Intra-Operative Behavioral Tasks in Awake Humans Undergoing Deep Brain Stimulation Surgery

Deep brain stimulation surgery offers an opportunity to examine information and coding in the awake human brain by taking micro electrode recordings on a human subject performing behavioral tasks. In this example, subjects are first trained to play a simple computer card game involving risk and reward. The subject is then prepped for deep brain stimulation, surgery, and micro electrodes are inserted into the target region of the brain.

In this case, the STN neuronal signals are recorded as the subject repeats. The card game. The data collected demonstrates the role of risk and reward on neuronal encoding in the STN.

Though the goals of the experiment can vary depending on the nucleus targeted for surgery. At the beginning, DVS was mainly used for motor disorders such as essential tremor, Parkinson, and dystonia. More recently is being used for the investigation for treatments of depression and obsessive compulsive disorder.

So this task has both a motor and a reward contingent component we recorded in the subthalamic nucleus, which lies at the interface of the motor and limbic systems of the brain. So this patient is a 62-year-old lady. She's very nice.

She's had Parkinson's disease for about 10 years. And the classic features of Parkinson's she has, so she has tremor, she has stiffness, and she has slowness of movement. And she initially responded well to medications, which is a good sign because it tells us that it's true Parkinson's disease.

But then as in many cases, over time, the medications become less effective. Basically the patients become brittle so that when she's off her medication, she has really severe symptoms of Parkinson's disease. She's tremulous, she's rigid, she's slow.

And then when she takes her medications, she gets a different kind of movement disorder called the dyskinesia where she moves too much and there's no longer a happy middle ground. So that's the time when surgery is a useful intervention because it really gets rid of those profound on off fluctuations and puts people at just an even keel. And basically they are at their best that they would be on their medication.

So that's the goal of the surgery. And the surgery itself, we target on two parts of the brain are potentially available. One is called the subthalamic nucleus.

That's what we did today. And one is called the globus palus internist. And both are roughly equally effective.

And the way we target them is we use a combination of things. We do it stereotactically using CT and MRI. We target them using physiology by doing micro electrode recordings.

And those are very important because they tell us, you know, in a, at a very high level of spatial resolution, the boundaries of the nucleus, the upper lower boundaries, and we, and to not only that, but to make sure that we're in the motor part of the nucleus. And then finally, when we put in the permanent electrode, we stimulate through it again to confirm that we're in the right place. So we're doing all of these things anyway to treat the patient.

And we're doing the micro electrode recordings anyway, so this just gives us a window when we have the micro electrodes in place. It's a rare opportunity to study neuronal activity in the human brain, which you'd never otherwise get to do. But since we're doing it anyway and the electrodes are in there anyway, then we take an extra 20 to 30 minutes to do, you know, whatever experiments we're interested in.

And they typically are experiments having to do with motor control or decision making or learning or motivation, those types of things. And almost all of em involve, you know, a video screen and some simple task that the subject does, whether it's moving a joystick or a button press, that kind of thing. Micro electrode recordings are routinely performed during DBS surgery, providing a unique opportunity for researchers to record firing patterns of individual neurons while a subject performs a behavioral task.

As a part of DBS surgery for Parkinson's disease, patients are admitted to the hospital one day prior to surgery. This provides an opportunity to train the patient on the behavioral task before the operation. This opportunity proves to be extremely useful when the behavioral task is cognitively challenging.

On the day of the surgery, a portable behavioral rig is set up for the subject in the case that the subject is trained on the night prior to surgery, the rig is equipped with the exact same behavioral task, which the subject is required to perform intraoperatively. In this example, the subject is asked to play a card game similar to the game of war. In the game, the subject bets either 20 or 5 as to whether his or her card is higher than that of the computer.

The intent of this task is to assay the role of reward and risk on neuronal encoding in a ophthalmic nucleus as a means of reducing the potential combinations and resulting confounds. Only even numbered cards of a single suit are used in each trial. The subject first sees a screen depicting their randomly dealt card and the back of the unknown computers card.

The screen then shows two wager options, 5 and 20 based on the relative strength of his or her card. The subject indicates the wager with a button push, after which the screen shows his or her card and the revealed computer's card. The final screen explicitly depicts the amount won or lost.

The subject is allowed to play the game until they fully understand the rules and can perform at a comfortable level. Now let's see the intraoperative experimental setup the day after training. Once the subject has been positioned on the surgical table, bring the rig containing the behavioral data acquisition and signal processing equipment into the operating room.

Rig positioning must take into consideration normal workflow and sterility issues related to the operating room setting. As components of these rigs are assembled and disassembled for each recording session, it is vital to check all equipment connections. Therefore, as each component is connected to the data acquisition system, check the integrity of the data first boot, the acquisition and the signal processing equipment.

Connect the outputs of the signal processing rig to the inputs of the acquisition rig. In this study, three extracellular action potential channels are acquired, corresponding to three paraag oriented electrodes that are advanced into the subject's brain during the surgery. Turn on the amplifiers one at a time to ensure that the acquisition system is acquiring the signals.

Using an appropriate adapter, secure the monitor to the OR table in comfortable viewing position. Ensure that the subject's hand is comfortably positioned to operate the input device used during the task. Now boot the behavioral system and ensure that the behavioral event markers are being captured by the acquisition rig.

Start the behavioral task and allow the subject to play a few trials of the task during this time. Ensure that the acquisition system is capturing the button box inputs and the behavioral markers generated by the behavioral rig with the experiments set up and ready to go. Let's see how STN neurons are surgically isolated.

The objectives of the surgery are to place chronic DBS leads into the motor region of the STN. Displacement is achieved through a combination of stereotactic imaging and neurophysiological recordings at Mass General Hospital. A Cosman Roberts Wells stereotactic frame and fiducial cage is applied and a head CT scan is obtained.

The CT with fiducials is merged with a previously obtained volumetric brain MRI on a neuro navigation system. In the operating room, the patient is positioned comfortably in a semi reclined position and prepped and draped using standard surgical technique. The coordinates of the left STN are programmed into the frame, which is positioned on the patient.

The surgeon incisors and retracts the skin. Bur holes are placed and a small duro opening is created. Cannula attached to a micro drive are brought into position and advanced until the tip of the cannula are 25 millimeters above the target.

Once the cannula are advanced into the brain, the internal styles are removed and replaced with high impedance micro electrodes. The signal processing rigs, pre amplifiers are connected to each electrode and the differential reference channel is connected to the outer cannula. On the signal processing rig, turn on the amplifiers and assess the extracellular or signal.

In addition, check the impedance for each electrode before advancing it further into the brain. Once everything has been checked, the surgeon advances the electrode slowly with 0.05 to 0.4 millimeter steps into the brain. The electrodes advanced starting 25 millimeters from the calculated target toward the S St N.This trajectory results in the electrode passing through the CAU eight nucleus, the thalamus, the zona Serta, and finally into the SDN.

Once the electrodes have entered the SDN, the physiologist manipulates the patient's contralateral limbs as a means of establishing whether the neuronal signal is motor responsive. When the surgeon and experimenter are satisfied with the electrodes position, the behavioral task can be initiated. Before starting the behavioral task, it is important to document the depth of the micro electrodes and the motor responsiveness of the isolated neuron.

Next, instruct the subject that the task will begin. Ensure that the button box is still comfortably positioned and the monitor completely visible. Start the data acquisition and acquire baseline activity for at least one minute prior to starting the behavioral task.

As the subject performs the task, it is important to monitor the captured data. With any disruption in the acquisition, the task should be stopped and the problem rectified. The tasks can be performed multiple times for each depth.

In the STN, however, experimental recording is limited to 30 minutes to prevent patient discomfort and undue prolongation of surgery. Let's just start. Can you open and close your hand for me wearing a light bulb?

Good.We'll go your right foot around. Repeat after me. I love tapioca pud.

I took a train to Topeka Kansas. Shown here are representative results from a single STN neuron recorded during the war game. RAs are depicted centered on four behaviorally relevant epochs in the task, the fixation period prior to each trial presentation of the subject's card, the button press indicating the subject's wager and presentation of the computer's card shown here are bend per stimulus time histograms.

This neuron does not respond robustly to presentation of the subject's card, but increases its firing significantly around the button push. This activity lasts until the computer's card is revealed, at which point firing decreases to baseline levels. This technique measures responses from individual neurons in the brain.

It can also be combined with other measures of neural activity, which measure population responses such as functional magnetic resonance imaging or magnetoencephalography. Once mastered, this technique can be set up and implemented in the OR in 25 minutes. Working with humans in the operating room comes with a number of limitations, including sterility time, and most importantly, patient welfare.

So keep these points in mind during all phases of the study.