Posterolateral Trajectories Favor a Longer Motor Domain in Subthalamic Nucleus Deep Brain Stimulation for Parkinson Disease

Accepted Manuscript Posterolateral trajectories favor a longer motor domain in STN DBS for Parkinson’s disease Idit Tamir, Odeya Marmor-Levin, Renana Eitan, Hagai Bergman, Zvi Israel PII:

S1878-8750(17)31086-0

DOI:

10.1016/j.wneu.2017.06.178

Reference:

WNEU 6049

To appear in:

World Neurosurgery

Received Date: 21 March 2017 Revised Date:

26 June 2017

Accepted Date: 29 June 2017

Please cite this article as: Tamir I, Marmor-Levin O, Eitan R, Bergman H, Israel Z, Posterolateral trajectories favor a longer motor domain in STN DBS for Parkinson’s disease, World Neurosurgery (2017), doi: 10.1016/j.wneu.2017.06.178. 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 Tamir Title: Posterolateral trajectories favor a longer motor domain in STN DBS for

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Parkinson’s disease

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Authors: Idit Tamir1,2,4, Odeya Marmor-Levin2, Renana Eitan3, Hagai Bergman2,3

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and Zvi Israel4

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5 Affiliations:

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1 – Department of Neurological Surgery, University of California San Francisco, San

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Francisco, CA, USA. Postal address: 505 Paranassus St. San Francisco, California, 94143

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(present address)

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2 – Department of Medical Neurobiology, Hadassah Hebrew University Medical Center,

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Jerusalem, Israel. POB 12271, ZIP 9112102.

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3 – Edmond and Lily Safra Center for Brain Research, The Hebrew University, Ein Krem

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Campus, Jerusalem, Israel. POB 12271, ZIP 9112102.

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4 – Department of Neurosurgery, Center for Functional and Restorative Neurosurgery,

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Hadassah-Hebrew University Medical Center, Jerusalem, Israel, 91120.

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ACCEPTED MANUSCRIPT Tamir Corresponding author:

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Dr. Idit Tamir, MD, PhD. Department of Neurosurgery, Center for Functional and

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Restorative Neurosurgery, Hadassah-Hebrew University Medical Center, Jerusalem,

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Israel, 91120. Email address: [email protected].

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26 Odeya Marmor-Levin, M.sc. [email protected]

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Renana Eitan, MD. [email protected]

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Hagai Bergman, MD, PhD. [email protected]

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Zvi Israel, MD. [email protected]

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Funding

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This research was supported by the following grants:

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1. Adelis Foundation and Israel-US Binational Science Foundation (BSF) to ZI, RE and HB.

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2. The Israel Science Foundation (ISF).

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3. The German Israel Science Foundation (GIF).

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4. The Canadian friends of the Hebrew university.

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5. The Rosetrees and Vorst Foundations.

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6. The Simone and Bernard Guttman chair in research – to HB

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ACCEPTED MANUSCRIPT Tamir Abstract

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Objective: The clinical outcome of Parkinson's disease (PD) patients that undergo

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Subthalamic Nucleus Deep Brain Stimulation (STN DBS) is, in part, determined by the

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length of the electrode trajectory through the motor STN domain, the Dorso-Lateral

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Oscillatory Region (DLOR). Trajectory length has been found to correlate with the

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stimulation-related improvement in patients’ motor function (estimated by part III of the

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United Parkinson’s Disease Rating Score (UPDRS)). Therefore, it seems that ideally

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trajectories should have maximal DLOR length.

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Methods: We retrospectively studied the influence of various anatomical aspects of PD

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patients’ brains and the geometry of trajectories planned on the length of the DLOR and

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STN recorded during DBS surgery. We examined 212 trajectories and 424 electrode

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MER tracks in 115 patients operated in our center between the years 2010 and 2015.

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Results: We found a strong correlation between the length of the recorded DLOR and

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STN. Trajectories that were more lateral and/or posterior in orientation had a longer STN

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and DLOR pass, although the DLOR/STN fraction length (%DLOR) remained constant.

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The STN target was more lateral when the third ventricle was wider, and the latter

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correlated with older age and male gender.

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Conclusions: Trajectory angles correlate with the recorded STN and DLOR lengths, and

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should be altered toward a more posterolateral angle in older patients and atrophied

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brains in order to compensate for the changes in STN location and geometry. These fine

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adjustments should yield a longer motor domain pass, thereby improving the patient's

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predicted outcome.

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Keywords: STN; Beta oscillations; DBS; Parkinson’s disease; LFP; Trajectory

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Introduction

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It is generally accepted that precise lead location in STN DBS will determine 1

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motor outcome in PD patients

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(motor) score.

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most centers target the dorsal motor part of the STN, some aim to different targets,

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including extra-STN areas, such as the Zona Incerta. 4-6 Therefore, it should come as little

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surprise that several studies have failed to find an association between changes in

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UPDRS scores and target coordinates.

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between UPDRS scores and beta band oscillatory activity in the STN DLOR.

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Therefore, the DLOR area, representing the motor sub-division of the STN, is believed to

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be the preferred target for DBS implantation. 10 11

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While

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The optimal STN target is a subject of unresolved controversy.

Other studies have shown a strong association 8 9

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as validated by improvement in the UPDRS part III

By this reasoning, directing implantation of the lead contacts to the longest

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recordable DLOR should be a central operative objective. Anatomical MRIs used for pre-

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operative target and trajectory planning as well as Diffuse Tensor Imaging (DTI)

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protocols are not yet routinely capable of differentiating between sub-territories of the

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STN.

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DLOR target thus avoiding suboptimal clinical results.

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Factors affecting STN targeting are thought to include variable target selection between

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different neurosurgeons,

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(MER),

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and awake MER-guided vs. asleep intraoperative Magnetic Resonance Imaging (iMRI) -

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guided DBS implantation. 21-23 Some papers discuss trajectory planning in the context of

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adverse effects,

Therefore, MER is still the only method to accurately detect and validate the

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effects of anesthesia on STN Microelectrode Recording

the type of imaging used for pre-op planning of target and trajectory,

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due to proximity to blood vessels, eloquent brain areas and the

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ventricles, and others discuss trajectory planning for DBS targets other than STN, such as

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Globus Pallidum internus (GPi)

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investigated the effects of patient-specific characteristics on STN geometry as revealed

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by intra-operative STN physiological recordings.

and Vim

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. However, none of these studies have

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The STN, first characterized by Jules in 1865, is a lens shaped diencephalic structure. It contains around 430,000 neurons, comprising a volume of 100-130 mm3.

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The STN lies between the Zona Incerta postero-dorsally, the Internal Capsule laterally

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and the Substantia Nigra antero-ventrally. Its long axis extends from anterolateral (in its

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dorsal portion) to posteromedial (in its ventral portion). Despite its preserved anatomy

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across species, some variation in its postural angle is evident within and between patients.

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Age has a particularly important effect on the anatomy of the STN in both healthy

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human subjects as well as in PD patients. The volume of the STN as well as its neuronal

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count decreases with age, with small variations between healthy human subjects.

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distance of the STN from the mid-sagittal plane increases with age, becoming more

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lateralized. The latter finding is observed in PD patients as well as in healthy controls. 30

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The

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In addition to age-related STN changes, other sub-cortical structures also tend to

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change morphometrically with age. These include decreased thalamic height and

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increased third ventricle width. In contrast, the AC-PC (Anterior Commissure – Posterior

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Commissure) length seems to be stable within various age groups. 31 All these anatomical

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alterations inevitably affect the way we target the STN and plan out trajectories.

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Intuitively, they should also have impact on the recorded STN length, and may have an

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effect on DLOR length as well. Brain atlases (Schaltenbrand-Warren and Schaltenbrand

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Bailey) that were based on a limited, non-diverse patient population, and are still being

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used for indirect targeting by some centers, should be viewed as inherently inaccurate. Driven by the finding that STN beta activity is directly correlated with the clinical

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outcome of PD patients undergoing STN DBS, 8 and by a recent case report that indicated

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a dramatic effect of trajectory angles on the side effects profile of the STN DBS,

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investigated the possible contribution of patient-specific demographic and anatomic

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factors on intra-operative STN physiology. We studied the contribution of three groups of

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factors: 1) Demographic: patients’ age, gender, and PD duration. 2) Anatomic: third

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ventricle length (AC-PC length), third ventricle width (both maximal width and width at

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mid-commissural point; MCP), and laterality (right vs. left hemisphere, and first vs.

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second operated side). 3) Trajectory-related: antero-posterior (ring) and medio-lateral

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(arc) trajectory angles used to target the STN, and microelectrode location (relative to the

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Microdrive’s BenGun central track).

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ACCEPTED MANUSCRIPT Tamir Methods

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Data Collection

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This study was authorized and supervised by the Institutional Review Board (IRB) of

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Hadassah Medical Center (reference code: 0168-10-HMO). The charts and operative

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reports of all PD patients who had undergone STN DBS at the Hadassah Hebrew

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university medical center in the years 2010-2015 were retrospectively reviewed. All

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patients signed informed consent and release forms for participating in studies that

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include analysis of data related to their clinical records and MERs.

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Overall, 115 patient datasets were included in this study. Most patients were

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implanted bilaterally, usually both sides in the same session or in some cases as a staged

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procedure. “Trajectory” was defined as a single pass to the target, having a specific set of

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trajectory angles (arc and ring). Routinely, we use two micro-electrodes in the BenGun,

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thus all trajectories had two MER datasets: one located centrally in the BenGun, and the

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other being either anterior (ventral) or posterior (dorsal) to the central microelectrode.

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Most patients had one pass to each brain target (right or left). However, a few patients

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required a second pass, due to unsatisfactory microelectrode recordings or clinical

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response to macro-stimulation in the first one. In these cases, a new set of trajectory

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angles might be used. Overall, 212 trajectories and 424 MER tracks were included in our

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data analysis.

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DBS surgery and MER

Surgery and MER techniques used are similar to those previously reported.

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Briefly, stereotactic localization was performed based on fusion of pre-operative

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ACCEPTED MANUSCRIPT Tamir Magnetic Resonance Imaging (MRI; either 1.5 or 3T axial and coronal slices using

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2*0.4*0.4 mm isotropic T1 and T2 weighted MR sequences) and stereotactic Computed

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Tomography (CT; performed on the morning of surgery, after fixation of a CRW

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(Cosman Robert Wells) stereotactic frame (Radionics, Burlington, MA, USA)), using

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Framelink 5 software (Medtronic, Minneapolis, USA).

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STN target coordinates were chosen based on direct visualization on the T2 MRI

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(targeting for the posterior dorsolateral STN). Trajectories were planned to avoid

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penetrating sulci, ventricles, blood vessels (as seen in T1 MRI with contrast media) and

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also eloquent brain areas. In some cases, trajectory angles were slightly modified during

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surgery, due to cortical blood vessels. Both the pre-operative targeting coordinates and

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MER- defined STN borders used in the analysis were those originally used for planning

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and treatment, and thus were blind to the goals of this study.

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MER was used in all patients to identify the STN DLOR for implantation of the

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DBS lead. MER was performed while the patients were awake (no sedation was given

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prior to recordings), and off dopaminergic medications (for at least 12 hours). The

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planned trajectory was used to insert two microelectrodes: one at the center and the

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second two mm apart, either anterior (ventral) or posterior (dorsal) to the central

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electrode. Overall, we had 212 central, 157 anterior and 55 posterior MER tracks. In all

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cases, recordings started at 10 mm above the planned target. This starting point fitted our

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targeting method in a way that we always encountered the STN at least a few millimeters

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below our starting point. Recorded data was acquired using MicroGuide and Neuro-

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omega systems (AlphaOmega Engineering, Nazareth, Israel). Neurophysiological activity

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was recorded via polyamide coated tungsten microelectrodes (Alpha Omega) with

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ACCEPTED MANUSCRIPT Tamir impedances ranging between 0.3-0.9 megaOhms (measured at 1 kHz at the beginning of

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each trajectory). The signal was amplified, band-passed from 250 to 6000 Hz (using a

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hardware four-pole Butterworth filter), and sampled at 48 kHz by a 12- or 16-bit Analog

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to Digital Converter.

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Spontaneous and evoked STN multi-unit MER activity was recorded. While in the

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STN, the two electrodes were simultaneously advanced in small discrete steps of ∼0.1

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mm.

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as a sharp increase and decrease in the background activity, respectively. The STN

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boundaries and the dorsolateral oscillatory region were further confirmed using a method

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for automatic detection of STN and DLOR borders.

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used to detect DLOR and STN borders are found in previous papers of our group. 33

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The STN entry and exit points were discerned visually by the neurophysiologist

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181 MER data analysis

Further details of the methods

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For each MER track, we calculated the STN length, the DLOR length and the

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fraction of the DLOR length out of STN length (%DLOR). Due to the insertion of two

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parallel microelectrodes in the microdrive for every trajectory, each trajectory included

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two distinct MER datasets, one from each microelectrode. Inasmuch as only the central

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microelectrode was truly directed toward the preoperatively defined target (and to a 2

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mm shifted target as the other non-central ones), we used only the central MER track for

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all statistical analysis. The non-central MER track was used only when a comparison was

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made between the central and the non-central MER tracks. In some trajectories, the

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central microelectrode failed to record STN activity. These trajectories were omitted for

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STN analysis (either averaging or correlations). Similarly, some central MER tracks

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failed to record oscillatory activity despite good STN recordings. These trajectories were

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omitted from the DLOR analysis. These “failed” STN and DLOR MER tracks were

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analyzed separately in regards to possible differences in trajectory angles.

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196 Demographic and Anatomic Patients Data

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Data extracted from the subjects’ medical records included: age at time of implantation,

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gender, Parkinson’s disease duration, and laterality of implantation (right vs. left

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hemisphere implantation).

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The AC-PC length, the AC-PC coordinates of the lead target (xyz), the two

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trajectory angles (angle 1=arc, i.e., lateral to the mid sagittal plane; angle 2=ring, i.e.,

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posterior to the anterior portion of the “axial” AC-PC plane), the length of the recorded

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STN (by MER), and the order of the implanted leads (the side operated and implanted

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first) were all extracted from the operative report. No correction was made for intra-

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operative fine tuning of the trajectory angles due to cortical vessels. However, these

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changes were very small (less than one degree) and unusual as most superficial vessels

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can be detected and avoided in the pre-operative planning session.

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The third ventricle length was defined as the AC-PC distance, as both AC and PC were

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marked at the anterior and posterior borders of the third ventricle, respectively. In order

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to unify the third ventricle length measurements, a single neurosurgeon (ZI) defined the

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AC and PC location for all patients, extracting the AC-PC length.

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Finally, the pre-op MRI (axial T2 and T1+Gadolinium protocol) was used in order to

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measure third ventricular width. This was measured by a single neurosurgeon (IT), in two

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different ways: as the maximal third ventricular width, and as the width at MCP. The two

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measurement methods were compared in relation to the other parameters to further

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improve the reliability of these measurements.

218 Statistical Analysis

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A statistical software program SigmaStat (Ver. 4, Systat software Inc.; San Jose,

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CA, USA) was used to determine potential interaction between age, gender, laterality,

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third ventricular width and length, AC-PC coordinates, STN and DLOR length, and

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trajectory angles.

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Each of the measured parameters mentioned above passed normality test

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(Kolmogorov-Smirnov test). Then, multiple linear regression analysis was performed

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with each of the trajectory angles as a function of age, gender, laterality, disease duration,

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third ventricle width and length, STN and DLOR length and relative DLOR length (as a

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% of STN length).

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As there were no obvious nonlinear relationships seen, a linear regression analysis

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was chosen for ease of interpretation. The suitability of a linear fit was further determined

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by the Constant Variance test and the Durbin Watson Statistic. Pearson’s r correlation

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coefficient was used to determine the strength of correlation between the individual

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factors (age, target coordinates, third ventricle width and length, disease duration, and the

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two trajectory angles). Statistical significance was defined as p < 0.05.

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Results

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Patients’ clinical and anatomical characteristics Overall, 115 patients (74 males and 41 females) fitted the study inclusion criteria.

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Table 1 summarizes the demographic and anatomic characteristics of these patients. The

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average values are aligned with the numbers reported previously in the DBS and

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anatomical literature.

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(Table 2), despite a slightly younger age at surgery.

Interestingly, men had larger third ventricles than women

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………..Table 1 near here …………..

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STN Target and trajectory coordinates

The AC-PC coordinates of the STN target are summarized in Table 2. Overall,

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these values are in agreement with the Schaltenbrand-Wahren atlas STN coordinates as

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well as other previous studies in the DBS literature.

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lateralized STN than women (Table 2), in line with the finding of wider third ventricle in

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men. Other AC-PC related coordinates were similar in men and women.

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Interestingly, men had a more

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The two trajectory angles are summarized in Table 3 (arc=angle 1, i.e., lateral to

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the mid sagittal plane; ring=angle 2, i.e., posterior to the anterior portion of the “axial”

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AC-PC plane). These angles were planned in a way to allow a maximal yet safe intra-

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nuclear trajectory. Overall, they fit a traditional frontal bi-oblique approach to STN.

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patient. The trajectory avoids penetration of the ventricular system, crossing cortical and

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subcortical blood vessels, eloquent brain areas, and the caudate nucleus. It sometimes

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crosses the lateral border of the Thalamus.

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The 3389 Medtronic lead is implanted so that the second contact (contact 1,

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contact 0 is the most ventral) will cover the center and lower half of the DLOR,

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according to the MER data of the same patient. The volumetric segmentation of the STN

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on top of T2 MRI was done using a prediction framework of subcortical structures based

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on PD patients’ 7 Tesla MRI data base.

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269 STN and DLOR recordings

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The recorded STN lengths, DLOR length and %DLOR (fraction of DLOR length

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out of STN length in percentage) for the central and non-central electrodes are

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summarized in Table 4. Interestingly, the central electrode recorded on average

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significantly longer STN and DLOR lengths (Table 4), while the %DLOR was not

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significantly different between the two. In 35% of trajectories the recorded STN length

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was longer in the non-central electrode, while in 37% of the trajectories the recorded

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DLOR length was longer in the non-central electrode.

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Association between recorded DLOR length and STN length We found a strong and significantly positive correlation between the STN

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recorded length and the DLOR recorded length (Fig. 2A). Omitting the MER tracks in

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which no DLOR was identified did not significantly change this correlation (Fig. 2B).

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A significant positive correlation was found between the DLOR (as a percentile

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fraction of the STN (%DLOR; see Methods) and the recorded STN length (Fig. 2C).

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However, when omitting the MER epochs that failed to detect DLOR activity, no

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correlation was found between STN length and %DLOR (Fig. 2D). To summarize, when

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DLOR was detected in the MER, its length increased linearly with the recorded STN

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length and the DLOR fraction remained unchanged.

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Next, we addressed the clinical relevance of longer STN and DLOR trajectories in

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DBS surgeries. We studied the correlation between the patients’ response to dopamine

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(pre-operative off – pre operative on medication UPDRS) and the recorded STN and

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DLOR lengths. We found a significant positive correlation between the right hemibody

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UPDRS scores and the left brain recorded STN lengths (Figure 2E) and DLOR lengths

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(Figure 2F). However, we were not able to detect similar significant correlations on the

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opposite side.

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Previous studies of our group showed highly significant positive correlation

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between the post-operative improvement in UPDRS (on vs. off medication and

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stimulation) and the DLOR length (r=0.67, p<0.001).

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longer STN trajectories will result in longer DLORs and better clinical outcome.

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Accordingly, we suggest that

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………..Fig. 2 near here …………..

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The effect of Trajectory angles on MER Due to the three dimensional (3D) complexity of the STN anatomy and trajectory

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parameters, we chose to look at each trajectory angle separately. All correlation data and

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significance are summarized in Table 5. We found a positive correlation between STN as

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well as DLOR lengths and the arc angle, meaning that STN and DLOR lengths increase

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as the trajectory becomes more laterally oriented. In contrast, the %DLOR was not

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correlated with arc angle. STN length, but not DLOR length or %DLOR, was also

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correlated with the ring angle. Together, these results mean that posterolateral trajectories

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tend to have a longer recorded STN, and more laterally oriented trajectories (regardless of

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the anteroposterior angle) also have a longer DLOR. However, the fraction of DLOR out

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of STN was independent of trajectory angles.

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Trajectories in which the central microelectrode failed to record any STN activity

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were slightly more anterior than trajectories that yielded STN recordings (Fig. 3A). No

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difference was found in regards to laterality between successful STN trajectories and

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failed ones (Fig. 3A). Interestingly, trajectories in which the central microelectrode failed

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to identify DLOR were significantly more medial (Fig. 3A) and slightly more anterior

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(Fig. 3A) than trajectories that succeeded in recording DLOR activity. Taken together,

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these data suggest higher failure rates for STN and/or DLOR detection in anteromedial

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trajectories. Still, the reported trajectory angles are within the standard trans-frontal

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approach angles to the STN.

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………..Table 5 near here …………..

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According to previous studies, showing an enlarged lateral and third ventricle in 42 43

atrophied brains

we suspected lead trajectories in patients with brain atrophy to be

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more laterally oriented. Surprisingly, there was no association between laterality of

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trajectories and third ventricular width, or laterality of trajectories and laterality of STN

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target (Table 5). On the other hand, we did observe an association between third

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ventricular length and anteriorly displaced trajectories angles (Table 5).

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We then combined the two trajectory angles by multiplication to create a vector

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directed to the STN. This choice was based on the working assumption that postero-

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lateral trajectories are more likely to parallel the long axis of the STN, and therefore more

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likely to result in a longer pass of the electrode through the STN. In addition, the beta

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oscillatory region of the STN is thought to be located on the dorso-lateral (postero-

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superior) aspect of the STN.

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We found a positive correlation between the STN length and the trajectory vector

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(Fig. 3B). However, when we omitted the MER tracks that failed to detect the DLOR, the

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correlation between STN length and trajectory vector did not reach statistical significance

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(Fig. 3C). Therefore, we suspected a positive correlation between STN length in failed

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DLOR trajectories and trajectory vectors. Indeed, we found a significant correlation

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between the two (Fig. 3D).

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Similarly, DLOR length was positively correlated with the trajectory vector when

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failed DLOR trajectories were included (Fig. 3E), but not correlated when failed DLOR

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trajectories were omitted from the correlation (Fig. 3F). Also DLOR fraction was

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positively correlated with trajectory vector when failed DLOR trajectories were included

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(Fig. 3G), but not when they were omitted (Fig. 3H).

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………..Fig. 3 near here …………..

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The effect of patient- and disease- specific characteristics on MER

Correlations of other variables that might contribute to the diversity of the STN

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and DLOR recorded length between patients are presented in Fig. 4. These included

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patient-specific clinical parameters, anatomy-related parameters, and 3D planning-related

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parameters.

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Regarding patient-specific parameters, the age of the patients at the time of

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surgery was not correlated with either STN length (Fig. 4A) or DLOR length (Fig. 4B).

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However, when omitting failed DLOR MER tracks, there was a trend towards negative

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correlation between patients’ age and DLOR length (Fig. 4C). Similarly, disease duration

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was not significantly correlated with either STN length (Fig. 4D) or DLOR length (Fig.

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4E). Omitting the failed DLOR MER tracks did not change the lack of correlation

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between DLOR length and disease duration (Fig. 4F).

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STN length and DLOR length were not significantly different between right and

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left hemisphere recordings (Fig. 4G). Also the %DLOR was not significantly different

369

between right and left sides (43±27% vs. 43±25%, p = 0.33, respectively; Data not

370

shown). In addition, the STN and DLOR lengths and the %DLOR were not significantly

371

different between the side that was operated first (n=147 trajectories) or the second

372

operated side (n = 65 trajectories; includes only patients that were operated bilaterally on

18

ACCEPTED MANUSCRIPT Tamir the same day; STN length: 5.4 ± 1.6 mm vs. 5.24 ± 1.7 mm, respectively, p = 0.26;

374

DLOR length: 2.96 ± 1.2 mm vs. 2.88 ± 1.2 mm, respectively, p = 0.33; %DLOR: 52.9 ±

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17.8% vs. 53.8 ± 19.4%, respectively, p = 0.38). However, the fraction of failed STN and

376

DLOR MER tracks (when considering only the central MER tracks) was slightly higher

377

on the second operated side than on the first one (failed STN: 9.23% vs. 7.48%; failed

378

DLOR: 13.4% vs. 11.0%, respectively).

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Finally, no differences were found in STN length and DLOR length between men

380

and women (Fig. 4H). Also %DLOR was not different between men and women (47.7%

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vs. 45.7%, p = 0.6, respectively; Data not shown).

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………..Fig. 4 near here …………..

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The effect of anatomy- specific characteristics on MER

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We next studied the contribution of ventricular size variability to the recorded

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STN and DLOR lengths. According to the literature, the variability in human ventricular

388

system between patients is related to differences in brain volume, size, age and brain

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atrophy. 31 42 43 Third ventricle width is a commonly used quantification measure, among

390

others, such as frontal horn index, Evans’ index, sulci width, and sub-arachnoid space

391

size.

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ventricle width and length as our measures to explore atrophy-related variability in STN

393

targeting.

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31 42 43

Due to the proximity of the STN to the third ventricle, we chose third

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ACCEPTED MANUSCRIPT Tamir 394

We found no correlation between either STN, or DLOR lengths and third

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ventricle length (Fig. 5A and Fig. 5B, respectively). Omitting failed DLOR MER tracks

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from the correlation analysis did not change these results (Fig. 5C). Third ventricle width measurements were not correlated with STN or DLOR

398

length, whichever one of the two measuring methods was used (Width at MCP: Fig. 5D;

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maximal width: Fig. 5E, Maximal width vs. STN length and Maximal width vs. DLOR

400

length: Table 5). Omitting the failed DLOR MER tracks from the correlation in fig. 5E

401

did not alter the results (Fig. 5F).

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Taken together, we conclude that in patients with atrophied brains an

403

“unintentional” lateral correction of the trajectory angle was used in the pre-op planning

404

in order to get a maximal intra-nuclear trajectory. Therefore, no marked differences in

405

STN or DLOR lengths were found in these patients.

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In order to specify which electrode position (either the central microelectrode

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position or the non-central (anterior/posterior) electrode) better targets the STN, we

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compared the length of STN and DLOR recorded in the central electrode (black bars)

409

with the ones recorded at the non-central electrodes (white bars). We found significantly

410

longer STN and DLOR trajectories at the central electrode compare to the non-central

411

one (Figure 5G). In addition, the fraction of the recorded DLOR out of STN was higher

412

in the central electrode compared to the non-central one (43 ± 26% vs. 33 ± 32%, p =

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0.03).

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To further analyze this data, we divided the non-central electrode group into two

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subgroups: anterior electrode position (used in our center until November 2014) and

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posterior electrode position (subsequent to Nov 2014; see Methods). We found no

20

ACCEPTED MANUSCRIPT Tamir difference between the average length of recorded STN in these two groups (4.4 ± 2.2

418

mm vs. 4.9 ± 1.8 mm, respectively; n=142 and n=54, respectively; p = 0.13). Robust

419

changes in DLOR length (anterior electrodes: 1.89±1.5 mm; posterior electrodes:

420

2.72±1.6 mm; p = 0.002) and %DLOR (anterior electrodes: 40.34 ± 32%; posterior

421

electrodes: 52.73 ± 26%; p = 0.01) were however detected between these two groups, to

422

favor the posterior trajectories.

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………..Fig. 5 near here …………..

426

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Anatomy considerations for targeting purposes

Brain atrophy is a prominent consideration in DBS surgery. Not only may the

428

cortical entry point be deeper to the skull burr-hole and the dural opening, also the brain

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target might have distorted relations to its surroundings. To clarify this, we studied the

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relationship between the AC-PC coordinates of the STN target (xyz) and the various

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parameters mentioned earlier.

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The x parameter (which represents the laterality of the target) was positively

433

correlated with the third ventricle width (Fig. 5H), and to a lesser extent also with the

434

third ventricle length (Fig. 5I). This means a more laterally positioned STN as the third

435

ventricle enlarges. Despite these results, we did not find any correlation between x and

436

patient age or PD duration (Table 5).

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The y parameter (represents the antero-posterior dimension) was slightly

438

correlated with age, but not correlated with disease duration, third ventricle length or

439

third ventricle width (Table 5).

21

ACCEPTED MANUSCRIPT Tamir 440

The z parameter (representing the rostro-caudal dimension) was significantly

441

correlated with disease duration and third ventricle width, but not with age or third

442

ventricle length (Table 5). We next studied the possible contribution of the targeting coordinates to the

444

variability of the STN and DLOR lengths. However, none of these multiple comparisons

445

yielded a significant effect of targeting on the MERs (Table 5).

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In order to identify a possible contribution of selected STN target coordinates to

447

trajectory failures, we compared AC-PC coordinates between MER tracks that

448

successfully recorded STN activity and those that failed to detect STN activity. However,

449

no significant differences were found between AC-PC target coordinates of the two sub-

450

groups (x: 11.96 ± 0.7 vs. 11.96 ± 0.6 mm, respectively, p = 0.5; Y: -3.19 ± 1.0 vs. 3.43 ±

451

0.5 mm, respectively, p = 0.18; Z: -4.54 ± 1.5 vs. -4.62 ± 0.7 mm, respectively, p = 0.4).

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A similar comparison was conducted between successful DLOR identifying MER

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tracks and DLOR failure sets. No differences were found in AC-PC coordinates between

454

the groups (x: 11.96 ± 0.7 vs. 11.82 ± 0.8 mm, respectively, p = 0.19; Y: -3.22 ± 1.0 vs. -

455

3.19 ± 1.0 mm, respectively, p = 0.47; Z: -4.59 ± 1.4 vs. 4.32±2.2 mm, respectively, p =

456

0.2).

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ACCEPTED MANUSCRIPT Tamir 457

Discussion This study shows for the first time that recorded STN DLOR (STN motor

459

domain) length is primarily determined by the STN length. The chosen trajectory angles

460

affect STN and DLOR lengths, favoring postero-lateral trajectories that tend to have

461

longer STNs and DLORs, while antero-medial ones tend to “fail” more often in detecting

462

STN and/or oscillatory (motor) activities. Nevertheless, atrophy-related changes in STN

463

geometry do not seem to alter the chosen trajectories. In patients with larger ventricles,

464

the STN target itself seems to shift laterally such that trajectory angles are not altered,

465

and the resulting STN and DLOR recorded lengths remain without significant change.

466

This scenario of enlarged ventricles seems to be more frequent in men than in women,

467

despite younger age and similar disease duration at surgery.

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468

DLOR-to-STN ratio is highest in the center of the STN and stable across different

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trajectories

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This study further provides compelling evidence that the beta oscillatory region of

472

the STN is located at the dorsal postero-lateral part of the nucleus. We show for the first

473

time that DLOR-to-STN proportion is stable across different trajectories. Therefore,

474

aiming for the longest STN trajectory should also result in a longer DLOR.

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Another interesting finding is the larger fraction of DLOR in the centrally-located

476

electrode in comparison with the peripherally (either anterior or posterior) located ones.

477

Since our target is planned to enter the center of the DLOR, these results suggest that the

478

oscillatory region is longer in the center of the postero-dorsolateral region of the STN

479

compared to the periphery of the nucleus. This is in agreement with a stronger beta signal

23

ACCEPTED MANUSCRIPT Tamir 480

(either power or coherence extracted from LFP signal or single unit analysis) in the

481

central trajectories, decreasing in strength from dorsal to ventral (along the recording

482

electrode path in the STN).

483

dorsolateral motor beta oscillatory activity toward the center of the dorsolateral STN

484

compared to its periphery. Therefore, in order to achieve maximal stimulation of the STN

485

motor area and inhibition of beta hyper-synchronized activity, the lead should be directed

486

to the center of the dorsolateral STN.

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Together, these data might suggest a higher density of

SC

44-46

This notion might be particularly important for future applications of multiple -

488

contact current steering electrodes and closed-loop DBS systems that rely on dorsolateral

489

STN beta power - derived algorithms for stimulus adaptation. 47 48 Such systems require a

490

reliable, strong and stable signal and a high signal to noise ratio. For this reason, precise

491

targeting of the DLOR is essential.

493

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STN and DLOR recorded lengths are larger in posterolateral trajectories Postero-lateral trajectories record longer STN and DLOR activity. Moreover,

495

these trajectories tend less to “fail”, in terms of detecting any STN and/or beta oscillatory

496

activity. This notion is true, despite significant variability of STN target coordinates

497

across patients. Most probably, postero-lateral trajectories follow the long axis of the

498

STN in the 3D space, therefore yielding longer recordings. However, DLOR geometry

499

might be more complex than that.

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Medial trajectories have been shown in the past to be less favorable due to worse 25

501

cognitive outcome, possibly due to penetration of the caudate nucleus.

502

these findings may also be attributed to a presumed longer pass through the ventromedial

24

Nevertheless,

ACCEPTED MANUSCRIPT Tamir ‘limbic/cognitive’ part of the STN when medial trajectories are used. Taken together with

504

our results, it might be beneficial in terms of targeting the oscillatory region, to aim for a

505

more postero-lateral trajectory. However, this should not, in any way, be considered as a

506

compensation for accidentally targeting the ventro-medial STN.

507 508

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Atrophy-related changes in STN geometry alter DBS target but not trajectory

An intuitive assumption that we had prior to this study was the tendency toward

510

more lateralized trajectory angles in older patients. We assumed older patients to have

511

larger ventricles, therefore forcing a more lateralized trajectory angle to the STN.

512

Surprisingly, we found that the trajectory angles were independent of ventricle size.

513

However, the STN target itself did show significant lateralization with increasing

514

ventricular size. This finding supports similar previous reports in the literature. 30 36 39 41

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We could not find any association between patients’ age and ventricular size or

516

target lateralization. This is in contrast to recent studies showing that the STN target

517

becomes more lateral with age in PD patients, either by using pre-operative planning or

518

post-operative results to define actual STN target location.

519

factors, such as disease severity or age at diagnosis, may explain brain atrophy changes in

520

this patient population.

Other contributing

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30 49

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Overall, our data led us to conclude that the lateralization shift of the STN target

522

compensates for the need of more lateralized trajectory angles. Due to the lateral shift of

523

the STN target and the more lateralized borders of the third ventricles, the distance

524

between these two intuitively should remain constant. This could be used as an extra

525

safety measure of target coordinates, but requires further study.

25

ACCEPTED MANUSCRIPT Tamir The laterality of the STN target in our study was also correlated with third

527

ventricle length, although to a lesser extent than width, meaning a more lateralized STN

528

target with longer third ventricles. The third ventricle length in general is a measure of

529

brain length and overall brain size 37 31 and is less likely to vary across patients, although

530

some studies have found such variability with age.

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We found men to have larger third ventricles than women (both length and

532

width), despite a slightly younger age at surgery. This finding is in accordance with

533

previous anatomical studies of normal brains revealing larger ventricles in men, measured

534

both directly and relative to brain size. 43 50

536 537

Study Importance and Limitations

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These results emphasize the importance of using microelectrode spike and Local Field Potential (LFP) recordings to guide electrode implantation in DBS surgery for PD.

539

Nevertheless, this study has several limitations. Analysis of the electrophysiology yields

540

the “functional” borders of the STN, while the anatomical STN borders as per their

541

appearance on imaging were not directly studied. Also the 3D relations between the

542

electrode trajectory and the STN anatomical borders were not thoroughly studied.

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This study did not attempt to correlate patient outcomes (pre/ post- surgery and

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544

on/off state - UPDRS scores), beta power and coherence with trajectory angles. In

545

addition, the results of this study have clinical implications only if the STN targeting

546

method used is directed to the DLOR, and if direct stimulation of the DLOR has clinical

547

benefit.

26

ACCEPTED MANUSCRIPT Tamir In addition, we cannot exclude the possibility that different parameters have

549

opposing effects. For example, brain atrophy may increase beta–band oscillatory activity

550

as part of disease progression, but also decrease STN volume and length. These

551

contradictory effects might obscure some of the correlations studied. Future studies

552

should try to overcome these obstacles.

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548

Finally, it is possible that minor differences in the recorded STN length are

554

negligible when inducing large electrical fields, especially with the current electrodes

555

available. Larger prospective studies, including post-operative UPDRS clinical data and

556

different lead types should be conducted in order to address these important questions.

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ACCEPTED MANUSCRIPT Tamir Acknowledgements

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The authors thank Dr. Noam Harel (Center for Magnetic Resonance Research, University

560

of Minnesota Medical School, Minneapolis, MN, USA) for his kindness to provide us

561

with figure 1.

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ACCEPTED MANUSCRIPT Tamir 562

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oscillatory activity in parkinsonian akinetic-rigid type and mixed type. Int J

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Neurosci. 2016; 126:819-828.

47. West T, Farmer S, Berthouze L, Jha A, Beudel M, Foltynie T et al. The Parkinsonian

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Subthalamic

Network:

Measures

of

Power,

Linear,

and

Non-linear

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Synchronization and their Relationship to L-DOPA Treatment and OFF State

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Motor Severity. Front Hum Neurosci. 2016; 10:517.

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48. Bour LJ, Lourens MA, Verhagen R, de Bie RM, van den Munckhof P, Schuurman PR

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et al. Directional Recording of Subthalamic Spectral Power Densities in

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Parkinson's Disease and the Effect of Steering Deep Brain Stimulation. Brain Stimul. 2015; 8:730-741.

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49. Keuken MC, Bazin PL, Schafer A, Neumann J, Turner R, Forstmann BU. Ultra-high

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7T MRI of structural age-related changes of the subthalamic nucleus. J Neurosci.

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2013; 33:4896-4900.

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50. Gyldensted C, Kosteljanetz M. Measurements of the normal ventricular system with

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computer tomography of the brain. A preliminary study on 44 adults.

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Neuroradiology. 1976; 10:205-213.

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ACCEPTED MANUSCRIPT Tamir Figure Legends

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Figure 1. 3D relationships between DBS lead trajectory and contacts to STN, and

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surrounding structures. The STN (in green) was volumetrically segmented using a

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prediction framework of subcortical structures based on PD patients’ 7 Tesla MRI

727

database. The electrode contacts (dark gray) were reconstructed from the post-operative

728

CT fused to the 3 Tesla pre-op MRI. The second contact (counting from the lead tip) was

729

aimed to the center of the DLOR. Therefore, the first contact covers the ventral STN, the

730

third contact was on the dorsolateral border of the STN, and the fourth contact was

731

outside of the STN, at the ZI (Zona Incerta). The intra-nuclear path was planned to be as

732

long as possible in the dorsolateral area of the STN, ideally > 6 mm inside the STN. Most

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patients were set on monopolar programming configuration, at the second contact.

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Bottom left (3D cube) – H=horizontal (axial) view, P=posterior (coronal) view. The

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picture is in courtesy of Noam Harel (see Acknowledgements).

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ACCEPTED MANUSCRIPT Tamir Figure 2. Longer intra-nuclear trajectories have longer recorded DLOR, but similar

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DLOR fraction. A. A plot of the relationship between the recorded DLOR length and the

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recoded STN length in 195 trajectories in 115 patients. This graph precludes trajectories

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in which no STN activity was found. Linear regression analysis showed a significant

740

correlation between the two parameters (Pearson’s r = 0.67; p< 0.0001). B. A plot of the

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recorded DLOR vs. the recorded STN lengths. This graph excludes trajectories that failed

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to detect both STN activity and DLOR activity (additional 23 trajectories). The

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correlation was still significantly positive (r = 0.61; p < 0.0001). C. Linear regression

744

analysis of the percentile fraction of recorded DLOR from recorded STN length vs. the

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STN length, in the same patient group as in A. Pearson’s r = 0.22, p < 0.0001. D.

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Correlation of %DLOR and STN length, using the same patient group as in B. Omitting

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the failed DLOR trajectories resulted a non-significant correlation (r = 0.02; p = 0.8). E.

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Significant positive correlation of the patients’ right hemibody improvement of UPDRS

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scores (pre-operative off – pre operative on medication UPDRS part III) and the left brain

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recorded STN lengths (r=0.17, p=0.05). F. Significant positive correlation of the patients’

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right hemibody improvement of UPDRS scores (pre-operative off – pre operative on

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medication UPDRS part III) and the left brain recorded DLOR lengths (r=0.17, p=0.05).

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ACCEPTED MANUSCRIPT Tamir Figure 3. Trajectory angles influences likelihood of long STN and DLOR

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recordings. A. Comparison of trajectory angles between successful and failed STN

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recording sets and between successful and failed DLOR sets. Failed STN recording sets

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had slightly more anterior trajectories (57.38 ± 3.5 degrees vs. 59.76 ± 5.2 degrees, p =

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0.08) but were not different in their laterality (arc: 20.64 ± 2.7 vs. 20.75 ± 2.8,

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respectively; p = 0.89). Failed DLOR sets had slightly more antero-medial trajectories in

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comparison to successful DLOR sets (arc: 19.61 ± 2.8 degrees vs. 20.95 ± 2.8 degrees, p

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= 0.01; ring: 58.16 ± 4.7 vs. 59.92 ± 5.1 degrees, respectively; p = 0.07). B. The X axis

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was truncated at 600 degrees^2 in all graphs. Positive correlation of the recorded STN

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length (in mm) with the trajectory vector (measured as the multiplication of the two

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trajectory angles (degrees^2); r = 0.22; p = 0.002). C. Same correlation as in B but

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including only the MER sets that succeeded in finding the DLOR. This correlation was

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not statistically significant (r = 0.03; p = 0.7). D. Positive correlation between STN

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length and trajectory vector in MER sets that failed to detect the DLOR (r = 0.46; p =

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0.05). E. Same correlation as in D but excluding failed DLOR MER sets did not find

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significant correlation between DLOR length and trajectory vector (r = 0.05; p = 0.5). F.

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Correlation graph of the recorded DLOR length with the trajectory vector. A significant

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positive correlation was found between the two parameters (r = 0.21; p = 0.003). G.

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Correlation graph of %DLOR vs. the trajectory vector showing a significant positive

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correlation between the two parameters (r = 0.18, p = 0.01). H. Same correlation graph as

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in G but excluding failed DLOR MER sets showed no significant correlation between

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%DLOR and trajectory vector (r = 0.02; p = 0.8).

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ACCEPTED MANUSCRIPT Tamir Figure 4. STN and DLOR lengths are not associated with patients’ age, PD

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duration, gender or lead laterality. A. Linear regression analysis found no significant

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correlation between the recorded STN length and the patient’s age (r = 0.05; p = 0.57). B.

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No correlation was found between the recorded DLOR length and the patient’s age (r =

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0.02; p = 0.8). C. Omitting the failed DLOR trajectories from the correlation presented in

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B revealed a trend of negative correlation between patients’ age and DLOR length (r =

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0.14; p = 0.08). D. No correlation was evident between STN length and the patients’

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disease duration (r = 0.04; p = 0.6). E. No correlation was evident between DLOR length

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and disease duration (r = 0.09; p = 0.25). F. Omitting the failed DLOR recording sets did

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not change the lack of correlation between DLOR length and disease duration (r = 0.01; p

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= 0.8). G. A bar graph presenting the differences in lengths of STN and DLOR as

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recorded from the right hemisphere (black bars) and the left hemisphere (white bars).

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Results are presented as mean ± SD. No significant difference was found (STN: 4.76 ±

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2.0 vs. 5.06 ± 2.3, respectively. p = 0.3; DLOR: 2.33 ± 1.6 vs. 2.4 ± 1.5, respectively. p =

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0.7). H. Similar bar graph presenting the differences in STN and DLOR lengths between

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males (black bars) and females (white bars). No significant differences were found (STN:

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5.42 ± 1.6 vs. 5.23 ± 1.9, respectively. p = 0.46; DLOR: 2.63 ± 1.4 vs. 2.45 ± 1.5,

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respectively. p = 0.4).

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ACCEPTED MANUSCRIPT Tamir Figure 5. Recorded STN and DLOR are longer in central electrode position, and are

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not influenced by third ventricle anatomy. A. scatter graph showing no correlation

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between STN length and third ventricle length (r = 0.11; p = 0.13). B. No correlation

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between DLOR length and third ventricle length (r = 0.11; p = 0.15). C. Omitting the

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failed DLOR MER sets from the correlation in B did not alter the resulted analysis (r =

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0.1; p = 0.2). D. No correlation was found between STN length and third ventricle width,

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measured at the MCP (r = 0.05; p = 0.5). E. No correlation was evident between DLOR

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length and third ventricle width (r = 0.02, p = 0.7). F. Omitting the failed DLOR MER

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sets from the correlation in E did not alter the resulted analysis (r = 0.03; p = 0.7). G. A

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bar graph comparing the differences in length of recorded STN and DLOR between the

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central electrode (black bars) and the non-central one (anterior or posterior; white bars).

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Results are presented as mean ± SD. Significant differences were found in STN length

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(5.06 ± 2.2 vs. 3.79 ± 2.5, respectively; p < 0.0001) as well as in DLOR length (2.4 ± 1.6

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vs. 1.7 ± 1.7, respectively; p = 0.0002) between the two electrodes. H. The x coordinate

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of the STN target was positively correlated with the third ventricle width (r = 0.69, p <

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0.0001). I. The x coordinate of the target was also correlated with the third ventricle

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length (r = 0.29, p = 0.0002).

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Table 1. Summarized Patients Demographics and Anatomical Characteristics.

(n = 115 patients) 62.04 ± 8.6 years

Disease Duration

9.43 ± 5.9 years

Third ventricle width (at MCP)

5.02 ± 1.8 mm

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Third ventricular length (AC-PC line)

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Maximal third ventricular width

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Age of Patients

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Mean ± SD

7.15 ± 2.0 mm

24.99 ± 1.4 mm

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Table 2. Averaged anatomical differences between men and women Men

Women

(n = 74)

(n = 41)

p value

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Parameter

25.3 ± 1.4 mm

24.5 ± 1.4 mm

3rd ventricle width

5.4 ± 1.6 mm

4.5 ± 2.0 mm

0.02*

60.77 ± 9.0 years

63.87 ± 7.5 years

0.08

11.6 ± 0.8 mm

0.0008†

STN |x| coordinate

12.1 ± 0.7 mm

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3rd ventricle length

0.006†

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* denotes statistical significance (p < 0.05) when comparing central to non-central electrodes

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Table 3. Averaged target coordinates and trajectory angles Mean ± SD

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(n = 212 trajectories)

11.95 ± 0.74 mm

Y of Target

-3.2 ± 0.99 mm

Z of Target

-4.54 ± 1.51 mm

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|X| of Target

Angle 1 (Arc)

20.82 ± 2.81 degrees 59.7 ± 5.09 degrees

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Angle 2 (Ring)

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Table 4. Averaged STN and DLOR lengths from MER

5.35±1.6 mm † (195)

DLOR length (not including failed DLOR)

2.94±1.2 mm * (172)

% DLOR (DLOR length*100/STN length)

53.17±18.2 % (172)

4.57±2.2 mm (185)

2.68±1.3 mm (148)

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STN length (not including failed STN)

Non-central electrode (n)

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Central electrode (n)

55.06±24.9 % (148)

The numbers represent mean ± standard deviation

* denotes statistical significance (p < 0.05) when comparing central to non-central electrodes

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Table 5. Correlation results between various patients parameters Pearson’s r

p value

STN length

Arc angle

0.16

0.02*

DLOR length

Arc angle

0.19

0.01*

%DLOR

Arc angle

STN length

Ring angle

DLOR length

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Independent Parameter

Dependent parameter

0.5

0.16

0.02*

Ring angle

0.04

0.6

%DLOR

Ring angle

0.08

0.3

Arc angle

3rd ventricle width

0.1

0.22

STNx

0.02

0.75

3rd ventricle length

0.18

0.02*

0.001

0.9

Max 3rd ventricle width

0.003

0.9

Patients age

0.11

0.16

STNx

PD duration

0.04

0.6

STNy

Patients age

0.15

0.05

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Arc angle

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Max 3rd ventricle width

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STN length DLOR length STNx

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0.04

PD duration

0.08

0.3

STNy

3rd ventricle length

0.04

0.6

STNy

3rd ventricle width

0.06

0.4

STNz

PD duration

0.3

0.0001†

STNz

3rd ventricle width

0.16

0.04*

STNz

Patients age

0.03

0.64

STNz

3rd ventricle length

0.07

0.3

STN length

STNz

0.06

0.42

DLOR length

STNz

0.04

0.53

STNx

0.1

0.19

STNx

0.01

0.89

STNy

0.06

0.45

STNy

0.06

0.43

Right UPDRS on-off

Left STN length

0.17

0.05*

Left UPDRS on-off

Right STN length

0.02

0.8

STN length

DLOR length

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Left DLOR length

0.17

0.05*

Left UPDRS on-off

Right DLOR length

0.06

0.5

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Right UPDRS on-off

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Highlights Recorded STN DLOR length is primarily determined by the STN length.

•

Postero-lateral trajectories have longer STNs and DLORs.

•

DLOR-to-STN proportion is stable across different trajectories.

•

Atrophy-related changes in STN geometry do not alter the chosen trajectories.

•

In patients with larger ventricles, the STN target shifts laterally.

•

Central electrodes has larger fraction of STN DLOR than peripheral ones.

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Abbreviation List %DLOR = the fraction of the DLOR length out of STN length 3D = Three Dimentional

CRW = Cosman Robert Wells CT = Computed Tomography DBS = Deep Brain Stimulation

GPi = Globus Pallidum internus IC = Internal capsule

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DLOR = Dorso Lateral Oscillatory Region

iMRI = intraoperative Magnetic Resonance Imaging IRB = Institutional Review Board

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LFP = Local Field Potential MCP = Mid Commissural Point

MER = Micro Electrode Recording

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MRI = Magnetic Resonance Imaging PC = Posterior Commissure

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PD = Parkinson’s Disease

PSA = Posterior Subthalamic Area SN = Substrantia Nigra

STN = Sub Thalamic Nucleus UPDRS = United Parkinson’s Disease Rating Scale ZI = Zona Incerta

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AC = Anterior Commissure

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Disclaimer

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Conflict of interest: none.