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Background and Purpose Deep brain stimulation (DBS) is the most common surgical treatment for essential tremor (ET), yet there is variation in outcome and stimulation targets. This study seeks to consolidate proposed stimulation “sweet spots,” as well as assess the value of structural connectivity in predicting treatment outcomes. Materials and Methods Ninety-seven ET individuals with unilateral thalamic DBS were retrospectively included. Using normative brain connectomes, structural connectivity measures were correlated with the percentage improvement in contralateral tremor, based on the Fahn-Tolosa-Marin tremor rating scale (TRS), after parameter optimization (range 3.1-12.9 months) using a leave-one-out cross-validation in 83 individuals. The predictive feature map was used for cross-validation in a separate cohort of 14 ET individuals treated at another center. Lastly, estimated volumes of tissue activated (VTA) were used to assess a treatment “sweet spot,” which was compared to seven previously reported stimulation sweet spots and their relationship to the tract identified by the predictive feature map. Results In the training cohort, structural connectivity between the VTA and dentato-rubro-thalamic tract (DRTT) correlated with contralateral tremor improvement (R=0.41; p<0.0001). The same connectivity profile predicted outcomes in a separate validation cohort (R=0.59; p=0.028). The predictive feature map represented the anatomical course of the DRTT, and all seven analyzed sweet spots overlapped the predictive tract (DRTT). Conclusions Our results strongly support the possibility that structural connectivity is a predictor of contralateral tremor improvement in ET DBS. The results suggest the future potential for a patient-specific functionally based surgical target. Finally, the results showed convergence in “sweet spots” suggesting the importance of the DRTT to the outcome.
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NeuroImage: Clinical 32 (2021) 102846
Available online 4 October 2021
2213-1582/© 2021 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
Connectivity correlates to predict essential tremor deep brain stimulation
outcome: Evidence for a common treatment pathway
Erik H. Middlebrooks
, Lela Okromelidze
, Joshua K. Wong
, Robert S. Eisinger
Mathew R. Burns
, Ayushi Jain
, Hsin-Pin Lin
, Jun Yu
, Enrico Opri
, Andreas Horn
, Lukas
L. Goede
, Kelly D. Foote
, Michael S. Okun
, Alfredo Qui˜
, Ryan J. Uitti
Sanjeet S. Grewal
, Takashi Tsuboi
Department of Radiology, Mayo Clinic, Jacksonville, FL, USA
Department of Neurosurgery, Mayo Clinic, Jacksonville, FL, USA
Department of Neurology, Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, USA
Department of Neurology, Emory University, Atlanta, GA, USA
Movement Disorder and Neuromodulation Unit, Department of Neurology with Experimental Neurology, Charit´
e Universit¨
atsmedizin Berlin, Corporate Member of
Freie Universit¨
at Berlin and Humboldt-Universit¨
at zu Berlin, Berlin, Germany
Department of Neurosurgery, Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, USA
Department of Neurology, Mayo Clinic, Jacksonville, FL, USA
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan
Center for Brain Circuit Therapeutics, Department of Neurology, Brigham & Womens Hospital, Harvard Medical School, Boston, MA, USA
Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
Essential tremor
Deep brain stimulation
Background and purpose: Deep brain stimulation (DBS) is the most common surgical treatment for essential tremor
(ET), yet there is variation in outcome and stimulation targets. This study seeks to consolidate proposed stim-
ulation sweet spots, as well as assess the value of structural connectivity in predicting treatment outcomes.
Materials and methods: Ninety-seven ET individuals with unilateral thalamic DBS were retrospectively included.
Using normative brain connectomes, structural connectivity measures were correlated with the percentage
improvement in contralateral tremor, based on the Fahn-Tolosa-Marin tremor rating scale (TRS), after parameter
optimization (range 3.112.9 months) using a leave-one-out cross-validation in 83 individuals. The predictive
feature map was used for cross-validation in a separate cohort of 14 ET individuals treated at another center.
Lastly, estimated volumes of tissue activated (VTA) were used to assess a treatment sweet spot,which was
compared to seven previously reported stimulation sweet spots and their relationship to the tract identied by
the predictive feature map.
Results: In the training cohort, structural connectivity between the VTA and dentato-rubro-thalamic tract (DRTT)
correlated with contralateral tremor improvement (R =0.41; p <0.0001). The same connectivity prole pre-
dicted outcomes in a separate validation cohort (R =0.59; p =0.028). The predictive feature map represented
the anatomical course of the DRTT, and all seven analyzed sweet spots overlapped the predictive tract (DRTT).
Conclusions: Our results strongly support the possibility that structural connectivity is a predictor of contralateral
tremor improvement in ET DBS. The results suggest the future potential for a patient-specic functionally based
surgical target. Finally, the results showed convergence in sweet spotssuggesting the importance of the DRTT
to the outcome.
Abbreviations: COG, center-of-gravity; DBS, deep brain stimulation; DRTT, dentato-rubro-thalamic tract; dDRTT, decussating portion of the DRTT; ET, essential
tremor; FEM, nite element method; FWE, family-wise error; MPRAGE, magnetization-prepared rapid gradient-echo; ndDRTT, non-decussating portion of the DRTT;
PSA, posterior subthalamic area; TRS, Fahn-Tolosa-Marin tremor rating scale; VIM, ventral intermediate nucleus; VOp, ventralis oralis posterior nucleus; VTA,
volume of tissue activated.
* Corresponding author at: Departments of Radiology and Neurosurgery, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224, USA.
E-mail address: (E.H. Middlebrooks).
Contents lists available at ScienceDirect
NeuroImage: Clinical
journal homepage:
Received 6 June 2021; Received in revised form 14 August 2021; Accepted 27 September 2021
NeuroImage: Clinical 32 (2021) 102846
1. Introduction
Essential tremor (ET) is one of the most common movement disor-
ders worldwide, with an estimated prevalence of 0.9% (Louis and Fer-
reira, 2010). Almost half of individuals with ET will fail pharmacological
therapy and require alternative treatments (Thanvi et al., 2006; Louis
et al., 2010). Deep brain stimulation (DBS) is well-established as the
most common surgical treatment for ET. Despite widespread use, there
continues to be variation in targeting approaches, as well as a failure to
converge on a single therapeutic target or pathway (Okun et al., 2005).
Thalamic DBS for ET has traditionally targeted the ventral interme-
diate nucleus (VIM) region of the thalamus. More recently, there has
been increasing interest in the posterior subthalamic area (PSA),
including the caudal zona incerta, but superiority of one target over
others has yet to be unequivocally proven (Eisinger et al., 2018; Fyta-
goridis et al., 2012; Holslag et al., 2018; Sandvik et al., 2012). Moreover,
recent studies have also postulated the existence of stimulation sweet
spots more anteriorly in the region of the ventralis oralis posterior
nucleus (VOp) or along the VIM/VOp border (Middlebrooks et al., 2018;
Middlebrooks et al., 2018; Elias et al., 2021; Kim et al., 2018; Pouratian
et al., 2011; Tsuboi et al., 2021). The heterogeneity between these tar-
geting sweet spots has left gaps in our understanding of a potential ideal
treatment target.
Brain connectivity, as assessed by MRI, has been increasingly
explored to understand and to predict DBS outcomes in ET. These studies
have collectively observed that stimulation in the cerebello-thalamo-
cortical motor network may be responsible for improved tremor con-
trol (Middlebrooks et al., 2018; Middlebrooks et al., 2018; Tsuboi et al.,
2021; Coenen et al., 2011; Coenen et al., 2020; Coenen et al., 2017;
Coenen et al., 2011; Al-Fatly et al., 2019; Akram et al., 2018; Fenoy and
Schiess, 2017; Fenoy and Schiess, 2018; Anthofer et al., 2017). A critical
component of this network has been historically referred to as the
dentato-rubro-thalamic tract (DRTT). The traditional description of this
tract is one that connects the dentate nucleus with the contralateral
thalamus and motor cortex; however, these bers do not synapse within
the red nucleus despite their name (Middlebrooks et al., 2020). While
these decussating bers (dDRTT) constitute the majority of the DRTT,
the existence of a smaller non-decussating portion (ndDRTT) has been
recently shown by MRI diffusion tractography and human histological
studies (Tsuboi et al., 2021; Middlebrooks et al., 2020; Meola et al.,
2016; Petersen et al., 2018; Tacyildiz et al., 2021). These decussating
and non-decussating bers have been shown to possess a distinct spatial
gradient within the thalamus, with the dDRTT bers in general situated
more anteriorly (Tsuboi et al., 2021; Middlebrooks et al., 2020; Petersen
et al., 2018).
Converging evidence highlights the potential of connectivity-based
targeting and programming for ET DBS. However, previous studies
have been limited by small sample size or the use of bilateral electrodes.
The inclusion of bilateral DBS electrodes has the potential to confound
the observed tremor improvement due to the potential for unpredictable
ipsilateral effects or unequal tract activation between the hemispheres
(Noecker et al., 2021). We aimed to show that structural connectivity
could be predictive of ET DBS outcome through modulation of the
cerebello-thalamo-cortical motor network in a large cohort of unilateral
ET DBS individuals. The predictive connectivity ngerprints from this
cohort were then used for validation in a second cohort drawn from
another institution. Additionally, we assessed the stimulation sweet
spotand compared it to existing reported sweet spots.We sought to
either conrm or deny the potential existence of a common tract uni-
fying the sweet spotsreported in the literature.
2. Methods
2.1. Study design
This multicenter, retrospective cohort study was approved by the
Institutional Review Boards of the University of Florida and Mayo Clinic
Florida. The inclusion criteria of the present study were (1) diagnosis of
essential tremor dened by the Movement Disorders Society (isolated
tremor syndrome of bilateral upper limb action tremor with or without
tremor in other body regions) (Bhatia et al., 2018); (2) unilateral
thalamic DBS implantation, (3) preoperative clinical evaluation using
the Fahn-Tolosa-Marin tremor rating scale (TRS), (4) postoperative TRS
after DBS programming optimization, (5) preoperative brain MRI
including a high-resolution, T1-weighted magnetization-prepared rapid
gradient-echo (MPRAGE) sequence and high-resolution postoperative
CT, (6) absence of other brain surgeries, and (7) absence of secondary
etiologies for tremor or neurodegenerative diseases. We excluded in-
dividuals with tremor syndromes with additional features of parkin-
sonism, ataxia, myoclonus, or questionable dystonia (i.e., essential
tremor plus). We identied 83 ET individuals in the training cohort from
the University of Florida and 14 in the validation cohort from Mayo
Clinic Florida meeting the inclusion criteria (total of 97 individuals
2.2. Perioperative procedures and assessments
As the standard of care at the University of Florida and Mayo Clinic
Florida, all the patients underwent unilateral DBS implantation, and
staged implantation of the other side was considered later. In this study,
tremor outcomes were assessed using the scores when the patients were
treated only with unilateral DBS. Imaging protocols have been previ-
ously described (Middlebrooks et al., 2018), and are also summarized in
Supplemental Methods. Perioperative procedures and assessments for
ET individuals from the University of Florida cohort have also been
previously described (Tsuboi et al., 2021). Briey, DBS leads were
implanted in the University of Florida cohort under local anesthesia with
intraoperative microelectrode recordings and macrostimulation testing.
Using in-house software (Morishita et al., 2010), we aimed to place the
electrode at the VIM/VOp border with the most ventral contact deep to
the thalamus and the dorsal contacts in the posterior aspect of the VOp.
Individuals recruited from the Mayo Clinic cohort were selected from
the Mayo Clinic Movement Disorders Neurology Clinic after decision to
undergo unilateral VIM DBS for ET. After application of a stereotactic
headframe, a stereotactic CT was performed. The CT images were cor-
egistered to the preoperative MRI on the surgical planning workstation.
Using Guiots relationships to target the Vim, an initial target was
planned at the level of the anterior commissure-posterior commissure
(AC-PC) and one-fourth the ACPC distance anterior to the PC. A lateral
coordinate equal to the sum of one-half the width of the third ventricle
plus 11.5 mm was initially selected. The electrode was advanced
through a burr hole with the patient in a semisitting position with 30-de-
gree head elevation. Macrostimulation was performed to assess tremor
improvement and thresholds for stimulation of the internal capsule,
paresthesias, speech disturbances, or other adverse effects. If tremor
control was adequate without adverse effects, no further adjustments
were made. If the result was unsatisfactory, the electrode was reposi-
tioned according to the stimulation effect obtained. Implants included
the model 3387 lead and pulse generator (Activa PC/SC or Soletra;
Medtronic Inc, Minneapolis, MN, USA) or an 8-contact lead or direc-
tional lead and pulse generator (Vercise or Vercise Cartesia; Boston
Scientic Corp, Marlborough, MA, USA). Approximately 3 months after
surgery, high-resolution CT was obtained using a dual-energy protocol
(80 kV and 150 kV) with an in-plane resolution of 0.5 ×0.5 mm and slice
thickness of 0.4 mm.
For both cohorts, monthly visits were scheduled to optimize stimu-
lation parameters. Optimization was typically achieved within 6 months
of initial programming. An itemized TRS score was assessed by a skilled
examiner prior to surgery and after programming optimization using the
optimized programming settings. The contralateral tremor score was
calculated from the lateralized TRS motor scores (items 5, 6, 8, 9, and
1114) on the body side contralateral to the DBS. Percentage
E.H. Middlebrooks et al.
NeuroImage: Clinical 32 (2021) 102846
improvement in contralateral tremor score from preoperative baseline
to optimized postoperative assessment was the primary outcome
2.3. Image processing
A forked version of the Lead-DBS software package (http://www.lea (Horn et al., 2019) was used for electrode localization and
estimation of volumes of tissue activated (VTA). Lead-DBS was modied
to integrate functionality for unilateral electrodes, and the code used is
freely available (
v_patched). Modications have now been integrated to the main
branch and are available from Lead-DBS v2.5 onwards.
The high-resolution postoperative CT images were coregistered to
preoperative MPRAGE images using a two-stage linear registration in
Advanced Normalization Tools (
(Avants et al., 2008). The images were then normalized into
MNI_ICBM_2009b_NLIN_ASYM spacebased on the MPRAGE image-
swith the SyN registration method in Advanced Normalization Tools
(Avants et al., 2008; Fonov et al., 2011). A ve-stage nonlinear trans-
form was applied: two linear (rigid and afne) registrations, whole-brain
nonlinear SyN-registration, and two nonlinear SyN-registrations with a
focus on subcortical nuclei (Sch¨
onecker et al., 2009). A subsequent
afne transform that was restricted to subcortical regions of interest was
performed to ensure accurate subcortical registration (Horn et al.,
2019). Electrodes were localized using an automated and phantom-
validated approach implemented in Precise and Convenient Electrode
Reconstruction for Deep Brain Stimulation (PaCER) (Husch et al., 2018)
and, after manual adjustment, visually inspected for accuracy.
Using a nite element method (FEM)-based model in Lead-DBS
(Horn et al., 2019), a VTA was estimated for each patients optimized
programming settings. The E-eld was estimated on a tetrahedral mesh
that includes two tissue compartments (gray and white matter), insu-
lating components, and electrode contacts. Conductivity values were
adapted for the range of frequencies used in this cohort: 0.092 S/m and
0.06 S/m for gray and white matter conductivity, respectively. A
modied FieldTrip-SimBio pipeline, implemented in Lead-DBS, was
used to estimate the E-eld distribution with VTA shape based on a
typical threshold of >0.2 V/mm (Astrom et al., 2015; Vorwerk et al.,
2018). The right hemisphere VTAs were nonlinearly ipped to the left
2.4. VTA analysis
Stimulation sweet spot was assessed for percentage improvement in
contralateral tremor score using modications of methods in Dembek
et al. (2017). The binary left hemisphere and mirrored right hemisphere
VTAs were multiplied by the subjects percentage improvement to
create a weighted improvement mask. The weighted improvement mask
was then averaged to generate an improvement heat map. Next, a mask
for statistical signicance was created using the masked weighted VTAs
in a voxel-wise, two-sided non-parametric permutation test using
10,000 permutations. Due to the large number of voxels in regions well
beyond the area of stimulation, p values from statistical tests can be
artifactually improved by the excessive directions of freedom. To ac-
count for this, all zero voxels and those voxels with VTA overlap in less
than 15% of subjects were excluded from analysis. The signicance
mask was generated for only those voxels with FWE-corrected p <0.05
and applied to the average improvement heat map. The sweet spot was
determined by assessing the cluster center-of-gravity (COG) for the
resulting heat map.
2.5. Structural connectivity processing
The left hemisphere and mirrored right-hemisphere VTAs were used
as seeds for structural connectivity assessment. A normal control dataset
of 124 healthy subjects in the Human Connectome Project (htt
ps:// (Setsompop et al., 2013) was uti-
lized, as detailed in Tsuboi et al. (2021) For each VTA, probabilistic
tractography was performed using probtrackx2_gpu from the FMRIB
Software Library v6.0.3 ( in each of the 124
subjects with 20,000 samples, curvature threshold of 0.2, modied Euler
streamlining, and step length of 0.5 mm. A region-of-avoidance included
the hemisphere contralateral to the VTA and corpus callosum. The
resultant probability paths were averaged for all 124 control subjects
giving an averaged probability map for each subjects VTA.
2.6. Structural connectivity analysis training dataset
Next, to assess whether the probability distribution was predictive of
improvement in the 83-patient training cohort, a leave-one-out cross
validation was performed using the averaged probability map for each
subject. We treated this probability distribution analogously as con-
nectivity ngerprints seeding from DBS stimulation sites. Group R-maps
(voxel-wise correlations of ngerprint values with clinical improvement
values) were generated with all individuals except one, which was
withheld for validation. The structural connectivity ngerprint for the
left-out patient was then again used to measure spatial similarity with
the R-map generated from the remainder of the cohort (using spatial
correlations). Pearson correlation was performed using the similarity
index versus measured clinical improvement and p <0.05 was consid-
ered statistically signicant.
2.7. Structural connectivity analysis validation dataset
To assess generalizability of the predictions, the structural connec-
tivity ngerprint for each patient in the 14-patient validation dataset
was used to measure spatial similarity with the R-map generated from
the complete 83-patient training cohort (same process as in the cross-
validation step). Pearson correlation was performed using the similar-
ity index versus measured clinical improvement and p <0.05 was
considered statistically signicant.
2.8. Comparison to previous sweet spots
To assess spatial location of the VTA sweet spot for contralateral
tremor improvement in the current cohort, as well as comparison of
previously reported targets (Elias et al., 2021; Tsuboi et al., 2021; Al-
Fatly et al., 2019; Akram et al., 2018; Papavassiliou et al., 2004; Mid-
dlebrooks et al., 2021; Kübler et al., 2021), each of the previously re-
ported MNI sweet spots (Table 2) were plotted in relation to the
predictive tract ngerprint. The R-map derived from the training cohort
was thresholded at R >0.1 and the distance from each coordinate to the
nearest predictive voxel was calculated as a 3D Euclidean distance.
2.9. Statistical analysis
Subject demographics, baseline scores, postoperative improvement,
and DBS parameters were expressed as mean and SD. Comparison be-
tween the training and validation cohorts was performed using a
nonparametric Mann-Whitney U test.
2.10. Data availability
Data are available upon specic request pending a formal data
sharing agreement and approval from the authorsand requesting re-
searchers local ethics committees.
E.H. Middlebrooks et al.
NeuroImage: Clinical 32 (2021) 102846
3. Results
3.1. Clinical outcomes
Demographic and clinical information are summarized in Table 1.
All individuals underwent unilateral thalamic DBS with a mean follow-
up period of 6.8 ±1.5 months (range 3.112.9 months). There was no
signicant difference in the age at surgery, sex, or age of onset between
the cohorts (p >0.05); however, the disease duration was greater in the
training cohort (28.4 vs. 18.4 years; p =0.04). Total TRS score at
baseline was greater in the training cohort compared to the validation
cohort (51.3% vs. 42.8%; p =0.003), but contralateral TRS tremor score
was not signicantly different (16.3% vs. 16.1%; p =0.97). Likewise,
there was a similar observed improvement in contralateral TRS score
after surgery between the training and validation cohort (71.4% vs.
69.1%; p =0.72).
3.2. VTA analysis
The electrode contact positions relative to VIM and VOp from the
DBS Intrinsic Atlas (DISTAL) (Ewert et al., 2018) are shown for the
training cohort in Fig. 1A and the validation cohort in Fig. 1B. The active
contact positions for the training cohort color-coded by contralateral
tremor improvement are shown relative to VIM and VOp (Fig. 1C) and to
dDRTT (Fig. 1D). The masked weighted VTA heat maps for contralateral
tremor improvement are shown in Fig. 2. The cluster peak COG for
contralateral tremor improvement was along the ventral VIM/VOp
border (MNI = 15.5/15.5/0.5) in the training cohort and was more
medial and superior in the validation cohort (MNI = 13.5/15.5/2).
3.3. Structural connectivity analysis
The mean structural connectivity for the training cohort is shown in
Fig. 3A and shows greatest connectivity to the primary motor, sensory,
supplementary motor, and premotor cortices. A similar pattern of mean
connectivity is seen in the validation cohort (Fig. 3B).
In the training cohort, a leave-one-out cross validation shows that
connectivity ngerprint is predictive of contralateral tremor improve-
ment within the cohort (r =0.41; p <0.0001). The group R-map (Fig. 3D-3F) shows that the voxels most predictive of contralateral
tremor improvement correspond to the DRTT. In cross-validation with
the separate validation cohort (Fig. 3G), the connectivity ngerprint
from the training cohort was predictive of tremor improvement (r =
0.59; p =0.025).
3.4. Comparison to previous sweet spots
Comparison of the current stimulation sweet spot with multiple
existing published sweet spots (Table 2) showed a mean distance of 0 ±
0 mm, meaning that every reported coordinate overlapped with the
predictive tract derived from the training cohort (Fig. 4A & 4B).
4. Discussion
Our study revealed that a structural connectivity ngerprint was an
independent predictor of contralateral tremor improvement within our
training cohort, as well as predictive of improvement in a separate in-
dependent cohort. Further, we showed that the heterogeneity in recently
reported stimulation sweet spotscan potentially be explained by their
distance to a common pathway, the dentato-rubro-thalamic tract.
The strengths of our study included the use of unilateral electrodes,
which minimized potential confounds from ipsilateral microlesion ef-
fects from a second DBS electrode on the measurement of contralateral
tremor change. Unilateral implants also facilitated the evaluation of
pure ipsilateral change in tremor without similar confounds. It is
possible that a higher incidence of stimulation-induced side effects in
Table 1
Baseline patient characteristics and DBS outcomes.
p value
n =83 n =14
Age at DBS (years) 68.2 ±9.9 69.1 ±8.4 0.81
Disease duration before DBS (years) 28.4 ±17.7 18.4 ±15.1 0.04
Age at onset (years) 39.8 ±20.7 50.8 ±13.6 0.07
Sex (male, %) 65.1% 42.9% 0.14
TRS total score at baseline 51.3 ±14.8 42.8 ±10.2 0.003
Contralateral TRS tremor score at
16.3 ±4.7 16.1 ±4.4 0.97
TRS total score improvement after
DBS (%)
54.7 ±21.2
Contralateral TRS tremor score
improvement after DBS (%)
71.4 ±22.2 69.1 ±24.1 0.72
Follow-up period after DBS (months) 6.8 ±1.5 7.1 ±1.9
Monopolar / Bipolar stimulation 54 / 29 2 / 12
Stimulation voltage (V) 2.5 ±0.8 3.1 ±1.0 0.01
Stimulation pulse width (
s) 97.2 ±23.4 74.3 ±13.4 <0.0001
Stimulation frequency (Hz) 149.1 ±
149.6 ±21.2 0.29
Data are presented as mean ±SD unless otherwise indicated. DBS =deep brain
stimulation; TRS =Fahn-Tolosa-Marin Tremor Rating Scale.
* Contralateral TRS motor scores indicate lateralized scores contralateral to DBS
implantations. Items 5, 6, 8, 9, and 1114.
Total TRS Score not available for validation cohort due to lack of TRS Part C on
follow up.
Fig. 1. Sagittal image showing the relationship of electrodes in the training
cohort (A) and validation cohort (B) relative to the ventral intermediate nucleus
(VIM) and ventralis oralis posterior (VOp) nucleus from the DISTAL atlas
(Ewert et al., 2018). (C) Active contacts weighted by percentage improvement
in contralateral tremor relative to VIM and VOp. (D) Active contacts weighted
by percentage improvement in contralateral tremor relative to the decussating
portion of the dentato-rubro-thalamic tract (dDRTT). Background brain tem-
plate provided by Edlow et al. (2019).
E.H. Middlebrooks et al.
NeuroImage: Clinical 32 (2021) 102846
bilateral implants could inuence the choice of stimulation parameters
and this could have introduced bias into our study. Despite this limita-
tion, we report the largest ET cohort, to our knowledge (N =97), to
undergo both connectivity and VTA analysis. Our results add a new
dimension to the several prior small studies and bilateral implant co-
horts (Middlebrooks et al., 2018; Middlebrooks et al., 2018; Coenen
et al., 2011; Coenen et al., 2020; Coenen et al., 2017; Coenen et al.,
2014; Coenen et al., 2011; Al-Fatly et al., 2019; Akram et al., 2018;
Fenoy and Schiess, 2017; Fenoy and Schiess, 2018; Anthofer et al.,
Our results show that contralateral TRS motor improvement was
predicted by structural connectivity to the DRTT. The predictive maps
revealed were consistent with those described by Al-Fatly et al. (Al-Fatly
et al., 2019) The DRTT has traditionally been described as efferent
cerebellar bers extending from the dentate nucleus through the
ipsilateral superior cerebellar peduncle before decussating in the
midbrain to reach the contralateral VIM and VOp, and ending in the
contralateral primary motor cortex (Petersen et al., 2018; Gallay et al.,
2008). Subsequently, a smaller portion of the DRTT consisting of bers
extending from the dentate nucleus to the ipsilateral thalamus and
motor cortex without decussating, the ndDRTT, were shown in animal
and human histological studies (Tacyildiz et al., 2021; Flood and Jansen,
1966; Wiesendanger and Wiesendanger, 1985). These ndings have
been supported by more recent exploration using MRI tractography and
brain microdissection in human (Middlebrooks et al., 2020; Meola et al.,
2016; Petersen et al., 2018; Tacyildiz et al., 2021). These ndDRTT bers
make up a minority of the DRTT (<25% of tracts) (Meola et al., 2016)
and their role in tremor has not been well established. Converging evi-
dence from functional and anatomical studies shows a lateral and
posteromedial motor region of the dentate nucleus, which contributes a
Fig. 2. Statistically signicant average improvement heat map for percentage improvement in contralateral tremor score (A, axial; B, coronal; and C, sagittal views)
relative to the ventral intermediate nucleus (VIM; green) and ventralis oralis posterior (VOp; blue) from the DISTAL atlas (Ewert et al., 2018). Crosshairs show the
cluster center of gravity indicating the point of greatest improvement. (For interpretation of the references to color in this gure legend, the reader is referred to the
web version of this article.)
Fig. 3. Results of structural connectivity analysis for the training cohort (A) and validation cohort (B). (C) Scatterplot illustrates the correlation between the
empirical improvement in contralateral tremor compared to similarity to the predictive R-map for each subject from the leave-one-out cross-validation (r =0.41; p <
0.0001). Sagittal (D), axial (E), and coronal (F) images show the tract most correlated with contralateral tremor improvement with greatest correlation seen with the
DRTT. (G) Scatterplot shows cross-validation results for the validation cohort from a second institution based on the connectome ngerprints from the training cohort
showing that the training cohort is predictive of outcomes in the second cohort (r =0.59; p =0.025).
E.H. Middlebrooks et al.
NeuroImage: Clinical 32 (2021) 102846
majority of bers to the dDRTT, with a smaller fraction to the ndDRTT,
potentially explaining reported ipsilateral motor effects. Meanwhile, the
ndDRTT constitutes a large fraction of anteriomedial dentate nucleus
bers, thought to contribute to nonmotor functions (Tacyildiz et al.,
2021; Küper et al., 2012; Ellerman et al., 1994; Middleton and Strick,
2000; Middleton and Strick, 1998). Nevertheless, the ndDRTT has been
used as a biomarker in several DBS studies, possibly due to challenges in
reconstructing crossing bers of the dDRTT using tractography (Coenen
et al., 2016; Sammartino et al., 2016; Coenen et al., 2011; Coenen et al.,
2020; Coenen et al., 2017; Coenen et al., 2014; Coenen et al., 2011). This
limitation is an important consideration given the variability in the
spatial location of these two components. While they are more coher-
ently organized within the ventral thalamic region, the tracts have a
more distinct spatial separation in the PSA (Middlebrooks et al., 2020;
Petersen et al., 2018). This anatomical distribution provides a critical
point for evaluating discrepancies in reporting stimulation sweet spots
for ET. Unfortunately, distinction between the effects of these tracts
from our cohort cannot be completely assessed due to the large amount
of overlap of both tracts in the ventral thalamic region, as well as
preferential tracking of ndDRTT bers by tractography algorithms.
Future studies will be needed to better understand the role of these two
different components of the DRTT.
Recently, connectivity and VTA studies have questioned the tradi-
tional mantra of VIM stimulation for tremor control (Middlebrooks
et al., 2018; Kim et al., 2018; Pouratian et al., 2011) despite criticism
(Akram et al., 2019). Such critiques were based on the traditional
concept of nuclear effects rather than the underlying tractographic
anatomy. Nevertheless, two of the largest cohorts of ET individuals
undergoing VTA sweet spot analysis, the current study and Elias et al.
(2021) have both revealed more anterior stimulations along the VIM/
VOp border and more anterior stimulations in VOp. These ndings are in
contradiction to the more posterior location of sweet spots in the more
ventral or posterior subthalamic region, which are more closely related
to the location of VIM. Our results can potentially reconcile these
Table 2
Summary of studies reporting stimulation sweet spots.
Reference Study Type Electrode Side
Number of
MNI Sweet Spot
Coordinates (x/
Outcome Scores
Total TRS
Score (mean)
Total TRS
Elias et al.
Unilateral 39 16.8 17.3 / 13.9 /
Total TRS 57.2 42.8%
Tsuboi et al.
Unilateral 20 6.6 15 / 17 / 1 Total TRS*, TRS Motor
Score, Contralateral
TRS Motor Score
54.2 58.0%
Al-Fatly et al.
Bilateral 36 12 16 / 20 / 2 Total TRS, Head
Tremor Score,
Contralateral UE Score
33.3 65.1%
et al. (2021)
Blinded Trial
Unilateral 6 3 15 / 18.5 /
Total TRS 34.3 64.5%
et al. (2004)
Unilateral and
37 26 14.5 / 17.7 /
Limited TRS of
Contralateral UE
**Akram et al.
Unilateral 5 23.6 12.5 / 16 /
Total TRS 81.6 34.0%
***Kübler et al.
Bilateral 30 14 12 / 19.5 /
TRS Parts A & B, TRS of
Contralateral UE
MNI =Montreal Neurological Institute template space; TRS =Fahn-Tolosa-Marin Tremor Rating Scale; UE =upper extremity.
* Unpublished data.
** Coordinates approximated from image gures.
*** Point of maximum tremor improvement.
Fig. 4. Relationship of the predictive tract derived from the training cohort (threshold R >0.1) to the current study sweet spot for contralateral tremor improvement
and previously reported tremor sweet spots (Elias et al., 2021; Tsuboi et al., 2021; Al-Fatly et al., 2019; Akram et al., 2018; Papavassiliou et al., 2004; Middlebrooks
et al., 2021; Kübler et al., 2021). (A) Sagittal and (B) coronal views show overlap of all targets with the predictive tract, which represents the DRTT. Background
provided by Edlow et al. (2019).
E.H. Middlebrooks et al.
NeuroImage: Clinical 32 (2021) 102846
variations in reported targeting by revealing a common underlying
pathway, the DRTT, along the course of both PSA and ventral thalamic
stimulation targets. There was reproducibility of tremor control at
various locations along the DRTT (e.g., PSA, VIM/VOp), and may
potentially explain observations that more posterior VIM stimulation
can lead to tolerance (Sandoe et al., 2018). In addition, our results
support the potential of individualized targeting of DRTT, which has
been recently shown as feasible and effective in clinical practice (Mid-
dlebrooks et al., 2021).
5. Limitations
Several limitations of the present study should be considered. First,
clinical assessments were limited to the retrospective analysis of patient
records. While metrics used for the study were meticulously documented
by experienced examiners, other information regarding side effects or
other outcomes may have been less consistent. Along the same lines, the
mean and median duration of follow up was slightly more than 6
months, which limits assessment of factors affecting long-term DBS
benet. Second, the use of normative connectomes poses a potential
limitation. While there may be pathological alterations in the repre-
sented networks in the setting of ET, the diffusion metrics are primarily
used in this study from an anatomic perspective only. The anatomic
connections from such normative connectomes compared to patient-
specic cohorts has been previously shown as a reliable metric (Wang
et al., 2021). Prior studies have also supported the use of normative
connectomes by their ability to predict both treatment effects and side
effects from DBS (Tsuboi et al., 2021; Al-Fatly et al., 2019; Tsuboi et al.,
2021; Horn et al., 2017; Baldermann et al., 2019). There were many
inherent limitations of tractography that have been previously well
described, such as difculty with modeling crossing bers and reliability
of tracking through regions with lower fractional anisotropy (e.g.
thalamic gray matter). We used a more computationally intensive
approach of probabilistic tractography, which is more favorable in
identifying such plausible tracts, at the risk of increased false bers.
Third, there are inherent limitations from lead localization, co-
registration, and normalization processes, as well as the inability to
directly visualize most thalamic nuclei on MPRAGE images resulting in a
reliance on atlases. Fourth, the presence of connectivity between two
regions does not ensure a stimulation effect occurs with specic stimu-
lation parameters (e.g., frequency, pulse width, etc.) (Middlebrooks
et al., 2020). Whether all regions connected to a VTA are affected by the
chosen stimulation parameters remains speculative. Fifth, the earlier
studies analyzed the sweet spots for tremor improvement using
different methodologies. Therefore, the meta-analysis of the current and
earlier studies should be interpreted carefully. Finally, we only included
individuals with ET, which limits the extrapolation of our ndings to
other tremor syndromes.
6. Conclusions
Using a large cohort of individuals with unilateral thalamic DBS, we
have shown the potential value of structural connectivity in predicting
ET outcomes. Additionally, our results reveal compelling evidence for a
common tract, the DRTT as the unifying sweet spot.We suggest that
the provision of a patient-specic network target for direct surgical
targeting and device programming has the potential to improve ET DBS
CRediT authorship contribution statement
Erik H. Middlebrooks: Conceptualization, Methodology, Software,
Formal analysis, Writing - original draft. Lela Okromelidze: Concep-
tualization, Methodology, Software, Data curation, Writing - review &
editing. Joshua K. Wong: Conceptualization, Methodology, Investiga-
tion, Data curation, Writing - review & editing. Robert S. Eisinger:
Conceptualization, Methodology, Investigation, Data curation, Writing -
review & editing. Mathew R. Burns: Investigation, Data curation,
Writing - review & editing. Ayushi Jain: Data curation, Writing - review
& editing. Hsin-Pin Lin: Investigation, Data curation, Writing - review
& editing. Jun Yu: Investigation, Data curation, Writing - review &
editing. Enrico Opri: Conceptualization, Methodology, Software,
Formal analysis, Writing - review & editing. Andreas Horn: Concep-
tualization, Methodology, Software, Formal analysis, Writing - review &
editing. Lukas L. Goede: Conceptualization, Methodology, Software,
Formal analysis, Writing - review & editing. Kelly D. Foote: Investiga-
tion, Writing - review & editing, Supervision. Michael S. Okun:
Conceptualization, Investigation, Writing - review & editing, Supervi-
sion. Alfredo Qui˜
nones-Hinojosa: Writing - review & editing, Super-
vision. Ryan J. Uitti: Conceptualization, Writing - review & editing,
Supervision. Sanjeet S. Grewal: Conceptualization, Methodology,
Writing - review & editing, Supervision. Takashi Tsuboi: Conceptuali-
zation, Methodology, Formal analysis.
Declaration of Competing Interest
Dr. Middlebrooks has received research support from Varian Medical
Systems, Inc. and Boston Scientic Corp. He has also received institu-
tional research support from Mayo Clinic and as a Site PI, Co-I, and
consultant on NIH supported grants unrelated to the current study. He is
also a consultant for Boston Scientic Corp.
Dr. Burns receives salary support from the Parkinsons Foundation.
Dr. Horn was supported by the German Research Foundation
(Deutsche Forschungsgemeinschaft, Emmy Noether Stipend 410169619
and 424778381 TRR 295) as well as Deutsches Zentrum für Luft- und
Raumfahrt (DynaSti grant within the EU Joint Programme Neurode-
generative Disease Research, JPND). A.H. is participant in the BIH-
e Clinician Scientist Program funded by the Charit´
atsmedizin Berlin and the Berlin Institute of Health.
Dr. Foote has served as a consultant for Medtronic and Boston Sci-
entic and has received honoraria for these services. He has received
research support from Medtronic, Boston Scientic, Abbott/St. Jude,
and Functional Neuromodulation. He has received fellowship support
from Medtronic.
Dr. Okun serves as a consultant for the National Parkinson Founda-
tion, and has received research grants from NIH, NPF, the Michael J. Fox
Foundation, the Parkinson Alliance, Smallwood Foundation, the
Bachmann-Strauss Foundation, the Tourette Syndrome Association, and
the UF Foundation. Dr. Okuns DBS research is supported by: R01
NR014852 and R01NS096008. Dr. Okun has previously received hon-
oraria, but in the past >60 months has received no support from in-
dustry. Dr. Okun has received royalties for publications with Demos,
Manson, Amazon, Smashwords, Books4Patients, and Cambridge
(movement disorders books). Dr. Okun is an associate editor for New
England Journal of Medicine Journal Watch Neurology. Dr. Okun has
participated in CME and educational activities on movement disorders
(in the last 36) months sponsored by PeerView, Prime, QuantiaMD,
WebMD, Medicus, MedNet, Henry Stewart, and by Vanderbilt Univer-
sity. The institution and not Dr. Okun receives grants from Medtronic,
Abbvie, Allergan, and ANS/St. Jude, and the PI has no nancial interest
in these grants. Dr. Okun has participated as a site PI and/or co-I for
several NIH, foundation, and industry sponsored trials over the years but
has not received honoraria.
Dr. Qui˜
nones-Hinojosa is supported by the Mayo Clinic Professorship
and a Clinician Investigator award, and Florida State Department of
Health Research Grant, and the Mayo Clinic Graduate School, as well as
the NIH (R43CA221490, R01CA200399, R01CA195503, and
Dr. Grewal is a consultant for Boston Scientic Corp. and Medtronic,
E.H. Middlebrooks et al.
NeuroImage: Clinical 32 (2021) 102846
We would like to thank Harith Akram, M.D. for his contribution of
prior study data. Mayo Clinic Florida data [in part] were previously
collected from study funded by Mayo Clinic Transform the Practice
Award. Additional data were provided [in part] by the Human Con-
nectome Project, WU-Minn Consortium (Principal Investigators: David
Van Essen and Kamil Ugurbil; 1U54MH091657) funded by the 16 NIH
Institutes and Centers that support the NIH Blueprint for Neuroscience
Research; and by the McDonnell Center for Systems Neuroscience at
Washington University. We acknowledge the Parkinsons Foundation
Center of Excellence at the University of Florida and the UF INFORM
This research did not receive any specic grant from funding
agencies in the public, commercial, or not-for-prot sectors.
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... VIM remains the most common target as it provides better long-term efficacy, and stimulation to deeper targets may result in higher rates of stimulation induced ataxia and dysarthria due to involvement of the cerebellothalmic tracts (Iorio-Morin et al., 2020;Wong et al., 2020;Kremer et al., 2021;Chandra et al., 2022). Stimulation to the dentatorubral-thalamic tracts (DRTT) with projected connections to the primary motor and supplementary motor cortices have been implicated to produce the most efficacy in tremor reduction (Iorio-Morin et al., 2020;Wong et al., 2020;Middlebrooks et al., 2021;Chandra et al., 2022). The DRTT connects the cerebellum to the thalamus with receiving fibers primarily in the VIM, and consists of both decussating (DRTT) and non-decussating (nDRTT) fibers (Gallay et al., 2008). ...
... The pathophysiology of dystonia is hypothesized to involve both the cerebello-thalamo-cortical and the basal ganglia-thalamo-cortical networks. A recent study by Tsuboi et al. demonstrated slightly different functional and structural connectivity between dystonic and essential tremor (Middlebrooks et al., 2021). Animal and small cerebellar DBS studies have demonstrated aberrant hyperexcitability of the deep cerebellar nuclei as the potential culprit for symptoms of ataxia and kinetic tremor (Tai and Tseng, 2022). ...
... ET-plus with dystonia subgroup has a more medially placed COG compared to that of ET-plus with ataxia, with unclear clinical significance. In addition, COG location relative to the DRTT showed that the VTAs for ET and ET-plus cohorts overlap significantly with this tract, which is likely the main contributor of tremor suppression as demonstrated in prior studies (Al-Fatly et al., 2019;Middlebrooks et al., 2021). ...
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Background Although ET is a phenomenologically heterogeneous condition, thalamic DBS appears to be equally effective across subtypes. We hypothesized stimulation sites optimized for individuals with essential tremor (ET) would differ from individuals with essential tremor plus syndrome (ET-plus). We examined group differences in optimal stimulation sites within the ventral thalamus and their overlap of with relevant white matter tracts. By capturing these differences, we sought to determine whether ET subtypes are associated with anatomically distinct neural pathways. Methods A retrospective chart review was conducted on ET patients undergoing VIM DBS at MUSC between 01/2012 and 02/2022. Clinical, demographic, neuroimaging, and DBS stimulation parameter data were collected. Clinical characteristics and pre-DBS videos were reviewed to classify ET and ET-plus cohorts. Patients in ET-plus cohorts were further divided into ET with dystonia, ET with ataxia, and ET with others. DBS leads were reconstructed using Lead-DBS ¹ and the volume of tissue activated (VTA) overlap was performed using normative connectomes. Tremor improvement was measured by reduction in a subscore of tremor rating scale (TRS) post-DBS lateralized to the more affected limb. Results Sixty-eight ET patients were enrolled after initial screening, of these 10 ET and 24 ET-plus patients were included in the final analyses. ET group had an earlier age at onset ( p = 0.185) and underwent surgery at a younger age ( p = 0.096). Both groups achieved effective tremor control. No significant differences were found in lead placement or VTA overlap within ventral thalamus. The VTA center of gravity (COG) in the ET-plus cohort was located dorsal to that of the ET cohort. No significant differences were found in VTA overlap with the dentato-rubral-thalamic (DRTT) tracts or the ansa lenticularis. Dystonia was more prevalent than ataxia in the ET-plus subgroups ( n = 18 and n = 5, respectively). ET-plus with dystonia subgroup had a more medial COG compared to ET-plus with ataxia. Conclusion VIM DBS therapy is efficacious in patients with ET and ET-plus. There were no significant differences in optimal stimulation site or VTA overlap with white-matter tracts between ET, ET-plus and ET-plus subgroups.
... 66 88 was used in nine studies. 72,[74][75][76][77][78][79][80]82 In two studies, clinical testing for motor symptoms were not assessed using standardised clinical scales. 73,81 Reporting clinical outcomes from deep brain stimulation ...
... Structural connectivity to primary, supplementary and premotor cortices, sensory cortex, and a tract corresponding to the DRTT were outlined as significant predictors for contralateral essential tremor improvements. 78 This result was obtained by training on a cohort of 83 patients and validating on 14 patients. In a cohort 20 patients with essential tremor and 20 patients with dystonic tremor, the role of decussating and non-decussating DRTT's were explored. ...
... Importantly, this was the case not only when the DRTT was explicitly investigated, [74][75][76]79 but also in whole-brain exploratory approaches. 72,78,80,82 Whilst the study identifying no association of contact proximity to the DRTT may have been restricted by a small sample size, 81 deterministic tractography used in the study has outlined poorer ability to reconstruct the DRTT, relative to probabilistic tracking. 183,184 Importantly, tractography performance is dependent upon the tract(s) of interest, and the purpose for reconstruction such that probabilistic tractography does not always offer superior efficacy for tract reconstruction. ...
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Patients with movement disorders treated by deep brain stimulation do not always achieve successful therapeutic alleviation of motor symptoms, even in cases where surgery is without complications. Magnetic resonance imaging (MRI) offers methods to investigate structural brain-related factors that may be predictive for clinical motor outcomes. This review aimed to identify features which have been associated with variability in clinical post-operative motor outcomes in patients with Parkinson’s disease, dystonia, and essential tremor from structural MRI modalities. We performed a literature search for articles published between January 01, 2000, and April 01, 2022, and identified 5197 articles. Following screening through our inclusion criteria, we identified 60 total studies (39 = Parkinson’s disease, 11 = dystonia syndromes and 10 = essential tremor). The review captured a range of structural MRI methods and analysis techniques used to identify factors related to clinical post-operative motor outcomes from deep brain stimulation. Morphometric markers, including volume and cortical thickness were commonly identified in studies focused on patients with Parkinson’s disease and dystonia syndromes. Reduced metrics in basal ganglia, sensorimotor and frontal regions showed frequent associations with reduced motor outcomes. Increased structural connectivity to subcortical nuclei, sensorimotor and frontal regions were also associated with greater motor outcomes. In patients with tremor, increased structural connectivity to the cerebellum and cortical motor regions showed high prevalence across studies for greater clinical motor outcomes. In addition, we highlight conceptual issues for studies assessing clinical response with structural MRI and discuss future approaches towards optimising individualised therapeutic benefits. Although quantitative MRI markers are in their infancy for clinical purposes in movement disorder treatments, structural features obtained from MRI offer powerful potential to identify candidates who are more likely to benefit from deep brain stimulation and provide insight into the complexity of disorder pathophysiology.
... The second method is to use the estimated VTA as a seeding region and investigate the connectivity pattern to the cortex in relation to clinical response [91,[95][96][97][98]. While this method can give useful information on brain network connections in relation to DBS and thereby further understanding of the mechanism of action, the first method might be more beneficial in a practical sense for the use of tractography in surgical planning. ...
... For over a decade, tractography has been investigated in DBS. The use of tractography in DBS has evolved towards tractography-based targeting [68,87,158,160] and connectomic profiling [96][97][98]. In this thesis, the focus was on ET and reconstructions of DRT. ...
... Many studies have investigated the relationship between DRT and tremor reduction [47,60,68,87,88,98,152,[161][162][163]. Coenen et al., [60] investigated the correlation between the distance from the active contact to the centre of the reconstructed DRT, but the result was not significant. ...
... A recent study evaluating efficacy of DBS for ET revealed that "sweet spots" reported by multiple groups all share overlap with a common tract, the DRTT. 33 DTI studies have also demonstrated that the dentatorubrothalamic tracts along with pallidothalamic fibers are the principal components of the PSA. 10-12 Accordingly, we believe that by using four tract tractography instead of indirect coordinates to target the dDRTT and ndDRTT at 1.2-1.5 mm superior to the AC-PC plane, there is corresponding extension of the thalamic lesion inferiorly into the portion of the PSA that contributes to the improved tremor response. ...
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MRI-guided high-intensity focused ultrasound thalamotomy is an incisionless therapy for essential tremor. To reduce adverse effects, the field has migrated to treating at approximately 2 mm above the anterior commissure-posterior commissure plane. We perform MRI-guided high intensity focused ultrasound with an advanced imaging targeting technique, four tract tractography. Four tract tractography uses diffusion tensor imaging to identify the critical white matter targets for tremor control, the decussating and non-decussating dentatorubrothalamic tracts, while the corticospinal tract and medial lemniscus are identified to be avoided. In some patients, four tract tractography identified a risk of damaging the medial lemniscus or corticospinal tract if treating at 2 mm superior to the anterior commissure-posterior commissure plane. In these patients, we chose to target 1.2-1.5 mm superior to the anterior commissure-posterior commissure plane. In these patients, post-operative imaging revealed that the focused ultrasound lesion extended into the posterior subthalamic area. This study sought to determine if patients with focused ultrasound lesions that extend into the posterior subthalamic area have greater tremor improvement than those without. 20 essential tremor patients underwent MRI-guided high intensity focused ultrasound and were retrospectively classified into two groups. Group 1 included patients with extension of the thalamic focused ultrasound lesion into the posterior subthalamic area. Group 2 included patients without extension of the thalamic focused ultrasound lesion into the posterior subthalamic area. For each patient, the percent change in postural tremor, kinetic tremor, and Archimedes spiral scores were calculated between baseline and a three-month follow-up. Two-tailed Wilcoxon rank sum tests were used to compare improvement in tremor scores, total number of sonications, thermal dose to achieve initial tremor response, and skull density ratio between groups. Group 1 had significantly greater postural, kinetic, and Archimedes spiral score percent improvement than Group 2 (p-values: 5.41 × 10−5, 4.87 × 10−4, and 5.41 × 10−5, respectively). Group 1 also required significantly fewer total sonications to control the tremor and a significantly lower thermal dose to achieve tremor response (p-values: 6.60 × 10−4 and 1.08 × 10−5, respectively). No significant group differences in skull density ratio were observed (p-value = 1.0). We do not advocate directly targeting the posterior subthalamic area with MRI-guided high-intensity focused ultrasound because the shape of the focused ultrasound lesion can result in a high risk of adverse effects. However, when focused ultrasound lesions naturally extend from the thalamus into the posterior subthalamic area, they provide greater tremor control than those that only involve the thalamus.
Tremor is one of the most frequent complaints in the movement disorder clinic. Not only it can be encountered in multiple different syndromes, but it can also present with variable characteristics of complexity, frequency, topography, and state-dependency within the spectrum of single disease. Pharmacological therapy of severe tremor is often unsatisfactory irrespective of the underlying diagnosis and phenomenology, and surgical treatment represents a highly effective alternative. Since the publication of the first edition of this book, an exponential progress of imaging techniques and device engineering has generated incredible advancements in the field of invasive neuromodulation, contributing to increase our knowledge of the physiopathology and improve surgical targeting and programming. Multiple references to these exciting developments are disseminated throughout this chapter, which start with a brief history of deep brain stimulation for tremor, followed by a description of the anatomy of surgical targets, and general principles of stimulation programming. The subsequent paragraphs are dedicated to the use of deep brain stimulation in the clinic, according to specific tremor diagnosis. Common indications such as Parkinson’s disease, essential tremor, and tremor associated with dystonia are discussed, as well as more phenomenologically complex, uncommon tremor syndromes. An account of side effects and their pathogenic mechanisms occupies the end of this section. Finally, a discussion of promising future directions in the field is included at the end of the chapter.
Introduction: Prompt dissemination of clinical trial results is essential for ensuring the safety and efficacy of intracranial neurostimulation treatments, including deep brain stimulation (DBS) and responsive neurostimulation (RNS). However, the frequency and completeness of results publication, and reasons for reporting delays, are unknown. Moreover, the patient populations, targeted anatomical locations, and stimulation parameters should be clearly reported for both reproducibility and to identify lacunae in trial design. Here, we examine DBS and RNS trials from 1997 to 2022, chart their characteristics, and examine rates and predictors of results reporting. Methods: Trials were identified using . Associated publications were identified using and . Pearson's χ2 tests were used to assess differences in trial characteristics between published and unpublished trials. Results: Across 449 trials, representing a cumulative cohort of 42,769 patient interventions, there were 37 therapeutic indications and 44 stimulation targets. The most common indication and target were Parkinson's disease (40.55%) and the subthalamic nucleus (35.88%), respectively. Only 0.89% of trials were in pediatric patients (11.58% were mixed pediatric and adult). Explored targets represented 75% of potential basal ganglia targets but only 29% of potential thalamic targets. Allowing a 1-year grace period after trial completion, 34/169 (20.12%) had results reported on , and 107/169 (63.31%) were published. ∼80% of published trials included details about stimulation parameters used. Published and unpublished trials did not significantly differ by trial characteristics. Conclusion: We highlight key knowledge and performance gaps in DBS and RNS trial research. Over one-third of trials remain unpublished >1 year after completion; pediatric trials are scarce; most of the thalamus remains unexplored; about one-in-five trials fail to report stimulation parameters; and movement disorders comprise the most studied indications.
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Objectives: Magnetic resonance-guided focussed ultrasound (MRgFUS) is an incisionless ablative procedure, widely used for treatment of Parkinsonian and Essential Tremor (ET). Enhanced understanding of the patient- and treatment-specific factors that influence sustained long-term tremor suppression could help clinicians achieve superior outcomes via improved patient screening and treatment strategy. Methods: We retrospectively analysed data from 31 subjects with ET, treated with MRgFUS at a single centre. Tremor severity was assessed with parts A, B and C of the Clinical Rating Scale for Tremor (CRST) as well as the combined CRST. Tremor in the dominant and non-dominant hand was assessed with Hand Tremor Scores (HTS), derived from the CRST. Pre- and post-treatment imaging data were analysed to determine ablation volume overlap with automated thalamic segmentations, and the dentatorubrothalamic tract (DRTT) and compared with percentage change in CRST and HTS following treatment. Results: Tremor symptoms were significantly reduced following treatment. Combined pre-treatment CRST (mean: 60.7 ± 17.3) and HTS (mean: 19.2 ± 5.7) improved by an average of 45.5 and 62.6%, respectively. Percentage change in CRST was found to be significantly negatively associated with age (β = -0.375, p = 0.015), and SDR standard deviation (SDRSD; β = -0.324, p = 0.006), and positively associated with ablation overlap with the posterior DRTT (β = 0.535, p < 0.001). Percentage HTS improvement in the dominant hand decreased significantly with older age (β = -0.576, p < 0.01). Conclusion: Our results suggest that increased lesioning of the posterior region of the DRTT could result in greater improvements in combined CRST and non-dominant hand HTS, and that subjects with lower SDR standard deviation tended to experience greater improvement in combined CRST.
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Background: While deep brain stimulation (DBS) therapy can be effective at suppressing tremor in individuals with medication-refractory Essential Tremor, patient outcome variability remains a significant challenge across centers. Proximity of active electrodes to the cerebellothalamic tract (CTT) is likely important in suppressing tremor, but how tremor control and side effects relate to targeting parcellations within the CTT and other pathways in and around the ventral intermediate (VIM) nucleus of thalamus remain unclear. Methods: Using ultra-high field (7T) MRI, we developed high-dimensional, subject-specific pathway activation models for 23 directional DBS leads. Modeled pathway activations were compared with post-hoc analysis of clinician-optimized DBS settings, paresthesia thresholds, and dysarthria thresholds. Mixed-effect models were utilized to determine how the six parcellated regions of the CTT and how six other pathways in and around the VIM contributed to tremor suppression and induction of side effects. Results: The lateral portion of the CTT had the highest activation at clinical settings (p < 0.05) and a significant effect on tremor suppression (p < 0.001). Activation of the medial lemniscus and posterior-medial CTT was significantly associated with severity of paresthesias (p < 0.001). Activation of the anterior-medial CTT had a significant association with dysarthria (p < 0.05). Conclusions: This study provides a detailed understanding of the fiber pathways responsible for therapy and side effects of DBS for Essential Tremor, and suggests a model-based programming approach will enable more selective activation of lateral fibers within the CTT.
Background and purpose: Given the increased use of stereotactic radiosurgical thalamotomy and other ablative therapies for tremor, new biomarkers are needed to improve outcomes. Using resting-state fMRI and MR tractography, we hypothesized that a "connectome fingerprint" can predict tremor outcomes and potentially serve as a targeting biomarker for stereotactic radiosurgical thalamotomy. Materials and methods: We evaluated 27 patients who underwent unilateral stereotactic radiosurgical thalamotomy for essential tremor or tremor-predominant Parkinson disease. Percentage postoperative improvement in the contralateral limb Fahn-Tolosa-Marin Clinical Tremor Rating Scale (TRS) was the primary end point. Connectome-style resting-state fMRI and MR tractography were performed before stereotactic radiosurgery. Using the final lesion volume as a seed, "connectivity fingerprints" representing ideal connectivity maps were generated as whole-brain R-maps using a voxelwise nonparametric Spearman correlation. A leave-one-out cross-validation was performed using the generated R-maps. Results: The mean improvement in the contralateral tremor score was 55.1% (SD, 38.9%) at a mean follow-up of 10.0 (SD, 5.0) months. Structural connectivity correlated with contralateral TRS improvement (r = 0.52; P = .006) and explained 27.0% of the variance in outcome. Functional connectivity correlated with contralateral TRS improvement (r = 0.50; P = .008) and explained 25.0% of the variance in outcome. Nodes most correlated with tremor improvement corresponded to areas of known network dysfunction in tremor, including the cerebello-thalamo-cortical pathway and the primary and extrastriate visual cortices. Conclusions: Stereotactic radiosurgical targets with a distinct connectivity profile predict improvement in tremor after treatment. Such connectomic fingerprints show promise for developing patient-specific biomarkers to guide therapy with stereotactic radiosurgical thalamotomy.
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The pathophysiology of dystonic tremor and essential tremor remains partially understood. In patients with medication-refractory dystonic tremor or essential tremor, deep brain stimulation (DBS) targeting the thalamus or posterior subthalamic area has evolved into a promising treatment option. However, the optimal DBS targets for these disorders remains unknown. This retrospective study explored the optimal targets for DBS in essential tremor and dystonic tremor using a combination of volumes of tissue activated estimation and functional and structural connectivity analyses. We included 20 patients with dystonic tremor who underwent unilateral thalamic DBS, along with a matched cohort of 20 patients with essential tremor DBS. Tremor severity was assessed preoperatively and approximately 6 months after DBS implantation using the Fahn-Tolosa-Marin Tremor Rating Scale. The tremor-suppressing effects of DBS were estimated using the percentage improvement in the unilateral tremor-rating scale score contralateral to the side of implantation. The optimal stimulation region, based on the cluster centre of gravity for peak contralateral motor score improvement, for essential tremor was located in the ventral intermediate nucleus region and for dystonic tremor in the ventralis oralis posterior nucleus region along the ventral intermediate nucleus/ventralis oralis posterior nucleus border (4 mm anterior and 3 mm superior to that for essential tremor). Both disorders showed similar functional connectivity patterns: a positive correlation between tremor improvement and involvement of the primary sensorimotor, secondary motor and associative prefrontal regions. Tremor improvement, however, was tightly correlated with the primary sensorimotor regions in essential tremor, whereas in dystonic tremor, the correlation was tighter with the premotor and prefrontal regions. The dentato-rubro-thalamic tract, comprising the decussating and non-decussating fibres, significantly correlated with tremor improvement in both dystonic and essential tremor. In contrast, the pallidothalamic tracts, which primarily project to the ventralis oralis posterior nucleus region, significantly correlated with tremor improvement only in dystonic tremor. Our findings support the hypothesis that the pathophysiology underpinning dystonic tremor involves both the cerebello-thalamo-cortical network and the basal ganglia-thalamo-cortical network. Further our data suggest that the pathophysiology of essential tremor is primarily attributable to the abnormalities within the cerebello-thalamo-cortical network. We conclude that the ventral intermediate nucleus/ventralis oralis posterior nucleus border and ventral intermediate nucleus region may be a reasonable DBS target for patients with medication-refractory dystonic tremor and essential tremor, respectively. Uncovering the pathophysiology of these disorders may in the future aid in further improving DBS outcomes.
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Objective Subthalamic deep brain stimulation (DBS) is an established therapy for Parkinson's disease. Connectomic DBS modeling is a burgeoning subfield of research aimed at characterizing the axonal connections activated by DBS. This article describes our approach and methods for evolving the StimVision software platform to meet the technical demands of connectomic DBS modeling in the subthalamic region. Materials and Methods StimVision v2 was developed with Visualization Toolkit (VTK) libraries and integrates four major components: 1) medical image visualization, 2) axonal pathway visualization, 3) electrode positioning, and 4) stimulation calculation. Results StimVision v2 implemented two key technological advances for connectomic DBS analyses in the subthalamic region. First was the application of anatomical axonal pathway models to patient‐specific DBS models. Second was the application of a novel driving‐force method to estimate the response of those axonal pathways to DBS. Example simulations with directional DBS electrodes and clinically defined therapeutic DBS settings are presented to demonstrate the general outputs of StimVision v2 models. Conclusions StimVision v2 provides the opportunity to evaluate patient‐specific axonal pathway activation from subthalamic DBS using anatomically detailed pathway models and electrically detailed electric field distributions with interactive adjustment of the DBS electrode position and stimulation parameter settings.
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Objectives: The aim of this study is to identify anatomical regions related to stimulation-induced dyskinesia (SID) after pallidal deep brain stimulation (DBS) in Parkinson's disease (PD) patients and to analyze connectivity associated with SID. Methods: This retrospective study analyzed the clinical and imaging data of PD patients who experienced SID during the monopolar review after pallidal DBS. We analyzed structural and functional connectivity using normative connectivity data with the volume of tissue activated (VTA) modeling. Each contact was assigned to either that producing SID (SID VTA) or that without SID (non-SID VTA). Structural and functional connectivity was compared between SID and non-SID VTAs. "Optimized VTAs" were also estimated using the DBS settings at 6 months after implantation. Results: Of the 68 consecutive PD patients who underwent pallidal implantation, 20 patients (29%) experienced SID. SID VTAs were located more dorsally and anteriorly compared with non-SID and optimized VTAs and were primarily in the dorsal globus pallidus internus (GPi) and dorsal globus pallidus externus (GPe). SID VTAs showed significantly higher structural connectivity than non-SID VTAs to the associative cortex and supplementary motor area/premotor cortex (P < 0.0001). Simultaneously, non-SID VTAs showed greater connectivity to the primary sensory cortex, cerebellum, subthalamic nucleus, and motor thalamus (all P < 0.0004). Functional connectivity analysis showed significant differences between SID and non-SID VTAs in multiple regions, including the primary motor, premotor, and prefrontal cortices and cerebellum. Conclusion: SID VTAs were primarily in the dorsal GPi/GPe. The connectivity difference between the motor-related cortices and subcortical regions may explain the presence and absence of SID. © 2020 International Parkinson and Movement Disorder Society.
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Brain connectivity profiles seeding from deep brain stimulation (DBS) electrodes have emerged as informative tools to estimate outcome variability across DBS patients. Given the limitations of acquiring and processing patient-specific diffusion-weighted imaging data, a number of studies have employed normative atlases of the human connectome. To date, it remains unclear whether patient-specific connectivity information would strengthen the accuracy of such analyses. Here, we compared similarities and differences between patient-specific, disease-matched and normative structural connectivity data and estimation of clinical improvement that they may generate. Data from 33 patients suffering from Parkinson's Disease who underwent surgery at three different centers were retrospectively collected. Stimulation-dependent connectivity profiles seeding from active contacts were estimated using three modalities, namely either patient-specific diffusion-MRI data, disease-matched or normative group connectome data (acquired in healthy young subjects). Based on these profiles, models of optimal connectivity were constructed and used to estimate the clinical improvement in out of sample data. All three modalities resulted in highly similar optimal connectivity profiles that could largely reproduce findings from prior research based on a novel multi-center cohort. In a data-driven approach that estimated optimal whole-brain connectivity profiles, out-of-sample predictions of clinical improvements were calculated. Using either patient-specific connectivity (R = 0.43 at p = 0.001), an age- and disease-matched group connectome (R = 0.25, p = 0.048) and a normative connectome based on healthy/young subjects (R = 0.31 at p = 0.028), significant predictions could be made and underlying optimal connectivity profiles were highly similar. Our results of patient-specific connectivity and normative connectomes lead to similar main conclusions about which brain areas are associated with clinical improvement. Still, although results were not significantly different, they hint at the fact that patient-specific connectivity may bear the potential of estimating slightly more variance when compared to group connectomes. Furthermore, use of normative connectomes involves datasets with high signal-to-noise acquired on specialized MRI hardware, while clinical datasets as the ones used here may not exactly match their quality. Our findings support the role of DBS electrode connectivity profiles as a promising method to investigate DBS effects and to potentially guide DBS programming.
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Deep brain stimulation is an established therapy for multiple brain disorders, with rapidly expanding potential indications. Neuroimaging has advanced the field of deep brain stimulation through improvements in delineation of anatomy, and, more recently, application of brain connectomics. Older lesion-derived, localizationist theories of these conditions have evolved to newer, network-based "circuitopathies," aided by the ability to directly assess these brain circuits in vivo through the use of advanced neuroimaging techniques, such as diffusion tractography and fMRI. In this review, we use a combination of ultra-high-field MR imaging and diffusion tractography to highlight relevant anatomy for the currently approved indications for deep brain stimulation in the United States: essential tremor, Parkinson disease, drug-resistant epilepsy, dystonia, and obsessive-compulsive disorder. We also review the literature regarding the use of fMRI and diffusion tractography in understanding the role of deep brain stimulation in these disorders, as well as their potential use in both surgical targeting and device programming.
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Introduction Deep brain stimulation alleviates tremor of various origins. The dentato-rubro-thalamic tract (DRT) has been suspected as a common tremor-reducing structure. Statistical evidence has not been obtained. We here report the results of an uncontrolled case series of patients with refractory tremor who underwent deep brain stimulation under tractographic assistance. Methods A total of 36 patients were enrolled (essential tremor (17), Parkinson’s tremor (8), multiple sclerosis (7), dystonic head tremor (3), tardive dystonia (1)) and received 62 DBS electrodes (26 bilateral; 10 unilateral). Preoperatively, diffusion tensor magnetic resonance imaging sequences were acquired together with high-resolution anatomical T1W and T2W sequences. The DRT was individually tracked and used as a direct thalamic or subthalamic target. Intraoperative tremor reduction was graded on a 4-point scale (0 = no tremor reduction to 3 = full tremor control) and recorded together with the current amplitude, respectively. Stimulation point coordinates were recorded and compared to DRT. The relation of the current amplitude needed to reduce tremor was expressed as TiCR (tremor improvement per current ratio). Results Stimulation points of 241 were available for analysis. A total of 68 trajectories were tested (62 dB leads, 1.1 trajectories tested per implanted lead). Tremor improvement was significantly decreasing (p < 0.01) if the distance to both the border and the center of the DRT was increasing. On the initial trajectory, 56 leads (90.3%) were finally placed. Long-term outcomes were not part of this analysis. Discussion Tremor of various origins was acutely alleviated at different points along the DRT fiber tract (above and below the MCP plane) despite different tremor diseases. DRT is potentially a common tremor-reducing structure. Individual targeting helps to reduce brain penetrating tracts. TiCR characterizes stimulation efficacy and might help to identify an optimal stimulation point.
Objective Observational studies utilising diffusion tractography have suggested a common mechanism for tremor alleviation in deep brain stimulation for essential tremor: the decussating portion of the dentato-rubro-thalamic tract. We hypothesised that directional stimulation of the dentato-rubro-thalamic tract would result in greater tremor improvement compared to sham programming, as well as comparable improvement as more tedious standard-of-care programming. Methods A prospective, blinded crossover trial was performed to assess the feasibility, safety and outcomes of programming based solely on dentato-rubro-thalamic tract anatomy. Using magnetic resonance imaging diffusion-tractography, the dentato-rubro-thalamic tract was identified and a connectivity-based treatment setting was derived by modelling a volume of tissue activated using directional current steering oriented towards the dentato-rubro-thalamic tract centre. A sham setting was created at approximately 180° opposite the connectivity-based treatment. Standard-of-care programming at 3 months was compared to connectivity-based treatment and sham settings that were blinded to the programmer. The primary outcome measure was percentage improvement in the Fahn–Tolosa–Marín tremor rating score compared to the preoperative baseline. Results Among the six patients, tremor rating scores differed significantly among the three experimental conditions ( P=0.030). The mean tremor rating score improvement was greater with the connectivity-based treatment settings (64.6% ± 14.3%) than with sham (44.8% ± 18.6%; P=0.031) and standard-of-care programming (50.7% ± 19.2%; P=0.062). The distance between the centre of the dentato-rubro-thalamic tract and the volume of tissue activated inversely correlated with the percentage improvement in the tremor rating score (R ² =0.24; P=0.04). No significant adverse events were encountered. Conclusions Using a blinded, crossover trial design, we have shown the technical feasibility, safety and potential efficacy of connectivity-based stimulation settings in deep brain stimulation for treatment of essential tremor.
Introduction: Deep brain stimulation (DBS) is a highly efficacious treatment for essential tremor (ET). Still, the optimal anatomical target in the (sub)thalamic area is a matter of debate. The aim of this study was to determine the optimal target of DBS for ET regarding beneficial clinical outcome and impact on activities of daily living as well as stimulation-induced side effects and compare it with previously published coordinates. Methods: In 30 ET patients undergoing bilateral DBS, severity of tremor was assessed by blinded video ratings before and at 1-year follow-up with DBS ON and OFF. Tremor scores and reported side effects and volumes of tissue activated were used to create a probabilistic map of DBS efficiency and side effects. Results: DBS was effective both in tremor suppression as well as in improving patient reported outcomes, which were positively correlated. The "sweet spot" for tremor suppression was located inferior of the VIM in the subthalamic area, close to the superior margin of the zona incerta. The Euclidean distance of active contacts to this spot as well as to 10 of 13 spots from the literature review was predictive of individual outcome. A cluster associated with the occurrence of ataxia was located in direct vicinity of the "sweet spot". Conclusion: Our findings suggest the highest clinical efficacy of DBS in the posterior subthalamic area, lining up with previously published targets likely representing the dentato-rubro-thalamic tract. Side effects may not necessarily indicate lead misplacement, but should encourage clinicians to employ novel DBS programing options.
Objective Projections from the dentate nucleus (DN) follow a certain organized course to upper levels. Crossing and noncrossing fibers of the dentatorubrothalamic (DRT) tract terminate in the red nucleus and thalamus and have various connections throughout the cerebral cortex. We aimed to establish the microsurgical anatomy of the DN in relation to its efferent connections to complement the increased recognition of its surgical importance and also to provide an insight into the network-associated symptoms related to lesions and microsurgery in and around the region. Methods The cerebellum, DN, and superior cerebellar peduncle (SCP) en route to red nucleus were examined through fiber dissections from the anterior, posterior, and lateral sides to define the connections of the DN and its relationships with adjacent neural structures. Results The DN was anatomically divided into 4 areas based on its relation to the SCP; the lateral major, lateral anterosuperior, posteromedial, and anteromedial compartments. Most of the fibers originating from the lateral compartments were involved in the decussation of the SCP. The ventral fibers originating from the lateral anterosuperior compartment were exclusively involved in the decussation. The fibers from the posteromedial compartment ascended ipsilaterally and decussated, whereas most anteromedial fibers ascended ipsilaterally and did not participate in the decussation. Conclusions Clarifying the anatomofunctional organization of the DN in relation to the SCP could improve microneurosurgical results by reducing the complication rates during infratentorial surgery in and around the nucleus. The proposed compartmentalization would be a major step forward in this effort.
Deep brain stimulation (DBS) depends on precise delivery of electrical current to target tissues. However, the specific brain structures responsible for best outcome are still debated. We applied probabilistic stimulation mapping to a retrospective, multi‐disorder DBS dataset assembled over 15 years at our institution (ntotal=482 patients; nParkinson’s disease=303; ndystonia=64; ntremor=39; ntreatment‐resistant depression/anorexia nervosa=76) to identify the neuroanatomical substrates of optimal clinical response. Using high‐resolution structural MR imaging and activation volume modelling, probabilistic stimulation maps (PSMs) that delineated areas of above‐mean and below‐mean response for each patient cohort were generated and defined in terms of their relationships with surrounding anatomical structures. Our results show that overlap between PSMs and individual patients’ activation volumes can serve as a guide to predict clinical outcomes but that this is not the sole determinant of response. In the future, individualized models that incorporate advancements in mapping techniques with patient‐specific clinical variables will likely contribute to the optimization of DBS target selection and improved outcomes for patients. This article is protected by copyright. All rights reserved.