Accepted Manuscript
Post traumatic tremor and thalamic deep brain stimulation: evidence for use of
Diffusion Tensor Imaging
Sandra G.J. Boccard, Ph.D., Pedro Rebelo, B.Sc., Binith Cheeran, Ph.D. MRCP,
Alexander Green, MD, James J. FitzGerald, Ph.D., Tipu Z. Aziz, FMedSc
PII:

S1878-8750(16)30909-3

DOI:

10.1016/j.wneu.2016.09.079

Reference:

WNEU 4619

To appear in:

World Neurosurgery

Received Date: 13 July 2016
Revised Date:

16 September 2016

Accepted Date: 20 September 2016

Please cite this article as: Boccard SGJ, Rebelo P, Cheeran B, Green A, FitzGerald JJ, Aziz TZ, Post
traumatic tremor and thalamic deep brain stimulation: evidence for use of Diffusion Tensor Imaging,
World Neurosurgery (2016), doi: 10.1016/j.wneu.2016.09.079.
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Post traumatic tremor and thalamic deep brain
stimulation: evidence for use of Diffusion Tensor

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Imaging
Sandra G. J. Boccard1*, Ph.D. & Pedro Rebelo1, B.Sc.*, Binith
Cheeran1, Ph.D. MRCP, Alexander Green1, MD, James J FitzGerald1,

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Ph.D., Tipu Z. Aziz1, FMedSc.

Oxford Functional Neurosurgery and Experimental Neurology Group, Nuffield

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Departments of Clinical Neuroscience and Surgery, University of Oxford, UK

* These authors contributed to the manuscript equally
Corresponding author:
Dr Sandra BOCCARD-BINET

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West Wing, Level 6, John Radcliffe Hospital
Headley way
OX3 9DU
Oxford

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sandra.boccard@ndcn.ox.ac.uk

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Running title: DTI of post-traumatic tremor DBS

Key words

Post-Traumatic Tremor
Deep Brain Stimulation
Thalamus
VOp
Tractography

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ABSTRACT
BACKGROUND: Deep Brain Stimulation (DBS) is a well-established treatment
to reduce tremor, notably in Parkinson Disease. DBS may also be effective in
posttraumatic tremor, one of the most common movement disorders caused by
head injury. However, these cohorts of patients often have multiple lesions that

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may impact the outcome depending on which fibre tracts are affected.

CASE DESCRIPTION: A 20-year-old man presented after road traffic accident
with severe closed head injury and polytrauma. CT-scan showed left frontal and
basal ganglia haemorrhagic contusions and intraventricular haemorrhage. A

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disabling tremor evolved in step with motor recovery. Despite high intensity
signals in the intended thalamic target, a visual analysis of the pre-operative
Diffusion Tensor Imaging revealed preservation of connectivity of the intended

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target, VOP. This was confirmed by the post-operative tractography study
presented here. DBS of the ventralis oralis posterior thalamic nucleus- zona
incerta VOP/ZI was performed. Six months post implant, marked improvement of
action (postural, kinetic and intention) tremor was achieved.
CONCLUSIONS: We demonstrated a strong connectivity between the (VOP) and

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the superior frontal gyrus containing the premotor cortex and other central brain
areas responsible for movement control. In spite of an existing lesion in the target,
the preservation of these tracts may be relevant to the improvement of the

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patient’s symptoms by DBS.

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INTRODUCTION
Movement disorders are a common and often delayed consequence of Traumatic
Brain Injury (TBI). After severe TBI between 13 and 66% of patients develop
movement disorders 1 of which 5% persist and can be disabling in nature 2. These

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movement disorders are typically tremor or tremor associated with ataxia.
Thalamotomy has been used in the past to alleviate the tremulous aspects of such
conditions but with variable outcomes 3 {Andrew, 1982 #16} {Bullard, 1984 #17}

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and a high incidence of complications 1. This led to the use of deep brain stimulation
(DBS) as a safer and reversible alternative, although outcomes remain variable 4-7

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{Umemura, 2004 #19} {Broggi, 1993 #30} {Diederich, 2008 #31} {Kudo, 2001 #32}
{Issar, 2013 #33}. In our experience, patient selection can be informed by Diffusion
Tensor Imaging (DTI) analysis - certain pathways, if intact, may predict the outcome
after surgery.

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We report the instructive case of a patient with post-TBI tremor which responded well
to thalamic deep brain stimulation and also the results of pre-operative DTI scan
studies. We confirmed the results of the pre-operative DTI studies with detailed post-

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operative tractographic analysis, indicating that DTI may be relevant in predicting

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outcomes in these patients.

CASE DESCRIPTION
History and Presentation
The patient is a right-handed man, 20-years old at the time of surgery. He was
involved in a road traffic accident (RTA) at the age of 18 years, and suffered multiple
injuries including severe closed head injury and polytrauma (bilateral pneumothorax
and fracture of the left femur). A CT-scan at the time showed left frontal and basal
ganglia haemorrhagic contusions as well as intraventricular haemorrhage. He was in a

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medically induced coma for 7 weeks then developed a Paroxysmal Autonomic
Instability and Dystonia syndrome in the months following the acute event 8, 9.
During neurological rehabilitation at the referring centre, it was noted that despite
improvements in motor power, functional ability lagged behind due to increasing

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ataxia and limb tremor. He was then referred to us as all conservative measures
including medication failed. At the time of referral for DBS, the patient had
continuing physical, cognitive and communication difficulties.

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A significant component of the disability was confirmed to be the cerebellar action
tremor and ataxia (affecting right upper limb more than the left). Prior to surgery the

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patient had a predominantly right sided tremor in upper and lower limb, present at rest,
posture and voluntary movement (goal-directed and non-goal directed). He was
totally incapacitated and unable to self care. He was also unable to write because of
tremor and ataxia, so no handwriting grading scale was possible. The severity of

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tremor was measured using Bain's standardised clinical rating scale for tremor 10 . His
total tremor score was 25 out of 220 from which 17/50 on the right arm, 4/50 on the
left arm and the right leg Ratings were scored out of 10 for each category with 0

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representing the absence of tremor and 10 being the most severe. Ratings were based

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on the amplitude, frequency and intermittency of tremor 11. Accelerometry was also
performed pre-operatively, as part of our routine pre-operative evaluation of tremor.
His tremor was found to have a single peak, which in a previous study of tremor
associated with ataxia (albeit in Multiple Sclerosis), predicted a good outcome from
DBS surgery targeting VOP/ZI 12. In a previous study we found that post brain injury
tremor responded best to stimulation of the thalamic VOP nucleus extending to
include the ZI {Sitsapesan, 2014 #29}. Pre-operative T1, IR, DTI MRI scans were
acquired for surgical planning. On scan there were multiple hyper intense lesions as

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expected from the immediate post TBI imaging. The most relevant lesion was one in
the thalamus, roughly in the region that would be the area of implantation of the deep
brain electrode. If there were significant loss of connectivity of the motor thalamus
the effects of surgery would possibly be compromised. In many centres, a lesion in

visually studied the connectivity of this region.

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the region of lead target is seen as a contra-indication for surgery. We therefore
As reported below, essential

connectivity was preserved. Two years after the RTA he was offered DBS of the left

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ventralis oralis posterior thalamic nucleus- zona incerta (VOP-ZI). The results of the

surgery is presented here.

Operation

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post-operative tractography analysis of the electrode location and outcome from

The surgical technique has been described previously 13, 14. Briefly, a Cosman-

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Roberts-Wells (CRW) stereotactic frame was applied to the patient's head and a
stereotactic CT-scan was performed; this was volumetrically fused with the preoperative MRI using Renishaw Neuroinspire® software (Renishaw, Gloucestershire,

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UK). The electrode was then placed unilaterally in the ventalis oralis posterior

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nucleus (VOp) of the left thalamus (Figure 1) along a trajectory traversing the
VOP/ZI. Coordinates relative to AC-PC: Laterality- 13.5mm, AP- 0.0mm, Vertical 1.5mm. After surgery, a second stereotactic CT-scan to check electrode position was
performed. Intra-operatively there was excellent tremor suppression on bipolar
stimulation at 0- 2+, 160 Hz, 2.7 V, and 70 µs. The DBS (Medtronic 3387) electrode
was then externalised to trial for a week to confirm efficacy. The system was
internalised after a one-week trial period of stimulation on the ward. During these
postoperative programming sessions, the most effective configuration was found to be

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with the deepest contact, ‘C0’, as the cathode, and ‘C2’ as the anode. The current
settings are now: 0+, 1-, 2-, 185 Hz, 3.0 V, and 70 µs.

Postoperative Period

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Six months after surgery, the patient had some residual right postural tremor with the
arm held close to the body. Suppression of kinetic and intention tremor was achieved
for the right arm. Accelerometric recordings comparing the right arm postural tremor

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are shown in Figure 1, to illustrate the magnitude of benefit. Most gratifyingly for the
patient, he was able to hold a pen and write his name for the first time since the

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accident. His handwriting was graded 8 out of 10 and spiral drawing was graded 3 out
of 10. His total tremor score is 7 out of 220 (72% improvement), from which 4/50 on
the right arm (76.5% improvement), 3/50 on the left arm (25% improvement) and

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0/50 on the right leg (100% improvement).

Post-operative tractography study

Brain images were transformed into a common coordinate space, the Montreal

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Neurological Institute (MNI) space. Subsequent coordinates are in millimetres. The
deepest contact location (C0-the cathode) was found at MNI coordinates (-12, -13, -2;

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X, Y, Z) and the anode (C2) at (-13, -10, 2; X,Y,Z). Contacts coordinates were used to
delineate the Volume of Activated Tissue (VAT), defined as the neural tissue
surrounding the electrodes affected by the stimulation. The VAT mask is displayed in
white on the thalamus of the Harvard-Oxford atlas (FSL software) opposed to the
Hassler’s thalamic horizontal section (Figure 2). This comparison confirms the
location of the electrode in the VOp area. Connectivity strength was measured
between the VAT around the electrodes and several cortical or subcortical brain areas
involved in movement disorders and/or highlighted by the connectivity map. For

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details regarding the data processing and tractography procedure, please refer to our
previous publication 15. Mapping the electrode location onto the pre-operative DTI
scans, we confirmed a strong connectivity along the cortico-thalamic tract, leading
mainly to the superior frontal gyrus (n=69.2) and precentral gyrus (n=7.6) (Table 1).

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These two areas are crucial in control of skeletal muscle movement as the precentral
gyrus is the primary motor cortex location, and the premotor cortex is part of the
superior frontal gyrus. To a lesser extent, a connectivity was also found to the middle

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front gyrus (n=2.3) and the brain stem (n=2.3). Figure 3 displays the previously cited

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areas.

DISCUSSION

As reviewed by Krauss et al., Traumatic Brain Injury can result in a broad spectrum
of movement disorders, from Parkinsonism to hemiballism. Overall, the incidence of

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Post TBI movement disorder occurrence is in the range of 13% to 66% 1. Even at the
lower end of this estimate, post TBI movement disorders are common enough to
warrant closer scrutiny. Of these movement disorders, tremor and dystonia are the

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most frequently recorded 1, 2. They may be observed at different times after the trauma,
and can even occur up to 20 years after the index event 16. They can result from

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primary lesions (focal contusions, axonal injury or hemorrhage) and secondary
damage (hypotension, hypoxia, increasing of intracranial pressure). The delayed onset,
often in lock step with recovery, could also be due to neuroplastic reorganisation of
motor networks 17.
Post-Traumatic Tremor (PTT) is often disabling, particularly the action tremor
component, as it interferes with patients’ goal directed movement control. Less
debilitating resting or purely postural tremors can also be observed 7.

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Some drugs may relieve the tremor: propanolol, benzodiazepines like clonazepam, Ldopa and anticholinergics are commonly employed 18-21. Stereotactic thalamotomy
can be also be effective in reducing post-traumatic tremor 3, 7, 22, 23. Krauss et al.
reported an improvement in 88% of patients with a long-term follow-up 7. However,

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, even in patients who have no beneficial effects on tremor.

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ablative surgery for tremor of any cause can induce irreversible long-term side-effects

Deep Brain Stimulation has since proved to be an efficacious and reversible

4, 30

, Holmes tremor 31, 32, multiple

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treat movement disorders: Parkinson disease

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alternative 24-28. Historically, DBS of the thalamus 22, 29 was a recognised procedure to

sclerosis (MS) tremor 30, 33-36 or essential tremor

30, 37, 38

. A comparative study by

Schuurman et al. demonstrated a similar efficacy in reducing tremor between
thalamotomy and DBS but fewer adverse effects and a greater functional
improvement with DBS 39. PTT characterised by a low frequency (2-3.5Hz) and a

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narrow frequency band, can be a relevant criteria to determine which patients would
benefit more from surgery to reduce their tremor, as shown in some MS patients 12

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{Sitsapesan, 2014 #29}. Our previous experience with post traumatic patients led us
to chose Vop/ZI over Vim to improve tremor {Sitsapesan, 2014 #29}.

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PTT is thought to result from pathological synchrony between cortical and subcortical areas and lesions of the cerebellothalamic tracts are a common structural
cause 24. The dentate-rubrothalamic tract (DRT) has been presented by Coenen et al.
as a possible pathway relevant to the tremor reduction obtained by DBS 40. Guided by
DTI tractography, they were able to target this tract and to treat a patient suffering
from therapy-refractory tremor. With its fibers terminating in the VOp and the Ventral
intermediate nucleus (Vim) of the thalamus which in turn project to the primary motor

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cortex, the DRT plays a crucial role in coordinating the somatomotor function 41. It
follows that these tracts may also be critical for the benefit seen after DBS.
In particular, preservation of the cortico-thalamic tract may be crucial if DBS of the

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thalamus nuclei is to be efficacious in reducing PTT. Similar to the work presented by
Coenen et al. on the DRT, the tractography study presented here showed that the
preserved connectivity between the VOp and the motor cortex may explain the

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success of the stimulation at reducing the tremor.

It is not uncommon to have multiple lesions in the brain after a severe head injury,

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and question of whether patients should be offered Thalamic DBS gets thornier when
lesion are present in or around the implant target. Preservation of relevant tracts may
support a trial of thalamic DBS in such patients as illustrated in this case.
CONCLUSION

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PTT is a very common symptom following TBI. Thalamotomy can be effective but
runs the risk of irreversible side-effects, even in those that do not benefit. DBS is a
reversible procedure but reports of success are equally variable. For the DBS to be

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effective in reducing PTT, clinicians should consider implementing preoperative
tractography to verify that the connectivity between the most relevant structures are

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preserved.

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Acknowledgments and Disclosure
The research was supported by the National Institute for Health Research (NIHR)
Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust
and University of Oxford, The Norman Collisson Foundation and The Charles
Wolfson Charitable Trust.

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The views expressed are those of the authors and not necessarily those of the NHS,
the NIHR or the Department of Health. The authors have no personal financial or
institutional interest in any of the drugs, materials, or devices described in this article.

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FIGURES LEGENDE

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Figure 1: Electrode and VAT location
A: Coronal view, B: Sagittal view, C: Axial view showing the deepest contact (C0)
on patient’s post-surgery CT-scan. VAT on 2mm MNI space (white) in the thalamus
of the Harvard-Oxford atlas (E) opposed to the Hassler’s horizontal section of the
thalamus (D).

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Figure 2: Post-operative improvements
A. Accelerometry: Pre- and post-operative accelerometry illustrating the near total
suppression of postural tremor following DBS. The most prominent channel from
triaxial accelerometric recording of tremor is shown, as a Fast-Fourier Transform
after a Hanning window was applied. Power correlates well to tremor severity on the
Bain Tremor scale. Also note the single peak nature of the recording, which in our
experience correlates to better outcomes after DBS 12. B. Post-operative Spiral
drawings with right and left hands.

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Figure 3: Connection probability maps seeded from the VAT. Sagittal, coronal and
axial views of the tracts (in a yellow-red range) and areas of the Harvard-Oxford atlas
(various colours) potentially stimulated by the electrode, in the 2mm MNI space.
Areas of the Harvard-Oxford atlas are numbered as the following: 3 - Superior frontal
gyrus; 4 - Middle frontal gyrus; 7 - Precentral gyrus/Primary motor cortex; 17 Postcentral gyrus/Primary somatosensory cortex; 26 - Secondary Motor Cortex; 29 Anterior Cingulate Cortex.

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Sup Front Gyrus
PreCentral Gyrus
Middle Front Gyrus
Brain Stem
SMC
ACC
PostCentral Gyrus
Insula

Connectivit
y
45832
2201
151
332
68
82
95
0

Pixels
(total)
5080
8573
5316
9047
1484
2592
6895
5623

Pixels
(non-zero)
662
288
67
145
34
46
68
0

Connectivity
strength
69.2
7.6
2.3
2.3
2.0
1.8
1.4
0.0

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Areas

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Table 1. Connectivity between the electrode and the brain areas
Sup Front Gyrus, Superior frontal gyrus; SMC, Supplementary motor cortex; ACC, Anterior
Cingulate Cortex.

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Highlights

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This is the first tractography study of a DBS patient with post-traumatic tremor
Stimulation of the Ventralis Oralis posterior was effective to treat the tremor
We found a strong connectivity to the superior frontal gyrus
And, to a lesser extent to the precentral gyrus

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Abbreviations and Acronyms
ACC: Anterior Cingulate Cortex
CT-scan: Computed Tomography scan
DBS: Deep Brain Stimulation
dMRI: diffusion Magnetic Resonance Imaging

DTI: Diffusion Tensor Imaging
ET: Essential Tremor
FSL: FMRIB Software Library
IPG: Implantable Pulse Generator
MNI: Montreal Neurological Institute

MS: Multiple Sclerosis
PTT: Post-Traumatic Tremor
RTA: Road Traffic Accident
SMC: Supplementary motor cortex
TBI: Traumatic Brain Injury

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VAT: Volume of Activated Tissue

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MRI: Magnetic Resonance Imaging

Vim: Ventral intermediate nucleus

VOp: Ventralis oralis posterior thalamic nucleus

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ZI: Zona Incerta

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DRT: Dentate Rubrothalamic Tract