common is the most common adult movement 
disorder? Update on the worldwide prevalence of essential tremor. Mov Disord 25:534-541 
28. Martinez-Martin P, Jimenez-Jimenez FJ, Carroza Garcia E, Alonso-Navarro H, Rubio L, 
Calleja P, Diaz-Sanchez M, Benito-Leon J (2010) Most of the Quality of Life in Essential 
Tremor Questionnaire (QUEST) psychometric properties resulted in satisfactory values. J 
Clin Epidemiol 63:767-773 
29. Medtronic (2010) http://professional.medtronic.com/interventions/deep-brain-
stimulation/overview/index.htm 
30. Mobin F, De Salles AA, Behnke EJ, Frysinger R (1999) Correlation between MRI-based 
stereotactic thalamic deep brain stimulation electrode placement, macroelectrode stimulation 
and clinical response to tremor control. Stereotact Funct Neurosurg 72:225-232 
31. Okun MS, Tagliati M, Pourfar M, Fernandez HH, Rodriguez RL, Alterman RL, Foote KD 
(2005) Management of referred deep brain stimulation failures: a retrospective analysis from 
2 movement disorders centers. Arch Neurol 62:1250-1255 
32. Papavassiliou E, Rau G, Heath S, Abosch A, Barbaro NM, Larson PS, Lamborn K, Starr 
PA (2004) Thalamic deep brain stimulation for essential tremor: relation of lead location to 
outcome. Neurosurgery 54:1120-1129 
33. Plaha P, Ben-Shlomo Y, Patel NK, Gill SS (2006) Stimulation of the caudal zona incerta 
is superior to stimulation of the subthalamic nucleus in improving contralateral parkinsonism. 
Brain 129:1732-1747 
34. Plaha P, Javed S, Agombar D, G OF, Khan S, Whone A, Gill S (2011) Bilateral caudal 
zona incerta nucleus stimulation for essential tremor: outcome and quality of life. J Neurol 
Neurosurg Psychiatry 82:899-904 
35. Rolston JD, Englot DJ, Starr PA, Larson PS (2016) An unexpectedly high rate of 
revisions and removals in deep brain stimulation surgery: Analysis of multiple databases. 
Parkinsonism Relat Disord 
36. Sandvik U, Koskinen LO, Lundqvist A, Blomstedt P (2012) Thalamic and Subthalamic 
DBS for essential tremor - Where is the optimal target. Neurosurgery 70:840-845 
37. SWEMODIS (2015) Swedish guidlines for evaluation and treatment of tremor. 
http://www.swemodis.se/images/Dokument/SweModis%20Riktlinjer%20Tremortillstnd%201
%202015.pdf 
38. Zrinzo L, Blomstedt P, Hariz M (2014) Letter to the editor: Deep brain stimulation for 
dystonia. J Neurosurg 120:1496-1497 
39. Zrinzo L, Foltynie T, Limousin P, Hariz MI (2012) Reducing hemorrhagic complications 
in functional neurosurgery: a large case series and systematic literature review. Journal of 
neurosurgery 116:84-94 
40. Zrinzo L, van Hulzen AL, Gorgulho AA, Limousin P, Staal MJ, De Salles AA, Hariz MI 
(2009) Avoiding the ventricle: a simple step to improve accuracy of anatomical targeting 
during deep brain stimulation. J Neurosurg 110:1283-1290