Clinical and postmortem diffusion MRI for deep brain stimulator

electrode localization in Essential Tremor patients

by
Jingxian Zhang
Trinity College Department of Neuroscience
Duke University

Thesis committee
Nandan Lad, MD, PhD; Supervisor

G. Allan Johnson, PhD

Evan Calabrese, PhD

Thesis submitted in fulfillment of

the requirements for the degree of
Graduation with Distinction in Bachelor of Science in the Department of
Neuroscience in Trinity College
of Duke University

2015

Dedication

This thesis is dedicated to my dearest siblings Alicia and Michael Zhang.

It is also dedicated to Karishma Popli, carry on Karishma!

Contents
Abstract .................................................................................................................................... 5
List of Tables ............................................................................................................................ 6
List of Figures .......................................................................................................................... 7
Acknowledgements................................................................................................................. 8
1. Introduction ......................................................................................................................... 9
2. Methods...............................................................................................................................12
2.1 DBS patient data .........................................................................................................12
2.1.1 Pre-operative anatomic MRI.............................................................................13
2.1.2 Pre-operative diffusion tensor MRI .................................................................13
2.1.3 Post-operative CT ..............................................................................................14
2.1.4 Post-operative electrode testing and outcomes...............................................14
2.2 Fiber tractography ......................................................................................................14
2.2.1 Deterministic fiber tractography in clinical diffusion MRI ............................15
2.2.2 Analysis of DBS contact proximity with clinical DRT tractography .............15
2.2.3 Probabilistic fiber tractography in postmortem diffusion MRI .....................16
2.2.4 Analysis of DBS contact proximity with postmortem DRT tractography ....17
2.2.5 Analysis of DBS contact proximity with postmortem rendering of Vim......18
3. Results .................................................................................................................................18
3.1 DBS Lead and Contact segmentation and modeling ...............................................19
3.2 Diffusion Tensor Imaging and Fiber tractography ..................................................20
3.3 Deterministic tractography........................................................................................21
3.4 Probabilistic tractography..........................................................................................21
3.5 Registration of postmortem MRI to clinical datasets...............................................22

3.6 Statistical analysis of DBS contact position and clinical efficacy ............................23
4. Discussion ...........................................................................................................................24
4.1 In vivo patient dataset analysis ..................................................................................24
4.2 Ex vivo patient dataset analysis .................................................................................26
References ...............................................................................................................................28

Abstract:
Deep brain stimulation (DBS) is now the preferred surgical treatment for a variety
of movement disorders. We propose standardized protocols for modeling implanted
DBS electrodes to better visualize and understand the correlation between contact
positioning, underlying tractography and efficacy of treatment outcomes. Imaging
datasets (stereotactic CT, MRI-FLAIR and DTI) of patients treated for essential tremor
with bilateral ventral intermediate (Vim) nucleus DBS were analyzed, and a
standardized protocol was developed to accurately model the placement of DBS leads
and individual contacts. This was paired with consistent fiber tractography of the
relevant dentatorubrothalamic tract in each patient dataset: deterministic fiber tracking
was performed on clinical MRI in Brainlab neuronavigation software, while probabilistic
fiber tracking was performed on a postmortem diffusion MRI template of the brainstem
and thalamus in Avizo 3D imaging software. A reliable and reproducible method to
segment DBS lead and contact positions in relation to the DRT validates the feasibility
of including DTI fiber tractography-based analyses when studying targeting, lead
location and programming for DBS. This work could provide further insight into circuit
modulation of underlying white matter pathways that appear to be the true targets of
neuromodulation by DBS.

Keywords: Deep brain stimulation; diffusion tensor imaging; fiber tractography;

Essential Tremor

List of Tables1
Table 1: Stereotaxic coordinates of DBS electrode contacts for each patient......................40
Table 2: Patient Demographics..............................................................................................43
Table 3: Summary of post-operative electrode testing outcomes .......................................44
Table 4: Results of Spearman rank correlation.....................................................................47

Table formatting credit to Dr. Evan Calabrese; Duke University Medical Center Dept. of Radiology CIVM

List of Figures
Figure 1: DRT mapped through three ROIs in the clinical MRI image set..33
Figure 2: Contact creation and fiber tractography ...............................................................34
Figure 3: Fiber tractography through contact ROI in 10 patients .......................................35
Figure 4: Probabilistic tractography of postmortem diffusion MRI DRT36
Figure 5: Registration between in vivo and postmortem MRI.............................................37
Figure 6: Probabilistic DRT shown with red nuclei, Vim, and implanted leads ...............38
Figure 7: DBS electrode position relative to postmortem template DRT in 12 patients....39

Acknowledgements:
This work was supported by the National Institutes of Health and the National
Institute of Biomedical Imaging and Bioengineering (grant number P41 EB015897). I
would like to sincerely thank and credit my team members and major contributors from
their various departments in Duke University Medical Center: Dr. Evan Calabrese and
Dr. G. Allan Johnson in Radiology, Mr. Peter Masso from Brainlab, Dr. Patrick Hickey in
Neurology, Dr. Christine Hulette in Pathology, Ms. Beth Parente in Surgery, Dr. Dennis
Turner in Surgery, Dr. Allen Song in Brain Imaging, and Dr. Guillermo Sapiro in Duke
Biomedical Engineering. I would also like to thank Percy Rochelle and Robert
Satterwhite for their help in procuring brain specimens, Mark Martin for help with clinical
image data, Porsche Atwater and Anne Jarvis for their guidance and support, and Dr.
Shouyin Zhang and Ms. Xiaoling Lu.
Most importantly, I would like to thank my principal investigator Dr. Nandan Lad
in Surgery, who has been an unwavering source of inspiration and support, for his
mentorship, time, and encouragement these past two years.

1. Introduction
Essential tremor (ET) is one of the most common neurological disorders
occurring in approximately 4.0% of individuals aged 40 years and older (Dogu et al.,
2003). ET is characterized by action and postural tremor of the arms, and may involve
the head and voice as well. Most patients experience progression in tremor severity
over time and other neurological signs such as rest tremor and ataxia may also arise.
Many patients with ET report only mild symptoms, however, about three quarters of
patients have significant disability and decreased quality of life. More than 90% of
patients who seek medical care report disability and 10% of patients who present to a
movement disorder clinic report severe motor disabilities, including tremor that
interferes with eating, drinking, writing, or communication (Louis et al., 2001) . First-line
medical treatments include propanolol and primidone, though medications are typically
effective in only 50% of patients and rarely reduce the tremor to asymptomatic levels
(Deuschl et al., 2011; Elble and Deuschl, 2009). For the subset of medically refractory
cases surgery is an effective option.
The ventralis intermedius (Vim) nucleus of the thalamus is the typical intervention
target structure in the ventral thalamus for patients with ET (Deuschl et al., 1998;
Hassler et al., 1979; Schaltenbraaand et al., 1977). Two primary surgical procedures
have been performed in patients with ET: thalamotomy and high frequency deep brain
stimulation (DBS) (Flora et al., 2010; Lehericy et al., 2001; Schuurman et al., 2008).
Both procedures target the Vim, however equal success has been reported with
posterior subthalamic area (PSA) modulation, prompting further investigation regarding
the optimal neuromodulation target for tremor suppression.

The Vim receives its major afferent projections from the deep cerebellar nuclei,
which then project to the motor cortex. Microelectrode recording of the Vim in patients
with ET identifies cells discharging in bursts that are time locked to the patients tremor,
indicating that tremor is associated with an abnormal discharge in the cerebellothalamic
pathway (Benabid et al., 1996). An interruption in this pathway from lesion or
stimulation provides some theoretical basis for the empirical observation of tremor
improvement, but a more precise understanding is still lacking.
High frequency deep brain stimulation (DBS) has largely replaced the ablative
procedures used in the past to treat such movement disorders (Flora et al., 2010). DBS
has been shown to be a reproducible, adjustable, and reversible neuromodulation
technique (Barkhoudarian et al., 2010; Kumar et al., 2003). Accurate targeting and
selective stimulation are essential in optimizing symptom alleviation and minimizing
potential side effects. The size and position of the neural targets is variable, and
indirect targeting is based on atlas-defined coordinates rather than patient-specific
anatomy, although new acquisition and processing approaches are addressing this
target localization challenge (Duchin et al., 2012; Kim et al., 2014; Lenglet et al., 2012).
Historically, various imaging modalities and targeting methods have been used to
achieve successful clinical outcomes, including MR imaging, CT scanning,
ventriculography, and microelectrode recording (De Salles et al., 2004; Lee et al., 2005;
Mori et al., 1999; Sedrak et al., 2008). Recent advances in imaging modalities have
refined the visualization of surgical targets and landmarks. Multi-modal and advanced
neuroimaging techniques such as diffusion tensor imaging (DTI) show great promise for
providing increased sensitivity and specificity of the underlying structurefunction

10

relationships (Basser et al., 2000; Coenen et al., 2011; Hyam et al., 2012; Mori et al.,
1999; Poupon et al., 2000). These techniques are also being explored for the more
immediate clinical needs of DBS lead targeting, intraoperative testing, postoperative
programming, patient-specific maps, algorithms and treatment strategies (Lenglet et al.,
2012; Kim et al., 2014).
Patients undergoing DBS offer a unique opportunity to study the functional
anatomy of stimulation targets in humans. Here, protocols are presented for modeling
implanted DBS electrode leads and evaluating electrode contact positions relative to
key fiber tracts mapped by diffusion tensor imaging and fiber tractography (FT).

This

has utility and implications not only for understanding circuit modulation of current grey
matter DBS targets (Vim, subthalamic nucleus, internal globus pallidus) in movement
disorder surgery, but is also critical for future white matter targets (e.g. fornix in memory
disorders, cingulate in mood disorders) (Gutman et al., 2009; Laxton et al., 2010;
Lozano et al., 2012; Mayberg et al., 2005). The analysis has been implemented on
individual clinical patient datasets as well as on a postmortem diffusion MRI template of
the brainstem and thalamus transformed into patient image space. The purpose of
developing these protocols was to standardize the imaging of these patients and better
visualize and understand the correlation between DBS electrode contact positioning and
efficacy of treatment outcomes in individual patients. The high resolution diffusion MRI
postmortem template with 3D nuclei and DRT tract reconstruction can be registered to
individual in vivo clinical images of DBS patients to correlate electrode proximity to the
DRT and test for surgical outcomes. Likewise, the direct analysis of electrode
positioning with DRT tractography in clinical images using Brainlab software can shed

11

light on how DBS lead localization in individual patient anatomy affects treatment
efficacy and potential side effects, while expanding the analysis pre-operatively will
pave the way for even better surgical results and more precise understanding of
structure-function relationships.

2. Methods

2.1. DBS patient data

All experiments on patient image datasets were approved by the Duke University
institutional review board (IRB). Twelve patients with medically refractory ET received
DBS targeted to the ventralis intermedius nucleus of the thalamus (Vim). Atlas based
targeting of the Vim nuclei was performed according to standard neuroanatomical
targets relative to the AC-PC plane (Schaltenbrand et al., 1977). The Vim target was
identified on FLAIR imaging using target coordinates 13 to 15 mm lateral to the anterior
commissure-posterior commissure (AC-PC) line, 0 mm below the AC-PC plane, and
30% of the total AC-PC distance posterior to the midpoint of AC-PC.
All patients underwent pre-operative structural and diffusion tensor MRI, as well
as post-operative x-ray computed tomography (CT) scans to localize electrode
placement. Patients undergoing bilateral VIM DBS were implanted with two quadripolar
electrodes (model 3389, Medtronic, Minneapolis, Minnesota) for a total of eight contacts
per patient. Contacts measure 1.5 mm in diameter with a 0.5 mm tip before the most
distal contact and 0.5 mm spacing between contacts. Final stereotaxic coordinates for
each electrode contact are provided in Table 1. Patient demographics for both studies

12

included 4 males and 8 females with average age 65 15 years (Table 2); two of the
patients from the postmortem diffusion MRI study were not used in the clinical study due
to CT slicing above 1mm in thickness.
Patients also underwent detailed preoperative, intraoperative and postoperative
neurological testing for motor and tremor control, sensory and cranial nerve testing,
muscle tone and spasticity, overall flexibility and reflexes, as well as cognitive
assessment. The physical examinations were performed by two senior clinicians
experienced with clinical care of patients with ET.
2.1.1 Pre-operative anatomic MRI2
Pre-operative MR imaging was performed on a 3 Tesla GE Discovery MR750
scanner (Waukesha, WI). T1-weighted structural images were obtained with a 3D fast
spoiled-gradient-recalled (FSPGR) pulse sequence (TR = 6.5 ms, TE = 2.5 ms, = 12,
BW = 140 kHz), at 1 mm isotropic resolution. T2 fluid attenuated inversion recovery
(FLAIR) images were acquired with an inversion-prepared spin echo pulse sequence
(TR = 10,000 ms, TE = 148 ms, TI = 2,250 ms, BW = 781 Hz/pixel) at 1 x 1 mm in-plane
resolution with 1 mm slice thickness and 1 mm spacing between slices.
2.1.2 Pre-operative diffusion tensor MRI
Diffusion tensor data were acquired with an echo-planar imaging sequence (TR =
8,000 ms, TE = 84.9 ms, BW = 1562 Hz/pixel) using a 30-direction gradient encoding
scheme at b = 1000 s/mm2 with 2 non-diffusion-weighted images. The acquisition

Sections 2.1.1 to 2.1.3 credit to Dr. Nandan Lad, Ms. Beth Parente, Dr. Allen Song; Duke University

Medical Center Dept. of Surgery; Duke-UNC Brain Imaging and Analysis Center

13

matrix was 128 x 128 over a 240 x 240 mm field of view (FOV) with a slice thickness of
2 mm. Data were zero-filled in k-space to a matrix size of 256 x 256 prior to
reconstruction for a final nominal voxel size of 0.94 x 0.94 x 2 mm.
2.1.3 Post-operative CT
CT images were acquired on a Siemens SOMATOM Definition Flash scanner
with a spiral scan using a 512 x 512 Matrix over a 250 x 250 mm FOV for an in-plane
resolution of 0.484 mm. Approximately 300 contiguous, non-overlapping, 0.625 mm
thick slices were acquired covering the entire neurocranium, Additional scan parameters
include MA setting = 250 and kVp = 120. The standard reconstruction algorithm was
used.
2.1.4 Post-operative electrode testing and outcomes3
Post-operative electrode testing was performed on DBS patients after initial
surgical recovery. Each contact was tested independently at voltages ranging from 0.5
to 3 volts dependent on patient tolerance, with frequency between 135-185 Hz and
pulse width between 60-90 microseconds. For each contact, treatment efficacy was
recorded on a three level subjective scale that included no effect, mild/moderate
control, and good/excellent control. Patients experiencing persistent undesired side
effects were recorded on as having significant side effects, while patients that did not
experience any side effects, experienced transient side effects, or only presented side
effects at very high testing voltages that were not used in the final voltage setting were
recorded as no significant side effects. Typical side effects included paresthesias,

Section credit to Dr. Patrick Hickey; Duke University Medical Center Dept. of Neurology

14

worsening of tremor, and/or dysarthria. In some cases an effective contact was

identified early in testing and the remaining contacts were not tested to avoid
unnecessary patient discomfort. The corresponding data points were recorded as n/a.
Outcome testing results are summarized in Table 3.
2.2 Fiber tractography
2.2.1 Deterministic fiber tractography in clinical diffusion MRI
Deterministic fiber tracking was performed using iPlan stereotaxy software
(Brainlab, Feldkirchen, Germany). Future research will consider further validation with
other techniques (Aganj et al, 2010; Aganj et al., 2011; Lenglet et al., 2012). All imaging
datasets were individually loaded into Brainlab iPlan. After ensuring accurate and
overlapping fusion of all dataset image pairs in the Image Fusion function, regions of
interest (ROI) were mapped under Fiber Tracking using the FLAIR MRI image set for
clear structural contrast. Fractional anisotropy threshold and minimum length were
standardized for all patients at 0.2 and 75 mm, while maximal angle change of fibers
was set at the default value of 70 degrees.
In the case of ET patients, the putative mechanism of action of DBS of the Vim
thalamus is the modulation of the underlying white matter fiber tract termed the
dentatorubrothalamic (DRT) tract (Groppa et al., 2014). The DRT tract is the primary
fiber bundle forming the superior cerebellar peduncle, which is one of the largest
efferent connections of the cerebellum and consists of axon fibers arising from cells
located in the dentate, emboliform, and globose nuclei. These fibers then project to the
thalamus and terminate in the ventral lateral and ventral posterolateral thalamic nuclei,
which go on to project to the primary motor cortex (Habas and Cabanis, 2007; Kwon et

15

al., 2011). As such, this system is functionally relevant for somatomotor coordination
and tremor control. Three cubic ROIs were marked for the DRT tract (Figure 1): 1) in
axial section, ROI around the red nucleus at its widest diameter, 2) in axial section, ROI
around resulting fibers which reached the precentral gyrus containing the primary motor
cortex (M1), 3) in axial section, end region ROI around the ipsilateral dentate nucleus to
include resulting fibers from the first ROI which traveled along the superior cerebellar
peduncle (Yousry et al., 1997). In addition, mapping of the most distal DBS active
contact (contact 0) and its relation to the DRT tract was performed by establishing two
cubic ROIs: 1) in axial cut, the cubic ROI generated for the most distal DBS active
contact (contact 0) and 2) in axial cut, ROI around the precentral gyrus to include
resulting fibers from the first ROI which traveled along the DRT tract.
2.2.2 Analysis of DBS contact proximity with clinical DRT tractography
The relevant active contact as determined by post-operative testing outcomes
was established as the sole ROI for fiber tracking. Tractography was performed on 10
ET patients using the FLAIR MRI image set for clear structural contrast at fractional
anisotropy threshold of 0.2 and minimum length 75 mm, while maximal angle change of
fibers was set at the default value of 70 degrees.
2.2.3 Probabilistic fiber tractography in clinical diffusion MRI4
Tractography regions of interest (ROIs) were manually segmented from both
anatomic and tensor-derived image data, using a histology-based human brainstem

Section credit to Dr. Evan Calabrese; Duke University Medical Center Dept. of Radiology CIVM

16

atlas for reference (Paxinos and Huang, 1995). ROIs for tracking the DRT included the
superior cerebellar peduncles, the red nuclei, and Vim nuclei of the thalamus.
Tractography fiber data were reconstructed using FSLs BedpostX, a direct,
multi-fiber orientation estimation algorithm that provides estimates of fiber distribution
error for probabilistic tractography (Behrens et al., 2007). These data were used for
probabilistic fiber tractography using FSLs ProbtrackX. Tractography of the bilateral
DRTs was generated using the superior cerebellar peduncle as a seed region, and the
contralateral red nucleus and Vim nucleus of the thalamus as waypoints. Tracking
parameters included 5000 seeds per voxel, a step size of 100 m, and a curvature
threshold of 45 per voxel. Resulting tractography data were thresholded at > 2000
tracks per voxel, or roughly 1%, consistent with previous work (Jbabdi et al., 2013).
2.2.4 Analysis of DBS contact proximity with postmortem DRT tractography
In order to validate the anatomic accuracy of postmortem tractography results,
we assessed the proximity of each DBS lead to dentatorubrothalamic tract tractography
from postmortem brainstem datasets after spatial transformation into the anatomic
space of each patient dataset. Individual DBS leads were clearly differentiated and
identified on the post-operative CT scan, and the proximity of each spherical lead to the
postmortem dentatorubrothalamic tract tractography were classified in a four rank
system. The eight leads per patient were analyzed as separate data points because
each lead was tested independently for treatment efficacy. DBS leads directly inside
the tract were ranked as inside, leads contacting the surface of the rendered tract
were ranked as touching, leads in close proximity to the tract but not contacting it were
ranked as close, and leads not in close vicinity of the tract were ranked as not

17

touching. The shape and size of the dentatorubrothalamic tract was highly dependent
on the threshold used for tractography. We determined the area inside the DRT tract to
be at a threshold of greater than 2000 fibers per voxel, which is consistent with optimal
threshold recommendations for probabilitstic tractography. The rank system for DBS
lead proximity was evaluated independently by two observers and then compiled into a
single numerically ranked datasheet and evaluated with a Spearman rank correlation.
2.2.5 Analysis of DBS contact proximity with postmortem rendering of Vim
We also assessed the proximity of each DBS lead to a rendering of the Vim from
the postmortem brainstem datasets to gauge the correlation between patient treatment
outcomes and stimulation of the Vim of the thalamus. Vim was segmented bilaterally
for the postmortem brainstem template referencing anatomy from the Mai-Paxinos
Human Nervous System atlas. The high contrast resolution of the postmortem
brainstem datasets allowed for accurate definition of the Vim apart from the surrounding
thalamic nuclei. Vim segmentation was transformed into each individual patients
anatomic space using the spatial transformations detailed earlier. A similar four rank
system as the analysis of DRT tract proximity was used respective to the Vim, after
which correlation was evaluated with a Spearman statistic test.

3. Results
Postoperative lead visualization and overlapping of contacts with their underlying
DTI target has been done in a limited fashion to date. We utilized the currently
commercially available DBS lead 3389 (Medtronic, Inc., Minneapolis, MN) to examine
the underlying fiber connectivity and putative circuits being modulated by stimulation.

18

The function of these circuits has been extensively studied in preclinical models,
however visualization in humans has been limited due to inability to reliably visualize the
lead and its contacts and their relation to associated fiber tractography in stereotactic
space.
Furthermore, the ability to visualize the underlying circuit being modulated and
regional neuroanatomy is critical for optimal clinical results (Coenen et al., 2011;
Henderson, 2012; Hyam et al., 2012). Specifically, it was found that the DRT tract was
reproducibly visualized passing through the active DBS contacts of 10 ET patients
undergoing Vim stimulation. These findings are discussed in detail as follows.

3.1. DBS Lead and Contact segmentation and modeling

Leads and contacts were segmented and modeled using the Object Creation
function after alignment in the View and Adjustment function in Brainlab software. The
post-operative CT image set was used to align the length of the lead parallel to the
vertical axis of the screen, with the bottom of the lead (where the contacts are located)
centered right on the horizontal axis.
The lead can then be made into an object using auto segmentation in Object
Creation; a histogram is provided in this function so that the lead can be outlined by its
difference in radiopacity. This provides a standardized way to accurately depict the
leads actual shape and slight curvature in its final location instead of relying on a linear
model as has been done previously (Coenen et al., 2011).
Contacts are 1.5 mm in diameter, and created as new objects standardized using
the brush function; this function allows users to adjust size of the brush diameter to
highlight and create an object. To correctly model the spacing of the contacts on the
19

lead in relation to each other, a void object was also made using brush size 0.5 mm;
this object is used in the sagittal view to fill out the 0.5 mm dead space at the tip of the
lead as well as adjusted to fill out space between contacts. The electrode pattern used
for patients had between contact spacing fixed at 0.5 mm for typical Vim DBS leads
(Model 3389). The standardized brush sizes used for contact and spacing coupled with
the exact outline of the lead by density allows for correct positioning of the dead space
at the lead tip and subsequent contacts/contact spacing in the simulation. To model
each contact as consistently as possible to their actual shape, the brush function set at
1.5 mm was used in the sagittal, coronal, and axial planes to create an approximate
sphere of volume 0.002 cm,verified in the Plan Content section.

3.2. Diffusion Tensor Imaging and Fiber tractography

To visualize relevant fiber tracts that cross through the individual DBS lead
contacts, the Fiber Tracking function was utilized to make a new region of interest from
the previously created contact using the Existing 3D Object selection. It is then possible
to track fibers that run through this contact to brain structures of interest (Figure 2A).
Figure 2B shows a sample ET patient treated with bilateral Vim DBS using
modeled electrodes created as regions of interest in the Fiber Tracking function. To
account for the specificity and small size of this ROI, minimum fiber length was adjusted
to 30 mm, while fractional anisotropy threshold and maximal angle change of fibers
were held constant at 0.2 and 70 degrees, respectively.
3.3 Deterministic tractography
Deterministic tractography through the active DBS contact set as the sole
region of interest yielded consistent fiber tracking patterns across the patient datasets
20

(Figure 3). It can be observed that these fiber tracts directly contacting the DBS
electrodes closely follow the DRT tract modeled previously, and this was consistently
seen throughout the 10 ET patients. As the DBS electrode itself is set as region of
interest, there is no need for a correlation analysis of the results: the fiber tracts shown
are in overlapping voxels as the active contact that is used for treatment. Overlay of
fiber tracts contacting the DBS electrodes with the target DRT tract can provide analysis
on correlation of electrode positioning with treatment outcomes for each patient.
3.4 Probabilistic tractography5
Probabilistic tractography with multiple fiber orientations was used to reconstruct
DRT probability maps in the postmortem brainstem dataset. The DRT courses from the
dentate nucleus of the cerebellum through the superior cerebellar peduncle, crosses the
midline in the mid pons, passes through and around the contralateral red nucleus, and
finally relays in the Vim nucleus of the thalamus before continuing to cortical motor
areas (e.g. Figure 4A). Importantly, routine clinical diffusion tractography data are
poorly suited for accurately representing crossing fibers, such as those present in the
midline crossing of the DRT between the dentate nucleus and the red nucleus.
Probabilistic tractography of the postmortem template correctly represented the midline
crossing of the DRT as well as its connections to the contralateral red nuclei and Vim
nuclei (Figure 4AC). Probabilistic tractography also revealed minor branches of the
DRT coursing along the medial aspect of the red nuclei (Figure 4B). These medial
pathways have been observed in histology studies of the human brainstem (Massion,
5

Sections 3.4 to 3.6 referenced from manuscript submitted to Human Brain Mapping co-authored

under Dr. Evan Calabrese

21

1967), but have not previously been demonstrated with diffusion tractography.
Visualization of probabilistic DRT tractography with surface renderings of the Vim nuclei
and red nuclei clearly demonstrates the close relationship between these structures in
the human brainstem, and highlights the potential difficulty in accurately targeting DBS
electrodes in this complex brain region (Figure 4C).
3.5 Registration of postmortem MRI to clinical datasets
Postmortem brainstem data were non-linearly registered to 12 patient datasets.
We observed considerable variation in patient brain anatomy, particularly with regard to
ventricle size. Nonetheless, registration of postmortem brainstem data to patient
datasets yielded good visual alignment (Figure 5). Major borders, such as the anterior
surface of the pons, the dorsal surface of the thalamus, and the posterior surface of the
tectum showed strong agreement between patient datasets and registered postmortem
data (Figure 5AB). Smaller features, such as the optic chiasm, were also very closely
aligned after registration (Figure 5BC).
Additional assets from the postmortem dataset, including probabilistic
tractography and 3D segmentations of the Vim and red nuclei, were also transformed
into patient image space. These data, combined with post-operative CT data for
electrode localization, allowed 3D visualization of the complex spatial relationships
between DBS contacts and the relevant nuclei and white matter tracts (Figure 6AD). In
most clinical datasets, DBS contacts were clearly visible in post-operative CT data as
four discrete bulges at the distal end of the electrode (e.g. Figure 6B). In cases where
contacts were not clearly visible in CT data, they could be inferred based on the specific
geometry of the electrodes used (Coenen et al., 2011b). Using these data, we

22

measured the position of each electrode contact with respect to the DRT and Vim from
the postmortem template. Across all patient datasets, 22/24 electrodes had a least one
contact directly touching the Vim nucleus segmented from the postmortem template
(e.g. Figure 6AB). In contrast, only 18/24 electrodes had at least one contact directly
touching the thresholded DRT model (Figure 7).

3.6 Statistical analysis of DBS contact position and clinical efficacy

In order to assess the accuracy of our postmortem template, we tested for
statistically significant correlation between electrode proximity to the DRT and Vim, and
clinical outcomes including treatment efficacy and the presence of side effects. The
non-parametric Spearman rank correlation was used because clinical outcomes were
assessed as ordinal variables. The calculated p-values and R-values (i.e. Spearman
correlation coefficients) for each comparison are presented in Table 4. We observed no
significant correlation between contact proximity to the DRT or Vim and the presence of
side effects. Despite the fact that the Vim nucleus of the thalamus was the explicit target
for DBS electrodes, we did not detect a statistically significant correlation between
treatment outcome and contact proximity to the Vim from the postmortem template. We
did, however, detect a highly significant, yet weak, positive correlation between
treatment efficacy and contact proximity to the DRT from the postmortem template (p =
0.005, R = 0.336). This correlation remained significant after Bonferroni correction for
multiple comparisons (pcorrected = 0.02). This correlation suggests that our postmortem
DRT model has at least some degree of anatomic relevance for DBS electrode targeting
in ET patients.

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4. Discussion
Our results describe new protocols for both in vivo and ex vivo MRI to
consistently model DBS electrode position in a standardized fashion relative to
visualizations of relevant pathways mapped by diffusion tensor imaging and fiber
tractography. Reliable fiber tracts and modulation of the associated sensorimotor
networks in patients with ET was seen, a finding that is consistent with prior studies
(Benabid et al., 1996; Coenen et al., 2011). The most striking findings in our analysis
are the intimate positioning of DBS leads with surrounding fiber tracts previously shown
to respond to neuromodulation of the sensorimotor system by modulating distinct white
matter circuits in ET. In particular, 1) we demonstrate using individual patient MRI that
fiber tracts approximating the DRT tract in ET patients are stimulated by their active
DBS contact in the thalamus, and 2) we analyze the correlation between patient DBS
contact positioning to probabilistic DRT tractography and 3D modeling of the Vim in a
high resolution postmortem brainstem and thalamus template.

4.1 In vivo patient dataset analysis

Seeding of the DRT pathway in patients undergoing Vim DBS for tremor showed
connections from the primary motor cortex (M1), ipsilateral red nucleus and cerebellum,
which is consistent with the published literature (Coenen et al., 2011). The Vim is
generally accepted to be the cerebellar receiving area of the thalamus before the fibers
are projected to the primary motor cortex (Hasslet et al., 1979; Carpenter, 1991).
Retrograde tracer studies of herpes simplex virus-1 from M1 injections in macaques
stains both the cerebellum and globus pallidus (Hyam et al., 2012).

24

In the in vivo portion of this study, we used physical localization of contacts from
individual cases to generate consistent fiber tractography of tracts directly touching the
contact. The tracts were then visually assessed to approximate the shape and position
of the DRT tract. Benefits of this approach include bypassing the statistic correlation
analysis of tract proximity to contact positioning, as the tracts shown are mapped
through the active contact as ROI. However, this approach can be greatly refined with 1)
overlaying the DRT tract generated through its three relevant ROIs (red nuclei, dentate
nucleus, precentral gyrus) on top of the active contact generated tractography to
determine if they indeed have significant overlap, 2) quantizing this overlap numerically
with fiber counts or another thresholded method, and 3) analyzing this degree of overlap
for each patient with their patient outcomes. Generation of connectomic maps of
cortical connectivity by selecting the entire thalamus or entire cortex relative to the DBS
contact of interest is an alternative to the approach we have used (Henderson, 2012).
Further study is required to test these methods in other regions of surgical interest such
as the sensory and anterior thalamic nuclei for pain and epilepsy surgery, respectively
(Bittar et al., 2005; Lega et al., 2010).
By combining patient dataset models with intraoperative and postoperative
clinical results, detailed analyses can be made for each patient to pinpoint correlations
in electrode placement and treatment outcome that can serve as a guide for
programming as well as creation of patient-specific models (Hagmann et al., 2010;
Lenglet et al., 2012). Further studies examining electrical fields of stimulation and
surrounding pathways will be critical to dissect therapeutic stimulation from potential
stimulation side effects. The ability to visualize the fiber target of interest in relation to

25

the surgical implant allows not only for more accurate sub-millimiter lead placement, but
also postoperative programming, current steering and novel stimulation algorithms. DTI
fiber tractography will likely play an increasingly important role for mapping proposed
white matter DBS targets for large neurological disorders including Alzheimers Disease
(Fornix stimulation) and Depression (Cingulate Cg25 stimulation).
4.2 Ex vivo patient dataset analysis6
In the ex vivo portion of this study, we present a high spatial and angular
resolution diffusion MRI template of the postmortem human brainstem and thalamus
with 3D reconstructions of the nuclei and white matter tracts involved in ET circuitry. We
demonstrate accurate registration of these data to in vivo, clinical images from patients
receiving DBS therapy, and correlate electrode proximity to tractography of the DRT
with improvement of ET symptoms. This serves as a proof of concept for using highresolution postmortem diffusion MRI reference atlases for DBS targeting. Our results
show that; 1) postmortem diffusion MRI can be used to create a high-quality, highresolution template of the human brainstem and thalamus; 2) these data can be
accurately aligned to patient datasets using automated image registration; and 3) that
electrode position within the registered template has a significant correlation with
treatment efficacy.
Postmortem diffusion tractography can provide increased anatomic accuracy
through improved image quality, increased spatial and angular (diffusion) resolution,

Section referenced from manuscript submitted to Human Brain Mapping co-authored under Dr.

Evan Calabrese

26

and reduced image artifacts. High angular resolution diffusion datasets also allow
advanced tractography methods including probabilistic tractography with multiple fiber
orientations, which may be more sensitive than standard deterministic tractography
(Behrens et al., 2007). We were able to achieve good registration between our
postmortem template and 12 patient datasets, particularly with regard to ventricular
and/or exterior borders of the brainstem and thalamus. We were able to show a
statistically significant correlation between treatment efficacy and contact proximity to
the DRT of our postmortem template. Although this correlation was highly significant, it
was relatively weak, suggesting that other factors play a role in treatment efficacy. One
interesting result of our study was the lack of a significant correlation between treatment
efficacy and contact proximity to the Vim, which was the intended electrode target.
There is increasing evidence that the anti-tremor effects of Vim DBS are related to
modulation of the DRT rather than the Vim itself. DRT fibers pass through a portion of
the Vim, and it is possible that stimulation of this area is principally responsible for
tremor control.
High-resolution MRI-based reference atlases, like the postmortem data
presented here, could improve on conventional histology-based atlases by incorporating
accurate volumetric imaging and 3D connectivity mapping from diffusion tractography.
Usage of such postmortem atlases in conjunction with individual deterministic
tractography of in vivo MRI datasets can serve as valuable tools to evaluating and
improving patient treatment efficacy.

27

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32

Figure 1. A) The dentatorubrothalamic tract (DRT) was mapped through three cubic
regions of interest (ROIs) in the FLAIR MRI image set; B) first ROI around the red
nucleus in axial view; C) the second ROI around the precentral gyrus; D) the third ROI
around the ipsilateral dentate nucleus.

33

Figure 2. Each contact object was standardized using the Axial Custom View in Object
Creation with brush size 1.5 mm to consistently model contacts as spheres with volume
0.002 cm. Contact objects were set as ROIs in the Fiber Tracking section; this enables
tracking of fibers running through each contact to target brain structures. A) Fibers
through contacts in sampled ET patients closely follow the relevant DRT pathway. B)
Close up of fibers directly passing through contacts 0 and 1 are shown.

34

Figure 3. Relevant active contact as determined by post-operative testing outcomes

was established as the sole region of interest for fiber tracking in each patient FLAIR
MRI for 10 ET patients; visualization of fiber tractography with the DBS electrodes (red).

35

Figure 4. Probabilistic tractography of the DRT from postmortem diffusion MRI of the
brainstem and thalamus. A) A schematic of the DRT is shown for reference. B)
Probabilistic tractography shows the course of the DRT, including minor branches that
pass medially to the red nucleus (arrowheads). C) Visualization of the spatial
relationships between the DRT, the red nucleus (red), and Vim nucleus of the thalamus
(blue).

36

Figure 5. Representative data showing registration between in vivo and postmortem

MRI datasets. A) A parasagittal in vivo image with a surface rendering of the registered
postmortem dataset superimposed. BD) Sagittal, axial and coronal slices, respectively,
of an in vivo dataset with the corresponding slices from the registered postmortem
anatomic image superimposed. Arrowheads indicate major borders that demonstrate
the accuracy of registration.

37

Figure 6. Visuospatial integration of image data including in vivo MRI, CT, and
registered postmortem data. In each panel, a single slice of the pre-operative FSPGR
image is shown with the corresponding slice of the registered postmortem dataset
superimposed. Probabilistic tractography of the DRT (orange) is shown along with
surface renderings of the red nuclei (red), the Vim nuclei of the thalamus (blue), and the
implanted DBS leads derived from post-operative CT data (green). AB) Posterior and
anterior views, respectively, of a coronal slice through the red nucleus. C) Mid-sagittal
slice. D) Oblique view of an axial slice through the red nucleus.

38

Figure 7. Visualization of DBS electrode position relative to the DRT from the
registered postmortem template for all 12 patient datasets examined in this study. For
each patient, we show a single oblique slice, roughly corresponding to the diagram in
the top left, along with probabilistic tractography of the DRT derived from the registered
postmortem template (orange), and a surface rendering of the implanted DBS
electrodes derived from post-operative CT data (green).

39

Table 1: Stereotaxic coordinates of each electrode contact for each patient included in
the study. Stereotaxic coordinates are provided in millimeters from the mid-commissural
point (MCP). Distance from the third ventricle (3V) in millimeters is also included. n/a
indicates missing data.
MCP Coordinates (mm)
Electrode Contact
Patient 01 Contact 0
Patient 01 Contact 1
Patient 01 Contact 2
Patient 01 Contact 3
Patient 01 Contact 8
Patient 01 Contact 9
Patient 01 Contact 10
Patient 01 Contact 11
Patient 02 Contact 0
Patient 02 Contact 1
Patient 02 Contact 2
Patient 02 Contact 3
Patient 02 Contact 8
Patient 02 Contact 9
Patient 02 Contact 10
Patient 02 Contact 11
Patient 03 Contact 0
Patient 03 Contact 1
Patient 03 Contact 2
Patient 03 Contact 3
Patient 03 Contact 8
Patient 03 Contact 9
Patient 03 Contact 10
Patient 03 Contact 11
Patient 04 Contact 0
Patient 04 Contact 1
Patient 04 Contact 2
Patient 04 Contact 3
Patient 04 Contact 8
Patient 04 Contact 9
Patient 04 Contact 10
Patient 04 Contact 11
Patient 05 Contact 0
Patient 05 Contact 1
Patient 05 Contact 2
Patient 05 Contact 3
Patient 05 Contact 8
Patient 05 Contact 9
Patient 05 Contact 10
Patient 05 Contact 11
Patient 06 Contact 0

Lateral (X)
12.88
13.57
14.94
15.07
11.56
12.79
13.04
13.79
13.66
14.46
14.66
-15.54
15.77
16.33
17.13
17.30
13.85
14.48
14.48
15.19
12.68
13.13
13.67
14.49
13.37
13.66
13.52
14.66
15.75
16.60
16.60
18.32
13.39
13.89
14.16
15.05
12.20
13.22
13.22
15.43
10.40

AP (Y)
-5.63
-4.68
-3.30
-2.80
-6.91
-5.93
-4.18
-3.81
-5.79
-4.99
-5.06
-3.97
-3.89
-3.08
-2.08
-1.08
-8.09
-6.76
-5.94
-5.15
-8.42
-7.79
-6.66
-5.66
-8.47
-7.19
-6.33
-5.05
-3.44
-3.21
-2.07
-1.78
-7.39
-6.13
-5.02
-3.57
-5.56
-4.62
-3.17
-1.91
-5.54

Vertical
(Z)
-1.98
0.00
1.59
3.97
0.49
2.51
4.63
6.51
-0.80
1.80
2.61
4.30
1.77
3.67
6.07
7.97
-3.43
-1.33
-0.06
1.12
-0.89
0.56
1.93
2.84
3.14
5.00
7.00
8.85
2.69
4.83
5.97
7.97
-1.59
-0.04
2.63
4.63
-1.30
0.25
2.37
4.37
-0.27

Distance
From 3V
12.3
12.0
13.0
13.0
9.5
10.0
11.6
12.6
11.1
11.0
11.8
13.4
11.6
14.2
15.5
15.7
12.1
11.5
10.2
11.8
8.1
9.0
10.6
10.5
9.3
9.9
11.4
12.7
10.7
12.5
13.0
13.8
11.1
11.0
10.6
13.7
11.0
10.6
12.7
13.1
9.0

40

Patient 06 Contact 1
Patient 06 Contact 2
Patient 06 Contact 3
Patient 06 Contact 8
Patient 06 Contact 9
Patient 06 Contact 10
Patient 06 Contact 11
Patient 07 Contact 0
Patient 07 Contact 1
Patient 07 Contact 2
Patient 07 Contact 3
Patient 07 Contact 8
Patient 07 Contact 9
Patient 07 Contact 10
Patient 07 Contact 11
Patient 08 Contact 0
Patient 08 Contact 1
Patient 08 Contact 2
Patient 08 Contact 3
Patient 08 Contact 8
Patient 08 Contact 9
Patient 08 Contact 10
Patient 08 Contact 11
Patient 09 Contact 0
Patient 09 Contact 1
Patient 09 Contact 2
Patient 09 Contact 3
Patient 09 Contact 8
Patient 09 Contact 9
Patient 09 Contact 10
Patient 09 Contact 11
Patient 10 Contact 0
Patient 10 Contact 1
Patient 10 Contact 2
Patient 10 Contact 3
Patient 10 Contact 8
Patient 10 Contact 9
Patient 10 Contact 10
Patient 10 Contact 11
Patient 11 Contact 0
Patient 11 Contact 1
Patient 11 Contact 2
Patient 11 Contact 3
Patient 11 Contact 8
Patient 11 Contact 9
Patient 11 Contact 10
Patient 11 Contact 11
Patient 12 Contact 0
Patient 12 Contact 1

11.35
11.79
12.32
14.19
14.09
15.12
16.44
13.73
13.51
13.68
14.01
11.09
12.20
12.12
12.78
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
13.32
13.83
14.96
15.56
12.59
13.16
13.72
14.40
13.64
14.42
15.15
16.32
11.96
11.81
12.74
14.10
16.35
16.41
16.55
16.82
9.49
9.86
10.23
10.73
14.34
14.51

-5.22
-4.35
-3.17
-4.68
-4.14
-2.57
-1.53
-10.95
-10.73
-9.81
-8.14
-8.79
-7.75
-6.53
-6.09
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
-8.37
-6.86
-5.29
-4.16
-8.23
-7.11
-5.98
-4.62
-5.82
-4.91
-3.60
-1.94
-6.01
-5.49
-4.11
-2.59
-7.32
-7.09
-6.38
-5.42
-8.81
-7.97
-7.14
-6.46
-7.58
-6.91

1.18
3.07
5.83
-1.69
-0.44
2.32
4.99
-2.66
1.21
0.79
3.23
-1.73
0.82
2.16
4.16
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
-3.41
0.70
2.22
4.93
-2.58
-0.77
1.15
3.63
-3.34
-0.44
-1.74
4.21
-2.03
-0.87
2.03
2.76
-5.18
-4.00
-2.05
0.73
-3.68
-1.64
0.29
2.11
-1.38
-0.03

8.3
10.6
11.3
12.2
12.2
13.5
14.1
11.7
10.8
9.7
10.0
9.4
8.6
8.0
8.9
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
11.3
10.2
11.4
12.4
10.7
10.0
10.5
12.2
12.0
10.6
12.2
13.6
10.3
9.3
10.7
13.3
15.1
14.9
14.5
14.7
8.4
8.0
8.6
9.5
12.4
11.0

41

Patient 12 Contact 2
Patient 12 Contact 3
Patient 12 Contact 8
Patient 12 Contact 9
Patient 12 Contact 10
Patient 12 Contact 11

14.85
15.18
12.17
12.66
13.38
14.40

-6.06
-5.04
-9.66
-8.94
-7.58
-6.56

2.18
4.38
-2.06
-0.40
1.97
3.32

11.7
12.9
10.7
9.6
10.3
12.0

42

Table 2: Demographic information for the 12 patients included in this study.

Patient
Patient 01
Patient 02
Patient 03
Patient 04
Patient 05
Patient 06
Patient 07
Patient 08
Patient 09
Patient 10
Patient 11
Patient 12

Gender
F
F
M
F
F
F
F
F
M
F
M
M

Age
32
75
74
39
61
68
71
84
72
65
72
69

43

Table 3: Treatment efficacy, side effects, and proximity to the DRT and Vim from the
postmortem model for each DBS contact (eight per patient). + indicates mild/moderate
tremor reduction and the presence of side effects. ++ indicates good/excellent tremor
reduction. - indicates no tremor reduction and the absence of side effects. n/a denotes
missing data points.
Electrode Contact
Patient 01 Contact 0
Patient 01 Contact 1
Patient 01 Contact 2
Patient 01 Contact 3
Patient 01 Contact 8
Patient 01 Contact 9
Patient 01 Contact 10
Patient 01 Contact 11
Patient 02 Contact 0
Patient 02 Contact 1
Patient 02 Contact 2
Patient 02 Contact 3
Patient 02 Contact 8
Patient 02 Contact 9
Patient 02 Contact 10
Patient 02 Contact 11
Patient 03 Contact 0
Patient 03 Contact 1
Patient 03 Contact 2
Patient 03 Contact 3
Patient 03 Contact 8
Patient 03 Contact 9
Patient 03 Contact 10
Patient 03 Contact 11
Patient 04 Contact 0
Patient 04 Contact 1
Patient 04 Contact 2
Patient 04 Contact 3
Patient 04 Contact 8
Patient 04 Contact 9
Patient 04 Contact 10
Patient 04 Contact 11
Patient 05 Contact 0
Patient 05 Contact 1
Patient 05 Contact 2
Patient 05 Contact 3
Patient 05 Contact 8
Patient 05 Contact 9
Patient 05 Contact 10
Patient 05 Contact 11
Patient 06 Contact 0

Efficacy

Side Effects

++
++
+
+
++
++
+
+
++
++
++
+
++
++
++
+
+
+
++
++
+
+
++
+
+
++
++
++
+
+
+
+
+
++
+
+
+
+

+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
-

DRT
Proximity
0 mm
0 mm
0 mm
0 mm
<1 mm
<1 mm
>1 mm
>1 mm
0 mm
0 mm
>1 mm
<1 mm
0 mm
<1 mm
>1 mm
>1 mm
>1 mm
>1 mm
>1 mm
>1 mm
0 mm
0 mm
0 mm
>1 mm
0 mm
<1 mm
>1 mm
<1 mm
<1 mm
<1 mm
<1 mm
>1 mm
0 mm
0 mm
0 mm
>1 mm
<1 mm
0 mm
<1 mm
>1 mm
>1 mm

Vim
Proximity
0 mm
0 mm
>1 mm
0 mm
0 mm
0 mm
>1 mm
0 mm
0 mm
0 mm
>1 mm
<1 mm
<1 mm
<1 mm
>1 mm
0 mm
0 mm
0 mm
>1 mm
<1 mm
0 mm
0 mm
<1 mm
0 mm
0 mm
0 mm
>1 mm
>1 mm
0 mm
0 mm
0 mm
0 mm
0 mm
0 mm
>1 mm
0 mm
0 mm
0 mm
>1 mm
>1 mm
0 mm

44

Patient 06 Contact 1
Patient 06 Contact 2
Patient 06 Contact 3
Patient 06 Contact 8
Patient 06 Contact 9
Patient 06 Contact 10
Patient 06 Contact 11
Patient 07 Contact 0
Patient 07 Contact 1
Patient 07 Contact 2
Patient 07 Contact 3
Patient 07 Contact 8
Patient 07 Contact 9
Patient 07 Contact 10
Patient 07 Contact 11
Patient 08 Contact 0
Patient 08 Contact 1
Patient 08 Contact 2
Patient 08 Contact 3
Patient 08 Contact 8
Patient 08 Contact 9
Patient 08 Contact 10
Patient 08 Contact 11
Patient 09 Contact 0
Patient 09 Contact 1
Patient 09 Contact 2
Patient 09 Contact 3
Patient 09 Contact 8
Patient 09 Contact 9
Patient 09 Contact 10
Patient 09 Contact 11
Patient 10 Contact 0
Patient 10 Contact 1
Patient 10 Contact 2
Patient 10 Contact 3
Patient 10 Contact 8
Patient 10 Contact 9
Patient 10 Contact 10
Patient 10 Contact 11
Patient 11 Contact 0
Patient 11 Contact 1
Patient 11 Contact 2
Patient 11 Contact 3
Patient 11 Contact 8
Patient 11 Contact 9
Patient 11 Contact 10
Patient 11 Contact 11
Patient 12 Contact 0
Patient 12 Contact 1

++
n/a
n/a
+
++
n/a
n/a
+
++
n/a
n/a
++
+
n/a

n/a
n/a
+
n/a
n/a
n/a
n/a
n/a

++
++
n/a
n/a
++
n/a
n/a
++
+
n/a
n/a
++
+
n/a
n/a
++
++
n/a
+
n/a
n/a
n/a
++
+
+
n/a
++
++
n/a
n/a
++
n/a

n/a
n/a
n/a
n/a
n/a
n/a
+
+
n/a
n/a
+
n/a
+
n/a
n/a
n/a
+
n/a
+
+
n/a
n/a
+
n/a

0 mm
0 mm
>1 mm
0 mm
<1 mm
>1 mm
>1 mm
>1 mm
>1 mm
>1 mm
>1 mm
>1 mm
>1 mm
>1 mm
>1 mm
0 mm
0 mm
<1 mm
<1 mm
>1 mm
>1 mm
>1 mm
>1 mm
<1 mm
0 mm
0 mm
<1 mm
<1 mm
0 mm
0 mm
<1 mm
0 mm
0 mm
0 mm
<1 mm
>1 mm
0 mm
0 mm
>1 mm
0 mm
>1 mm
>1 mm
>1 mm
>1 mm
>1 mm
>1 mm
<1 mm
<1 mm
>1 mm

0 mm
>1 mm
>1 mm
<1 mm
<1 mm
>1 mm
<1 mm
0 mm
0 mm
>1 mm
0 mm
0 mm
0 mm
0 mm
0 mm
>1 mm
0 mm
0 mm
0 mm
>1 mm
0 mm
0 mm
0 mm
>1 mm
<1 mm
<1 mm
<1 mm
>1 mm
0 mm
0 mm
0 mm
>1 mm
<1 mm
0 mm
0 mm
<1 mm
0 mm
0 mm
0 mm
>1 mm
>1 mm
0 mm
0 mm
0 mm
0 mm
0 mm
0 mm
>1 mm
0 mm

45

Patient 12 Contact 2
Patient 12 Contact 3
Patient 12 Contact 8
Patient 12 Contact 9
Patient 12 Contact 10
Patient 12 Contact 11

n/a
n/a
++
n/a
n/a

n/a
n/a
n/a
n/a

>1 mm
>1 mm
>1 mm
0 mm
<1 mm
>1 mm

0 mm
0 mm
>1 mm
>1 mm
0 mm
0 mm

46

Table 4: Results of Spearman rank correlation. * denotes statistical significance.

Spearman Correlation
Contact Proximity to Vim vs Side Effects
Contact Proximity to DRT vs Side Effects
Contact Proximity to Vim vs Efficacy
Contact Proximity to DRT vs Efficacy

Correlation
Coefficient
0.015
0.029
0.043
0.336

p-value
0.902
0.815
0.726
0.005*

47