Deep brain stimulation surgery offers a unique opportunity to examine information encoding in the awake human brain. This article will describe intra-operative methods used to perform cognitive and behavioral tasks while simultaneously acquiring physiological data such as EMG, single-unit neuronal activity and/or local field potentials.
Deep brain stimulation (DBS) is a surgical procedure that directs chronic, high frequency electrical stimulation to specific targets in the brain through implanted electrodes. Deep brain stimulation was first implemented as a therapeutic modality by Benabid et al. in the late 1980s, when he used this technique to stimulate the ventral intermediate nucleus of the thalamus for the treatment of tremor 1. Currently, the procedure is used to treat patients who fail to respond adequately to medical management for diseases such as Parkinson’s, dystonia, and essential tremor. The efficacy of this procedure for the treatment of Parkinson’s disease has been demonstrated in well-powered, randomized controlled trials 2. Presently, the U.S. Food and Drug Administration has approved DBS as a treatment for patients with medically refractory essential tremor, Parkinson’s disease, and dystonia. Additionally, DBS is currently being evaluated for the treatment of other psychiatric and neurological disorders, such as obsessive compulsive disorder, major depressive disorder, and epilepsy.
DBS has not only been shown to help people by improving their quality of life, it also provides researchers with the unique opportunity to study and understand the human brain. Microelectrode recordings are routinely performed during DBS surgery in order to enhance the precision of anatomical targeting. Firing patterns of individual neurons can therefore be recorded while the subject performs a behavioral task. Early studies using these data focused on descriptive aspects, including firing and burst rates, and frequency modulation 3. More recent studies have focused on cognitive aspects of behavior in relation to neuronal activity 4,5. This article will provide a description of the intra-operative methods used to perform behavioral tasks and record neuronal data with awake patients during DBS cases. Our exposition of the process of acquiring electrophysiological data will illuminate the current scope and limitations of intra-operative human experiments.
1. Subject Recruitment and Consent
2. Behavioral Training and Rig Setup
3. Intra-operative – Experimental Setup
4. Isolation of Subthalamic Nucleus Neurons
5. Data Acquisition
6. Data Analysis
Representative Results:
Figure 1 depicts representative results from a single STN neuron recorded during the War game described above. The top panels depict rasters 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. The bottom panels represent binned (50 ms bins) peri-stimulus time histograms (PSTHs). 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.
Figure 1. Representative STN neuron. Rasters (top panels) and peri-stimulus time histograms (PSTHs) centered on behaviorally relevant epochs are depicted for a representative single STN neuron. This neuron’s firing increases significantly around the time of the button push indicating the subject’s wager.
Deep Brain Stimulation surgery offers a valuable opportunity to examine the activity of individual neurons in the human brain. To date this opportunity has permitted numerous descriptive studies that characterize the activities of different deep nuclei. More recently, intra-operative tasks have become more sophisticated in order to address various aspects of behavior and cognition. The intent of the current protocol is to provide a guide for implementing successful intra-operative behavioral tasks. The goals of the task and the purpose of the study will of course vary depending on the nucleus targeted for surgery. Given the increasing number of applications for DBS surgery and correspondingly increasing variety of targets, we expect burgeoning opportunities for studying human brain function at the level of individual neurons.
There are a number of factors and critical steps that need to be considered when implementing an intra-operative study. Foremost, there are considerable time limitations to these studies, which results in a limited number of behavioral trials that can be gathered for each subject. Hence, when designing a task, one should thoughtfully limit the number of conditions in the task to ensure sufficient statistical power to see an effect. There are a number of ways to overcome this limitation. One could try to reduce the number of trial condition permutations, simplify the complexity of trial sequences, and/or simply gather more data. A second substantial limitation to these studies is the quality of the neurophysiological data. Because single-unit isolation is done in the operating room setting and not the laboratory, stable high signal-to-noise ratio recordings are difficult to achieve. If the quality of the neuronal signal decreases early in a behavioral session, it is recommended that one stop the task and isolate new neurons. One final, critical step is allowing the patient sufficient time to master the behavioral task. If this step is overlooked, the data gathered will most likely be confounded by learning effects. Therefore, utilize the pre-operative period to ensure that the subject is trained and fully understands the task.
Intra-operative studies provide a truly unique opportunity to understand the human brain and pathology. However, these experiments occur in the dynamic conditions of an operating room and are therefore subject to complications not typically seen in the well controlled environment of a research laboratory.
The authors have nothing to disclose.
Material Name | Type | Company | Catalogue Number | Comment |
---|---|---|---|---|
Behavioral Rig | ||||
PC with dual Video Out | Dell Computers* | Optiplex 745 | ||
Digital Boards | National Instruments** | PCI-6229 | ||
Connector Board | National Instruments** | BNC-2090a | ||
Software | The MathWorks | Matlab 2007b*** | ||
Behavioral Software | Eskandar Lab | www.Monkeylogic.net | ||
Acquisition Rig | ||||
PC | Dell Computers * | Optiplex 745 | ||
Digital Boards | Cambridge Electronic Designs* | Power 1401 | ||
Software | Cambridge Electronic Designs* | Spike2 | ||
Signal Processing | Alpha-Omega Engineering* | Micro-Guide Pro | ||
Analysis | ||||
Neuonal Signal post-processing | Plexon * | Offline Sorter | ||
Software | The MathWorks * | Matlab 2007b | ||
Button Box | Refer to ‘Button Assembly’ |
*Denotes that this items can be substitute for by comparable equipment or software;
** Denotes that substitute National Instruments components can be used (refer to www.Monkeylogic.net for compatibility);
*** Refer to www.Monkeylogic.net for specific required Matlab toolboxs.