Performing Behavioral Tasks in Subjects with Intracranial Electrodes

Summary

Patients implanted with intracranial electrodes provide a unique opportunity to record neurological data from multiple areas of the brain while the patient performs behavioral tasks. Here, we present a method of recording from implanted patients that can be reproducible at other institutions with access to this patient population.

Abstract

Patients having stereo-electroencephalography (SEEG) electrode, subdural grid or depth electrode implants have a multitude of electrodes implanted in different areas of their brain for the localization of their seizure focus and eloquent areas. After implantation, the patient must remain in the hospital until the pathological area of brain is found and possibly resected. During this time, these patients offer a unique opportunity to the research community because any number of behavioral paradigms can be performed to uncover the neural correlates that guide behavior. Here we present a method for recording brain activity from intracranial implants as subjects perform a behavioral task designed to assess decision-making and reward encoding. All electrophysiological data from the intracranial electrodes are recorded during the behavioral task, allowing for the examination of the many brain areas involved in a single function at time scales relevant to behavior. Moreover, and unlike animal studies, human patients can learn a wide variety of behavioral tasks quickly, allowing for the ability to perform more than one task in the same subject or for performing controls. Despite the many advantages of this technique for understanding human brain function, there are also methodological limitations that we discuss, including environmental factors, analgesic effects, time constraints and recordings from diseased tissue. This method may be easily implemented by any institution that performs intracranial assessments; providing the opportunity to directly examine human brain function during behavior.

Introduction

Epilepsy is one of the most common brain disorders, characterized by chronically recurrent seizures resulting from excessive electrical discharges from groups of neurons. Epilepsy affects about 50 million people worldwide and approximately 40% of all individuals with epilepsy have intractable seizures that cannot completely be controlled by medical therapy¹. Surgery may result in seizure free status if the brain areas responsible for the generation of seizures (the epileptogenic zone - EZ) are localized and surgically removed or disconnected. In order to define the anatomical location of the EZ and its proximity with possible cortical and subcortical eloquent areas, an array of non-invasive tools are available: analysis of seizure semiology, video-scalp electroencephalographic recordings (ictal and interictal recordings), neuropsychological testing, magnetoencephalography (MEG) and MRI². When the noninvasive data is insufficient to precisely define the location of the hypothetical EZ, when there is the suspicion of early involvement of eloquent cortical and subcortical areas or when there is the possibility for multi-focal seizures, chronic invasive monitoring may be required^3,4.

Methods of chronic invasive monitoring for defining the location and boundaries of an EZ may include subdural grids and strips, with electrodes placed on the brain’s surface, and stereo-electroencephalography (SEEG), when multiple depth electrodes are placed in the brain in a three-dimensional fashion. Subdural intracranial recordings were initially reported in 1939 when Penfield and colleagues used epidural single contact electrodes in a patient with an old left temporal-parietal fracture and whose pneumoencephalography disclosed diffuse cerebral atrophy⁵ . Subsequently, the use of subdural grid arrays became more popular after multiple publications during the 1980's demonstrated their safety and efficacy⁶. The SEEG method was developed and popularized in France by Jean Tailarach and Jean Bancaud during the 50’s and has been mostly used in France and Italy as the method of choice for invasive mapping in refractory focal epilepsy^7-9.

The principle of SEEG is based on anatomo-electro-clinical correlations, which takes as its main principle the 3-dimensional spatial-temporal organization of the epileptic discharge within the brain in correlation with seizure semiology. The implantation strategy is individualized, with electrode placement based on a preimplantation hypothesis that takes into consideration the primary organization of the epileptiform activity and the hypothetical epileptic network involved in the propagation of seizures. According to several European and recent North American reports, SEEG methodology enables precise recordings from deep cortical and subcortical structures, multiple noncontiguous lobes, and bilateral explorations while avoiding the need for large craniotomies^10-15. Afterwards, postoperative images are taken to obtain the exact anatomical position of the implanted electrodes. Subsequently, a monitoring period starts in which patients remain in the hospital for a period of 1 to 4 weeks in order to record interictal and ictal activities from the implanted electrodes. This monitoring period is an opportune time for studying brain function using event-related SEEG analysis, as there is no added risk and the patient typically views the research study as a welcome reprieve from the mundane monitoring period. The recordings garnered from intracranial electrodes are not only vital to improved evaluation and care of epilepsy patients, but additionally provide the exceptional opportunity to study human brain activity during behavioral paradigms.

Several researchers have already realized the opportunity to study invasive recordings from epilepsy patients. Hill et al. reported on the methodology for recording electrocorticographic (ECoG) signals from patients for functional cortical mapping¹⁶. ECoG recordings have also provided insight to motor-language coupling¹⁷. Patients with implanted depth electrodes have performed navigational tasks to study brain oscillations in memory, learning¹⁸ and movement¹⁹. Depth electrode recordings were also used to study paradigms with otherwise unattainable temporal resolution such as hippocampal evoked activity²⁰, neural activity in the default-mode network²¹, and the temporal course of emotional processing²². Hudry et al studied patients with temporal lobe epilepsy who had SEEG electrodes implanted into their amygdala for short-term olfactory stimuli matching²³. Another group has studied simple limb movements such as hand flexion or unilateral movement of the hand or foot in healthy brain sites from epileptic patients with implanted SEEG^24,25.

The studies described above are a small sampling of a very diverse collection of relevant literature. There exists an insurmountable potential to learn and understand how the human brain works using a combination of behavioral tasks and intracranial recordings. While there are other methods for achieving this goal, intracranial recordings possess several benefits including high temporal and spatial resolution as well as access to deeper structures. The authors aim to describe the general methodology for recording from patients with intracranial electrodes during behavioral tasks. However, there are several deterrents and barriers to successfully completing clinical research in patients receiving care. Limitations, confounding effects, and significance of this research will also be identified and explored.

Protocol

All tasks were performed according to an approved protocol submitted to the Institutional Review Board (IRB) of the Cleveland Clinic Foundation. An informed consent process was conducted with each patient prior to all research activities. In this example, a subject that meets study criterion that has had stereo-electroencephalography (SEEG) electrodes implanted for seizure is chosen. The project was discussed with the subject and they have consented to participate.

1. Patient Enrollment

1. Evaluate patients with refractory epilepsy in consideration for intracranial electrode implantation. If the patient is a good candidate for the invasive surgery, analyze the patient’s MRI, PET and MEG along with the seizure pathology in order to optimize placement of the electrodes. A clinical team carries out all evaluations and no decisions are made for research purposes. .
2. Identify eligible patients for the study subsequent to evaluation for implantation and verify the patients per the approved IRB protocol based on the inclusion/exclusion criteria.
   NOTE: It is in the best interest of the patient to include subjects with an aura in the inclusion criteria. Patients with auras are able to notify the researchers that they are about to have a seizure; giving the researchers and patient time to take the necessary precautions (pressing the seizure alarm to notify the clinical staff and pulling all equipment out of the way). However, if subjects are recruited that do not have an aura, ensure that the patient input devices can be readily removed from the patient area and that the staff is aware of the research equipment and protocol.
3. Obtain informed consent prior to any research activities in accordance with the IRB. During the informed consent, explain the research, emphasizing that participation is strictly voluntary and will in no way impact the patients clinical care. In most cases there is no direct benefit to the patient and their willingness to participate is altruistic.
4. Maintain respect for the patient’s rights and privacy at all times. Remind the patients that their information will remain anonymous and confidential and they may cease participation in the study at any time under no consequence.
5. Have the patient sign and date the informed consent if he or she understands and agrees to participate in the study. Leave one copy is left with the patient to review; should they have any questions or concerns encourage the patients to contact the PI.

2. Behavior System Set-up

1. Before bringing the equipment into the room, ensure that there is sufficient space in the patient’s room, as well as access to the necessary outlets (2).
2. Check that all equipment and wires are ready to expedite the set up. The behavioral system includes an FDA approved robotic arm (which allows the subject to control a cursor during the task), a laptop computer to control the behavioral program, a monitor for presenting the task stimuli, and a data acquisition system to store the electrophysiological and behavioral data.
   NOTE: Make necessary modifications to meet specific needs of one’s research. For instance, use a button box for the patient interface instead of the robotic arm.
3. If the patient is not presently positioned in a manner suitable to complete the task, assist the patient to a reclining chair (or bed) with arms, should they have a seizure.
   NOTE: It is a good idea to discuss the study design, equipment, etc. with all the members of the monitoring unit to inform them of what is going on, how the group will be interacting with the patients, and any possible issues that may arise.
4. When the patient is ready, bring the behavioral system into the room and begin booting up the behavioral system and robotic arm.
5. Connect the digital event marker output from the behavioral computer to the DC channels of the electrophysiological acquisition system in order to time lock the recorded SEEG signals with behavioral event markers.
   NOTE: At this center there is a separate electrophysiological acquisition system designated for research purposes, which does not interfere with the clinical acquisition system. However, it is possible to use the clinical acquisition system by working with the appropriate personnel. All efforts should be made not to disrupt the clinical acquisition.
6. Calibrate the robotic arm and position it such that the range of motion is comfortable for the patient. If using another interface device, ensure that the equipment is operating correctly and is positioned comfortably for the subject to use.
7. While using the robotic arm, ensure that the emergency stop buttons are easily accessible by the researchers throughout the behavioral task. In the event of a seizure, the emergency stop button is pressed and the equipment is pulled away from the patient so that they do not harm themselves. In addition, we do not use the velcro straps that come with the robot system to facilitate removal from the patient in case a seizure occurs.
   NOTE: In this example, the parallel port of the behavior rig is connected to the digital input port of the acquisition system using a parallel port cable. Additional analog signals such as the x & y position of the robotic arm are recorded simultaneously.

3. Behavioral Task

1. Explain the task to the patient following the completion of the rig set up and calibration of the interface device.
2. Use a behavioral task similar to the children’s card game of “war”. Ask the patient to make wagers as to whether their card is greater than the computer’s card. The choice of the wager is based on the patients’ perception of the relative value of their card. Simplify the task for subsequent analysis, by only using cards of one suit and limiting the deck to the 2, 4, 6, 8, and 10 numbered cards.
3. Show a fixation cue on the screen for 350 msec. Ensure the patient holds the cursor over the fixation mark to initiate the task.
4. Show the stimulus for 1,000 msec. Allow the patient to see their card with the computer’s card next to it face down.
5. Following the cards disappearance, show a go-cue (<5,000 msec) displaying two options, asking the patient to bet either $5 or $20, based on their card. Ask the patient to place the bet by moving the cursor using the robotic arm, over their chosen wager. Randomize the wager position from trial to trial to ensure no bias based on position.
6. After the wager has been selected, notice a 250 - 500 msec delay (blank screen), followed by the revelation of the computer’s card (1,000 - 1,250 msec). Observe the outcome (1,000 msec), whether the trial was a win, lose, or draw and how much was won or lost.
7. Allow the patient to practice until they are confident in their performance and have no questions.

4. Data Acquisition

1. Record the data when the patient is ready and verify that the settings on the research (or clinical) acquisition system are appropriately selected.
2. Turn off the room lights and TV to keep the background noise to a minimum during the recording. Additionally, ask the patient to refrain from behaviors such as tapping their foot, talking or shaking their legs.
3. Begin the task and record the patient performing the task. Ask the subject to perform the task for 30 min. The sampling rate of the robotic arm system is 1 KHz, and that of SEEG recording system is 2 KHz.
   NOTE: This duration may be different for other paradigms.

5. Data Analysis

1. First, de-identify the recorded SEEG data to ensure that the patient’s information remains confidential and that his/her data is submitted anonymously.
2. Obtain the coordinates of the electrode locations from the postoperative CT and preoperative MRI.
3. Align the neurophysiological recordings with the digital timestamps of interests from the behavioral task.
4. Apply signal analysis methods to analyze the event dependent brain activity modulation.
   NOTE: In this study, power spectral density (PSD) of the event related SEEG signals was calculated using Chronux multitaper toolbox^26,27. Each trial data was aligned with respect to the relevant event (time zero), and the calculated PSD was normalized in each frequency bin with respect to the baseline PSD.

Results

In these results we present the analysis of the SEEG data from the limbic system captured in one subject playing the War Task. We can demonstrate that various aspects of the War Task evoke significant gamma-band (40 - 150 Hz) modulation in the limbic system (Figure 1). As seen, in the visual cortex, the presentation of an object on the screen results in a fast latency (~200 msec) wide band response regardless of the task contingency. In addition, there appears to be differences in the duration of the res...

Discussion

Here we have presented a method for performing intracranial electrophysiological studies in humans as they engage in a behavioral task. This methodology and its simple permutations are important for studying human movement and cognition. While there inherently exists advantages and disadvantages to any technique, recording from intracranial electrodes has advantages over other electrophysiological and imaging techniques. Two of the major advantages are the ability to collect high quality data with better control and desi...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
InMotion ARM	Interactive Motion Technologies	InMotion Arm	http://interactive-motion.com/inmotion-arm-the-new-standard-of-care/ Equipment our lab used, can use other equipment to collect data
MATLAB	Mathworks Inc	MATLAB	http://www.mathworks.com/ Need version r2007b or higher to run Monkeylogic
Data Acquisition Toolbox	Mathworks Inc	Data Acquisition Toolbox	http://www.mathworks.com/products/daq/ Must have to run Monkeylogic
Image Processing Toolbox	Mathworks Inc	Image Processing Toolbox	http://www.mathworks.com/products/image/ Must have to run Monkeylogic
Monkeylogic	Wael Asaad and David Freedman	Monkeylogic	http://www.brown.edu/Research/monkeylogic/ Free download, must have MATLAB to run
Chronux	Medametrics, LLC	Data Processing Toolbox	http://www.chronux.org/
Brainstorm		MEG/EEG Analysis Application	http://neuroimage.usc.edu/brainstorm/
Laptop	Dell	Latitude E5530	http://www.dell.com/us/business/p/latitude-e5530/pd?ST=dell%20latitude%20e5530&dgc=ST&cid=263756&lid=4781504&acd=12309152537461010
NI Card	National Instruments	NI USB-6008	http://sine.ni.com/nips/cds/view/p/lang/en/nid/201986 12-Bit, 10 kS/sec Low-Cost Multifunction DAQ