Optimal Fixation Position of Deep Brain Stimulation Electrodes for Parkinson's Disease in Humans

Summary

The fixation of deep brain stimulation microelectrodes for Parkinson’s disease requires brain surgery. This work describes a method to determine the optimal position of the stimulation electrodes during surgery, which requires a combination of techniques.

Abstract

Certain cases of Parkinson’s disease are treated with deep brain stimulation (DBS), applying electrical stimuli to the subthalamic nucleus (STN) in the brain. Stimuli are provided by inserted stimulation electrodes within the brain that supply a square voltage signal generated in a control unit (IPG) typically located in the chest. The elimination of Parkinson’s symptoms depends directly on the location of the stimulation electrodes. This work describes a method used to determine the best fixation position of the stimulation electrodes during surgery. The procedure provides guidance to the surgeon and requires the use of three techniques: 1) use of a stereotactic frame and stereotactic robot, 2) medical imaging (e.g., MRI and CT), and 3) signal analysis provided by microelectrode recording. In DBS surgery, the patient is usually awake with light sedation; however, one of the main advantages of this method is that the patient is fully sedated with anesthesia to avoid any distress or nervousness. Deciding where to perform electrode fixation is a result of combining intraoperative imaging and signal analysis to detect the the electrode position with the highest probability of blocking the PD symptoms. A software tool for signal analysis (DBScan) was developed, assisting the surgical team in determining the location for electrode fixation. In long-term postsurgical analysis, PD disorders were successfully eliminated in all operated patients.

Introduction

Parkinson’s disease (PD) is a major health problem affecting ~1–2% of people over 65 years of age worldwide¹, causing motor disorders (e.g., bradykinesia, tremor at rest, rigidity, postural instability), and non-motor disorders (e.g., sleep disorders, cognitive dysfunctions)^2,3. The deep brain stimulation (DBS) technique consists of applying electrical stimuli to the subthalamic nucleus (STN) region of the brain. This treatment has proved to be very efficient in blocking PD motor disorders in the patient⁴, allowing a better quality of life.

In order to stimulate the STN, a surgical procedure is necessary to insert one electrode in its left and one in its right region and then fix them in place. The success of the operation, measured by the improvement in the patient’s quality of life after surgery, greatly depends on the optimal fixation position of the stimulating electrodes. The STN is a relatively small oval region between 4 mm and 10 mm length⁵, so it is difficult to target. However, it is not only necessary to place the electrodes in the STN but also carefully select the electrode positions within it.

The optimal electrode position is given by the beta band activity. It is widely accepted that the main indicator for PD is directly related to beta band activity measured by the spectral power in the band: higher activity indicates more severe PD disorders^6,7. Brain spectral analysis divides the brain waves into bandwidths; the beta spectral band is the frequency band ranging from 13 Hz to 30 Hz. Activity in the beta band is associated with sensorimotor processing, has been observed in various different cortical areas, and is implicated in a wide range of cognitive functions⁸. When this activity appears in the STN, it is considered to be pathological and associated to PD. Electrical stimulation provided by DBS reduces beta band activity.

The surgical procedure for DBS implantation varies upon the technological equipment available at the hospital and to the neurosurgery team in charge. First, preoperative MRI images are fused with a stereotactic volumetric frame-based CT on the day of surgery for direct anatomical targeting. Then, during surgery, with the use of a stereotactic frame and an arc-shaped device attached to it, it is possible to plot the coordinates and drive the electrode to the exact location and depth in the brain using a mechanically or electrically assisted submillimeter displacement electrode driver. Prior to the placement of the stimulation electrodes, the intraoperative physiological verification of the STN is necessary. For this, a cannula with microelectrodes for signal recording (MER) are inserted at a distance calculated according to the MRI and within planned trajectory and, with the patient awake, some motor activities are performed while the brain signal activity is monitored in order to fine tune the position in view of the brain activity. According to the surgeon and the commonly accepted brain pattern criteria⁴, the final fixation position is decided. The MER are then extracted, and the stimulation electrodes are inserted and fixed to the specified position. One of the main features of the proposed protocol is that, unlike other methods, the patient is completely sedated and less anxious or uncomfortable. Additionally, the aim of DBS is to reduce the beta band activity in the STN, which will reduce beta activity in the cortex and eliminate the PD disorders. In this case, the fixation position decision for the stimulation electrode is based on the beta band activity in the STN, supported by intraoperative computed tomography (CT) images. The procedure is integrated in a developed software called DBScan that makes use of signal analysis and artificial intelligence algorithms. Some STN localization algorithms are proposed⁹, but they are not integrated in the surgical procedure and, in practice, they cannot be used. This work describes the use of the DBScan tool for STN localization used during the surgical procedure.

The objective of this work is to describe the method followed during DBS implantation surgery and the novel techniques supporting the operation. The procedure is derived from the standard practices in DBS surgery^10,11, but several improvements have been made and results show that all patients obtained satisfactory results (1% had some surgery problems not directly associated to the DBS). In comparison, when using previous surgery methods, 5% of patients required repositioning or had undesired disorder blocking.

Protocol

This clinical procedure was approved by the Ethical Committee for Biomedical Research of La Fe Hospital with registration number 2015/0824 in May 17, 2016. All participants signed written informed consents. These investigations using human data were carried out following the rules of the Declaration of Helsinki and its updates.

1. Presurgery: Patient screening for DBS implantation

1. Detect patients with increased drug dosages required to block PD disorders.
   NOTE: The main drugs used to block PD are dopamine agonist (DA) and levodopa (LD). Which one is used depends on the neurologist's criteria and the patient’s state. The degree of suppression of the beta oscillations by DA/LD therapy correlates with improvement of the hypokinetic symptoms of Parkinson’s disease⁷. However, DA/LD therapy in high doses generates adverse effects to the patient, with DBS being the only remedy left to block PD disorders. The limit of drug dosage to support the use of DBS surgery depends on the patient’s symptoms, especially when psychiatric disorders appear. Surgery is recommended when the patient presents dyskinesia, behavioral disorders, and must take a DA/LD dose of 100 mg every 2 h or less in order to block PD disorders.
2. Have the neurologist perform several tests (e.g., motor, sensory, speech, and psychiatric) on potential candidates and decide whether they are suitable for DBS surgery¹².
3. Several days before surgery, perform a T2-weighted MRI.
   NOTE: Figure 1 shows an example of an obtained T2-MRI.
4. Visually perform a volumetric analysis of the acquired T2-MRI images. Locate the STN region and estimate its location in a maximum of four MRI cuts (i.e., in an estimated area covering a 2.4 mm brain thickness).
   NOTE: Typically, each MRI image slice corresponds to 0.6 mm of brain thickness and 650 images (cuts) per brain are obtained from the MRI. Thus, a total of 390 mm is covered.
5. Rebuild axial images for a 0.6 mm thickness using cranial software (e.g., Medtronic S7)¹³.
6. Based on the MRI, define the incision trajectory to reach the STN. When planning the trajectory, consider the STN position and other physiological issues such as the presence of big veins or arteries, sulci, and other formations in the brain tissue that could cause damage to the patient.
7. Before surgery, ensure that the patient had an off-period medication (usually 24 h).

2. DBS surgery, phase 1: In-operating room patient preparation and incisions

1. Anesthetize the patient (i.e., full sedation using intravenous general anesthesia). During surgery, have an anesthesiologist monitor heart rate, blood pressure, breathing, and other vital signs to make sure patients are normal and steady¹⁴.
2. Use a stereotactic frame to hold the patient’s head.
   NOTE: It is not necessary to use the arc-shaped part of the frame to obtain the fiducial points.
3. Once the patient is in position, perform the first intraoperative image acquisition using CT.
4. In the cranial software, click on both MRI (step 1.3) and CT images (step 2.3) and select the image fusion option to perform image fusion of overlapping MRI and CT images, including the previously estimated electrode insertion trajectories (step 1.6) to obtain the incision point coordinates in the skull.
   NOTE: Image fusion is an option provided by the software to superimpose MRI and CT images, and a certain degree of transparency can be automatically adjusted. Figure 2 shows two images from the data fusion used to determine the incision point.
5. Transfer the obtained positions to the stereotactic robot. Move the stereotactic robot with a fiducial end-point tool so that it can accurately point to the incision location using a laser light.
   NOTE: Figure 3 shows the patient in the operating room, the intraoperative CT, and the stereotactic robot for the fiducial point determination.
6. Using a cranial drill (craniotome) with an 18 mm drill bit, make two burr holes (one hole for each hemisphere) in the skull at the incision point indicated by the stereotactic robot.
7. Place a cannula in each hole for further MER electrode insertion.
   NOTE: The same cannula will also be used to insert the stimulation electrode.
8. Replace the fiducial end-point tool in the robot with an electrode driver (motorized positioning microdrive), used later for insertion of micrometric step MER electrode and stimulation electrodes.

3. DBS surgery, phase 2: Microelectrode Recording (MER) insertion

1. Perform a second intraoperative CT to verify that the cannula is located 10 mm from the target fixation point (Figure 4-1).
2. Using cranial software, perform data fusion of CT (step 3.1) with initial MRI images (step 1.3) and define the trajectory that the MER electrodes must follow to reach the STN area (Figure 4-2).
   NOTE: The surgical team, through visual observation, defines the target STN area and trajectory.
3. Cranial software provides the distance from the surface to the target point by the obtained trajectory. Thus, insert the MER electrodes through the cannula.
   NOTE: Typically, MER electrodes are composed of two tracks with 2 mm between them.
4. Using the robot with the motorized driver, insert the MER electrodes through the defined trajectory to 10 mm from the estimated target point.
   NOTE: The motorized driver displaces the electrodes the exact distance specified by the surgeon.
5. Perform MER signal data acquisition, recording using a portable MER system (Table of Materials). Acquire data over 10 s.
   NOTE: Data acquisition parameters are automatically set by the equipment. Data are stored either in Alpha-Omega or EDF (i.e., European Data Format) formats.
6. Move MER electrodes 0.5 mm further, and acquire and record data again after 10 s. Repeat this process to 4 mm from the estimated target point. During data acquisition and recording, visually inspect the signal monitor to verify that signal patterns correspond to those in the STN, according to brain atlas data^4,9.
   NOTE: In total, data from 30 depths, 2 MER electrodes per trajectory, and two trajectories are obtained and saved in a removable device.

4. DBS surgery, phase 3: Signal analysis for determination of electrode fixation position

1. Insert the removable device where data are stored in the computer running the DBScan tool¹⁴.
2. For one trajectory, execute the DBScan¹⁵ time and frequency signal analysis module by selecting frequency and pressing the trajectory analysis button. Next, select time and press trajectory analysis and visually inspect all results. For each MER in the trajectory, DBScan displays the basal level, the dominant frequency in the beta band, and their spectrograms as a function of depth (Figure 5). Repeat the procedure for the second trajectory.
   NOTE: Higher beta band activity provides information about the depth location of the motor area in STN.
3. Execute the DBScan classification analysis module by selecting zone estimation and pressing the trajectory analysis button so that the software provides the probability of optimal STN location (higher percentage provides better position) for each depth, each MER electrode, and each trajectory (Figure 6).
4. With all information (i.e., image fusion, DBScan results, and cranial software information), decide on the best stimulation electrode location (target position) and move the MER electrodes to this position.
5. Perform a third intraoperative CT and verify that the MER electrodes are at the target point (Figure 4-3,4-4).
6. Upon confirmation of the proper position, remove the MER electrodes from the brain, leaving the cannula.

5. DBS surgery, phase 4: Fixation of DBS stimulation electrode and final verification during surgery

1. Using the motorized driver, insert the DBS stimulation electrode through the cannula according to the best trajectory determined in step 4.4 and place it in the target position.
2. Perform a fourth intraoperative CT and data fusion with MRI in order to verify the correct stimulation electrode position (Figure 4-5,4-6).
3. Activate the stimulation electrodes with the implantable pulse generator (IPG) to verify the absence of undesired side effects such as abnormal movements in the patient.
   NOTE: The IPG device will be inserted in the patient’s chest.
4. If a mixed electrode is used (i.e., electrode combining acquisition and stimulation leads), use cranial software to verify that beta band energy decreases when stimulation is activated. If only a stimulation electrode is used, verify that the beta band energy decreases in the cortex by regular EEG.
5. Once confirmation of beta band attenuation is obtained and no side effects are observed, extract the cannula and proceed to the fixation of the electrodes in the skull by lead anchoring (Table of Materials).
6. Seal the skull orifices using acrylic glue to prevent any infection in the area.
7. Make a 2 cm skin incision at the postauricular scalp where the lead is relayed, and a 5 cm skin incision in the chest (subclavicular) or nearby area for the IPG insertion. Fix the IPG using a silk suture, connecting the stimulation electrode leads. Close the skin using a subcutaneous absorbable suture.
   NOTE: The IPG must be superficially located (i.e., no more than 10 mm deep) in order to access configuration data and recharge the battery wirelessly.

6. Postsurgery analysis

1. After anaesthesia effects, verify that the PD disorders have disappeared, or they are minimal in comparison with the patient’s previous situation.
2. After one week of surgery, perform a CT 3D imaging.
3. Perform a data fusion of this CT with presurgical MRI (step 1.3) and also with the intraoperative CT (step 3.1) in order to verify that the stimulating electrode position is still fixed in the initially estimated area (Figure 7).
4. Evaluate the patient periodically (~6 months) to verify that PD disorders are kept blocked.

Results

DBS surgery is the last resort for PD patients who do not respond to drug therapy or patients having adverse side effects with drug therapy (e.g., psychiatric or behavioral disorders). After DBS implantation, the drug dose administered to the patient is reduced by two thirds of the dose before implantation. Additionally, DBS provides better quality of life, reducing tremors and psychological side effects of drugs, and also reduces the number of patient visits to the doctor.

Regarding precision...

Discussion

The main improvements provided by this DBS surgery method are the following: full sedation of the patient, use of a stereotactic robot for electrode insertion, and use of DBScan software for high precision fixation of the stimulation electrodes. The method provides complete confidence about the fixation location, supported by the postsurgical results showing successful blocking of PD effects.

Currently, 5% of the patients required a new DBS surgery. This was due to problems during surgery not ...

Materials

Name	Company	Catalog Number	Comments
CT - Computed Tomography	Philips	Brillance Essencial	Preoperative CT
DBS lead anchoring	Medtronic	Stimloc	Fixation system for stimulation electrode leads in the skull
DBS stimulation electrodes	Medtronic	model 3389	4 contacts
DBScan software	Univ. Valencia		Developed by authors for brain signal analysis and classification
Frameless patient registration module	Renishaw	Neurolocate	Used for fiducial points
Image Fusion and trajectory planning software	Alpha Omega	Stealthstation S7 with Framelink planning	Used for target and trajectory definition
Intraoperative CT	Medtronic	O-ARM	Used for image fusion during DBS surgery
MER electrodes	Alpha-Omega	Acute Electrode	Tungsten, glass coating, 125mm shank diameter, 2mm exposed wire, 1mm male pin, 1MW
Miroelectrode and Local Field Potential Register with automatic neuro navigation	Alpha Omega	NeuroSmart	Brain signal recorder and visualizer
Motorized electrode driver	Alpha Omega	Micromotor NeuroNav Drive	Insertion and extraction of MER and stimulation electrodes
MRI – magnetic resonance	Philips	Intera 1.5 T	Preoperative MRI
S7 Cranial software	Medtronic	S7 Cranial software
StealthStation S7	Medtronic	StealthStation S7
Stereotactic frame	Elekta	Leksell	Only used for head support, no skin incisions for fiducial positioning
Stereotactic robot	Renishaw	Neuro Mate	Substitute of arc-shaped stereotactic frame. Also used for electrode driver support