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. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT Post traumatic tremor and thalamic deep brain stimulation: evidence for use of Diffusion Tensor RI PT Imaging Sandra G. J. Boccard1*, Ph.D. & Pedro Rebelo1, B.Sc.*, Binith Cheeran1, Ph.D. MRCP, Alexander Green1, MD, James J FitzGerald1, 1 SC Ph.D., Tipu Z. Aziz1, FMedSc. Oxford Functional Neurosurgery and Experimental Neurology Group, Nuffield M AN U Departments of Clinical Neuroscience and Surgery, University of Oxford, UK * These authors contributed to the manuscript equally Corresponding author: Dr Sandra BOCCARD-BINET TE D West Wing, Level 6, John Radcliffe Hospital Headley way OX3 9DU Oxford EP sandra.boccard@ndcn.ox.ac.uk AC C Running title: DTI of post-traumatic tremor DBS Key words Post-Traumatic Tremor Deep Brain Stimulation Thalamus VOp Tractography ACCEPTED MANUSCRIPT 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 RI PT 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 SC 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 M AN U 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 TE D 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 AC C EP patient’s symptoms by DBS. ACCEPTED MANUSCRIPT 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 RI PT 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} SC 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 M AN U {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. TE D 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- EP operative tractographic analysis, indicating that DTI may be relevant in predicting AC C 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 ACCEPTED MANUSCRIPT 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 RI PT 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. SC 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 M AN U 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 TE D 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 EP representing the absence of tremor and 10 being the most severe. Ratings were based AC C 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 ACCEPTED MANUSCRIPT 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. RI PT 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 SC ventralis oralis posterior thalamic nucleus- zona incerta (VOP-ZI). The results of the surgery is presented here. Operation M AN U post-operative tractography analysis of the electrode location and outcome from The surgical technique has been described previously 13, 14. Briefly, a Cosman- TE D 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, EP UK). The electrode was then placed unilaterally in the ventalis oralis posterior AC C 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 ACCEPTED MANUSCRIPT 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 RI PT 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 SC 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 M AN U 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 TE D 0/50 on the right leg (100% improvement). Post-operative tractography study Brain images were transformed into a common coordinate space, the Montreal EP Neurological Institute (MNI) space. Subsequent coordinates are in millimetres. The deepest contact location (C0-the cathode) was found at MNI coordinates (-12, -13, -2; AC C 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 ACCEPTED MANUSCRIPT 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). RI PT 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 SC front gyrus (n=2.3) and the brain stem (n=2.3). Figure 3 displays the previously cited M AN U 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 TE D 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 EP 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 AC C 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. ACCEPTED MANUSCRIPT 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, 1 , even in patients who have no beneficial effects on tremor. RI PT 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 M AN U treat movement disorders: Parkinson disease SC 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 TE D 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 EP {Sitsapesan, 2014 #29}. Our previous experience with post traumatic patients led us to chose Vop/ZI over Vim to improve tremor {Sitsapesan, 2014 #29}. AC C 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 ACCEPTED MANUSCRIPT 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 RI PT 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 SC success of the stimulation at reducing the tremor. It is not uncommon to have multiple lesions in the brain after a severe head injury, M AN U 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 TE D 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 EP effective in reducing PTT, clinicians should consider implementing preoperative tractography to verify that the connectivity between the most relevant structures are AC C preserved. ACCEPTED MANUSCRIPT 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. AC C EP TE D M AN U SC RI PT 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. ACCEPTED MANUSCRIPT FIGURES LEGENDE RI PT 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). M AN U SC 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. AC C EP TE D 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. 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Individual fiber anatomy of the subthalamic region revealed with diffusion tensor imaging: a concept to identify the deep brain stimulation target for tremor suppression. Neurosurgery. Apr 2011;68(4):1069-1075; discussion 1075-1066. Coenen VA, Allert N, Madler B. A role of diffusion tensor imaging fiber tracking in deep brain stimulation surgery: DBS of the dentato-rubrothalamic tract (drt) for the treatment of therapy-refractory tremor. Acta neurochirurgica. Aug 2011;153(8):1579-1585; discussion 1585. ACCEPTED MANUSCRIPT 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 RI PT Areas AC C EP TE D M AN U SC Table 1. Connectivity between the electrode and the brain areas Sup Front Gyrus, Superior frontal gyrus; SMC, Supplementary motor cortex; ACC, Anterior Cingulate Cortex. AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT ACCEPTED MANUSCRIPT Highlights EP TE D M AN U SC RI PT 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 AC C • • • • ACCEPTED MANUSCRIPT 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 TE D VAT: Volume of Activated Tissue M AN U MRI: Magnetic Resonance Imaging Vim: Ventral intermediate nucleus VOp: Ventralis oralis posterior thalamic nucleus AC C EP ZI: Zona Incerta SC RI PT DRT: Dentate Rubrothalamic Tract