This work was supported by EFRI-MC3: # 1137237 awarded to S.V.S. and J.T.G.

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
<ol>
	<li>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&#8217;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. .</li>
	<li>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.</li>
	<li>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.</li>
	<li>Maintain respect for the patient&#8217;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.</li>
	<li>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.</li>
</ol>
2. Behavior System Set-up
<ol>
	<li>Before bringing the equipment into the room, ensure that there is sufficient space in the patient&#8217;s room, as well as access to the necessary outlets (2).</li>
	<li>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&#8217;s research. For instance, use a button box for the patient interface instead of the robotic arm.</li>
	<li>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.</li>
	<li>When the patient is ready, bring the behavioral system into the room and begin booting up the behavioral system and robotic arm.</li>
	<li>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.</li>
	<li>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.</li>
	<li>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 &#38; y position of the robotic arm are recorded simultaneously.</li>
</ol>
3. Behavioral Task
<ol>
	<li>Explain the task to the patient following the completion of the rig set up and calibration of the interface device.</li>
	<li>Use a behavioral task similar to the children&#8217;s card game of &#8220;war&#8221;. Ask the patient to make wagers as to whether their card is greater than the computer&#8217;s card. The choice of the wager is based on the patients&#8217; 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.</li>
	<li>Show a fixation cue on the screen for 350 msec. Ensure the patient holds the cursor over the fixation mark to initiate the task.</li>
	<li>Show the stimulus for 1,000 msec. Allow the patient to see their card with the computer&#8217;s card next to it face down.</li>
	<li>Following the cards disappearance, show a go-cue (&#60;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.</li>
	<li>After the wager has been selected, notice a 250 - 500 msec delay (blank screen), followed by the revelation of the computer&#8217;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.</li>
	<li>Allow the patient to practice until they are confident in their performance and have no questions.</li>
</ol>
4. Data Acquisition
<ol>
	<li>Record the data when the patient is ready and verify that the settings on the research (or clinical) acquisition system are appropriately selected.</li>
	<li>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.</li>
	<li>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.</li>
</ol>
5. Data Analysis
<ol>
	<li>First, de-identify the recorded SEEG data to ensure that the patient&#8217;s information remains confidential and that his/her data is submitted anonymously.</li>
	<li>Obtain the coordinates of the electrode locations from the postoperative CT and preoperative MRI.</li>
	<li>Align the neurophysiological recordings with the digital timestamps of interests from the behavioral task.</li>
	<li>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 toolbox26,27. 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.</li>
</ol>

<ol>
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Neurosurg. 22 (4), 174-180 (1995).</li><li>Jayakar, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Invasive+EEG+monitoring+in+children:+When,+where,+and+what.">Invasive EEG monitoring in children: When, where, and what.</a> J Clin Neurophysiol. 16, 408-418 (1999).</li><li>Almeida, A. N., Martinez, V., Feindel, W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+first+case+of+invasive+EEG+monitoring+for+the+surgical+treatment+of+epilepsy:+Historical+significance+and+context.">The first case of invasive EEG monitoring for the surgical treatment of epilepsy: Historical significance and context.</a> Epilepsia. 46, 1082-1085 (2005).</li><li>Dinner, D. S., Luders, H. 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The authors have no conflicts to disclose.

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...

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 required3,4.
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&#8217;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&#39;s demonstrated their safety and efficacy6. The SEEG method was developed and popularized in France by Jean Tailarach and Jean Bancaud during the 50&#8217;s and has been mostly used in France and Italy as the method of choice for invasive mapping in refractory focal epilepsy7-9.
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 craniotomies10-15. 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 SEEG24,25.
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.

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

performing behavioral tasks in subjects with intracranial electrodes

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.

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...

Watch this Scientific Journal Video about Performing Behavioral Tasks in Subjects with Intracranial Electrodes at JoVE.com

Performing Behavioral Tasks in Subjects with Intracranial Electrodes

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.

Patients having stereo-electroencephalography (SEEG) electrode, subdural grid or depth electrode implants have a multitude of electrodes implanted in ...

performing-behavioral-tasks-in-subjects-with-intracranial-electrodes

Research

JoVE Journal

Behavior

11.3K Views.  Cleveland Clinic Foundation.  Patiënten geïmplanteerd met intracraniële elektroden bieden een unieke kans om neurologische gegevens uit verschillende gebieden van de hersenen nemen terwijl de patiënt voert gedragstaken. Hier presenteren we een methode van het opnemen van geïmplanteerde patiënten die reproduceerbaar bij andere instellingen kunnen zijn die toegang hebben tot deze patiëntengroep. 

Video: Performing Behavioral Tasks in Subjects with Intracranial Electrodes

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

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.

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 ...

Medicine

Combined Invasive Subcortical and Non-invasive Surface Neurophysiological Recordings for the Assessment of Cognitive and Emotional Functions in Humans

In spite of the success in applying non-invasive electroencephalography (EEG), magneto-encephalography (MEG) and functional magnetic resonance imaging (fMRI) for extracting crucial information about the mechanism of the human brain, such methods remain insufficient to provide information about physiological processes reflecting cognitive and emotional functions at the subcortical level. In this respect, modern invasive clinical approaches in humans, such as deep brain stimulation (DBS), offer a tremendous possibility to record subcortical brain activity, namely local field potentials (LFPs) representing coherent activity of neural assemblies from localized basal ganglia or thalamic regions. Notwithstanding the fact that invasive approaches in humans are applied only after medical indication and thus recorded data correspond to altered brain circuits, valuable insight can be gained regarding the presence of intact brain functions in relation to brain oscillatory activity and the pathophysiology of disorders in response to experimental cognitive paradigms. In this direction, a growing number of DBS studies in patients with Parkinson&#39;s disease (PD) target not only motor functions but also higher level processes such as emotions, decision-making, attention, memory and sensory perception. Recent clinical trials also emphasize the role of DBS as an alternative treatment in neuropsychiatric disorders ranging from obsessive compulsive disorder (OCD) to chronic disorders of consciousness (DOC). Consequently, we focus on the use of combined invasive (LFP) and non-invasive (EEG) human brain recordings in assessing the role of cortical-subcortical structures in cognitive and emotional processing trough experimental paradigms (e.g. speech stimuli with emotional connotation or paradigms of cognitive control such as the Flanker task), for patients undergoing DBS treatment.

The present protocol aims at assessing cognitive-emotional functions in the basal ganglia by simultaneous neurophysiological recording of local field potentials and non-invasive brain cortical activity (EEG). The procedure is exemplified by the use of paradigms involving speech stimuli with emotional connotation or the Flanker task involving cognitive control.

In spite of the success in applying non-invasive electroencephalography (EEG), magneto-encephalography (MEG) and functional magnetic resonance imaging ...

Surgical Implantation of Chronic Neural Electrodes for Recording Single Unit Activity and Electrocorticographic Signals

The success of long-term electrophysiological recordings often depends on the quality of the implantation surgery. Here we provide useful information for surgeons who are learning the process of implanting electrode systems. We demonstrate the implantation procedure of both a penetrating and a surface electrode. The surgical process is described from start to finish, including detailed descriptions of each step throughout the procedure. It should also be noted that this video guide is focused towards procedures conducted in rodent models and other small animal models. Modifications of the described procedures are feasible for other animal models.

We provide useful information for surgeons who are learning the process of implanting chronic neural recording electrodes. Techniques for both penetrating and surface electrode systems are described in a rodent animal model.

The success of long-term electrophysiological recordings often depends on the quality of the implantation surgery.  Here we provide useful information for ...

Neuroscience

Recording Human Electrocorticographic (ECoG) Signals for Neuroscientific Research and Real-time Functional Cortical Mapping

Neuroimaging studies of human cognitive, sensory, and motor processes are usually based on noninvasive techniques such as electroencephalography (EEG), magnetoencephalography or functional magnetic-resonance imaging. These techniques have either inherently low temporal or low spatial resolution, and suffer from low signal-to-noise ratio and/or poor high-frequency sensitivity. Thus, they are suboptimal for exploring the short-lived spatio-temporal dynamics of many of the underlying brain processes. In contrast, the invasive technique of electrocorticography (ECoG) provides brain signals that have an exceptionally high signal-to-noise ratio, less susceptibility to artifacts than EEG, and a high spatial and temporal resolution (i.e., &lt;1 cm/&lt;1 millisecond, respectively). ECoG involves measurement of electrical brain signals using electrodes that are implanted subdurally on the surface of the brain. Recent studies have shown that ECoG amplitudes in certain frequency bands carry substantial information about task-related activity, such as motor execution and planning1, auditory processing2 and visual-spatial attention3. Most of this information is captured in the high gamma range (around 70-110 Hz). Thus, gamma activity has been proposed as a robust and general indicator of local cortical function1-5. ECoG can also reveal functional connectivity and resolve finer task-related spatial-temporal dynamics, thereby advancing our understanding of large-scale cortical processes. It has especially proven useful for advancing brain-computer interfacing (BCI) technology for decoding a user's intentions to enhance or improve communication6 and control7. Nevertheless, human ECoG data are often hard to obtain because of the risks and limitations of the invasive procedures involved, and the need to record within the constraints of clinical settings. Still, clinical monitoring to localize epileptic foci offers a unique and valuable opportunity to collect human ECoG data. We describe our methods for collecting recording ECoG, and demonstrate how to use these signals for important real-time applications such as clinical mapping and brain-computer interfacing. Our example uses the BCI2000 software platform8,9 and the SIGFRIED10 method, an application for real-time mapping of brain functions. This procedure yields information that clinicians can subsequently use to guide the complex and laborious process of functional mapping by electrical stimulation.
Prerequisites and Planning:
Patients with drug-resistant partial epilepsy may be candidates for resective surgery of an epileptic focus to minimize the frequency of seizures. Prior to resection, the patients undergo monitoring using subdural electrodes for two purposes: first, to localize the epileptic focus, and second, to identify nearby critical brain areas (i.e., eloquent cortex) where resection could result in long-term functional deficits. To implant electrodes, a craniotomy is performed to open the skull. Then, electrode grids and/or strips are placed on the cortex, usually beneath the dura. A typical grid has a set of 8 x 8 platinum-iridium electrodes of 4 mm diameter (2.3 mm exposed surface) embedded in silicon with an inter-electrode distance of 1cm. A strip typically contains 4 or 6 such electrodes in a single line. The locations for these grids/strips are planned by a team of neurologists and neurosurgeons, and are based on previous EEG monitoring, on a structural MRI of the patient's brain, and on relevant factors of the patient's history. Continuous recording over a period of 5-12 days serves to localize epileptic foci, and electrical stimulation via the implanted electrodes allows clinicians to map eloquent cortex. At the end of the monitoring period, explantation of the electrodes and therapeutic resection are performed together in one procedure.
In addition to its primary clinical purpose, invasive monitoring also provides a unique opportunity to acquire human ECoG data for neuroscientific research. The decision to include a prospective patient in the research is based on the planned location of their electrodes, on the patient's performance scores on neuropsychological assessments, and on their informed consent, which is predicated on their understanding that participation in research is optional and is not related to their treatment. As with all research involving human subjects, the research protocol must be approved by the hospital's institutional review board. The decision to perform individual experimental tasks is made day-by-day, and is contingent on the patient's endurance and willingness to participate. Some or all of the experiments may be prevented by problems with the clinical state of the patient, such as post-operative facial swelling, temporary aphasia, frequent seizures, post-ictal fatigue and confusion, and more general pain or discomfort.
At the Epilepsy Monitoring Unit at Albany Medical Center in Albany, New York, clinical monitoring is implemented around the clock using a 192-channel Nihon-Kohden Neurofax monitoring system. Research recordings are made in collaboration with the Wadsworth Center of the New York State Department of Health in Albany. Signals from the ECoG electrodes are fed simultaneously to the research and the clinical systems via splitter connectors. To ensure that the clinical and research systems do not interfere with each other, the two systems typically use separate grounds. In fact, an epidural strip of electrodes is sometimes implanted to provide a ground for the clinical system. Whether research or clinical recording system, the grounding electrode is chosen to be distant from the predicted epileptic focus and from cortical areas of interest for the research. Our research system consists of eight synchronized 16-channel g.USBamp amplifier/digitizer units (g.tec, Graz, Austria). These were chosen because they are safety-rated and FDA-approved for invasive recordings, they have a very low noise-floor in the high-frequency range in which the signals of interest are found, and they come with an SDK that allows them to be integrated with custom-written research software. In order to capture the high-gamma signal accurately, we acquire signals at 1200Hz sampling rate-considerably higher than that of the typical EEG experiment or that of many clinical monitoring systems. A built-in low-pass filter automatically prevents aliasing of signals higher than the digitizer can capture. The patient's eye gaze is tracked using a monitor with a built-in Tobii T-60 eye-tracking system (Tobii Tech., Stockholm, Sweden). Additional accessories such as joystick, bluetooth Wiimote (Nintendo Co.), data-glove (5th Dimension Technologies), keyboard, microphone, headphones, or video camera are connected depending on the requirements of the particular experiment.
Data collection, stimulus presentation, synchronization with the different input/output accessories, and real-time analysis and visualization are accomplished using our BCI2000 software8,9. BCI2000 is a freely available general-purpose software system for real-time biosignal data acquisition, processing and feedback. It includes an array of pre-built modules that can be flexibly configured for many different purposes, and that can be extended by researchers' own code in C++, MATLAB or Python. BCI2000 consists of four modules that communicate with each other via a network-capable protocol: a Source module that handles the acquisition of brain signals from one of 19 different hardware systems from different manufacturers; a Signal Processing module that extracts relevant ECoG features and translates them into output signals; an Application module that delivers stimuli and feedback to the subject; and the Operator module that provides a graphical interface to the investigator.
A number of different experiments may be conducted with any given patient. The priority of experiments will be determined by the location of the particular patient's electrodes. However, we usually begin our experimentation using the SIGFRIED (SIGnal modeling For Realtime Identification and Event Detection) mapping method, which detects and displays significant task-related activity in real time. The resulting functional map allows us to further tailor subsequent experimental protocols and may also prove as a useful starting point for traditional mapping by electrocortical stimulation (ECS).
Although ECS mapping remains the gold standard for predicting the clinical outcome of resection, the process of ECS mapping is time consuming and also has other problems, such as after-discharges or seizures. Thus, a passive functional mapping technique may prove valuable in providing an initial estimate of the locus of eloquent cortex, which may then be confirmed and refined by ECS. The results from our passive SIGFRIED mapping technique have been shown to exhibit substantial concurrence with the results derived using ECS mapping10.
The protocol described in this paper establishes a general methodology for gathering human ECoG data, before proceeding to illustrate how experiments can be initiated using the BCI2000 software platform. Finally, as a specific example, we describe how to perform passive functional mapping using the BCI2000-based SIGFRIED system.

Recording Human Electrocorticographic ECoG Signals for Neuroscientific Research and Real-time Functional Cortical Mapping

We present a method for collecting electrocorticographic signals for research purposes from humans who are undergoing invasive epilepsy monitoring. We show how to use the BCI2000 software platform for data collection, signal processing and stimulus presentation. Specifically, we demonstrate SIGFRIED, a BCI2000-based tool for real-time functional brain mapping.

Neuroimaging studies of human cognitive, sensory, and motor processes are usually based on noninvasive techniques such as electroencephalography (EEG), ...

Investigating the Function of Deep Cortical and Subcortical Structures Using Stereotactic Electroencephalography: Lessons from the Anterior Cingulate Cortex

Stereotactic Electroencephalography (SEEG) is a technique used to localize seizure foci in patients with medically intractable epilepsy. This procedure involves the chronic placement of multiple depth electrodes into regions of the brain typically inaccessible via subdural grid electrode placement. SEEG thus provides a unique opportunity to investigate brain function. In this paper we demonstrate how SEEG can be used to investigate the role of the dorsal anterior cingulate cortex (dACC) in cognitive control. We include a description of the SEEG procedure, demonstrating the surgical placement of the electrodes. We describe the components and process required to record local field potential (LFP) data from consenting subjects while they are engaged in a behavioral task. In the example provided, subjects play a cognitive interference task, and we demonstrate how signals are recorded and analyzed from electrodes in the dorsal anterior cingulate cortex, an area intimately involved in decision-making. We conclude with further suggestions of ways in which this method can be used for investigating human cognitive processes.

Stereotactic Electroencephalography (SEEG) is an operative technique used in epilepsy surgery to help localize seizure foci. It also affords a unique opportunity to investigate brain function. Here we describe how SEEG can be used to investigate cognitive processes in human subjects.

Stereotactic Electroencephalography (SEEG) is a technique used to localize seizure foci in patients with medically intractable epilepsy. This procedure ...

Rodent Behavioral Testing to Assess Functional Deficits Caused by Microelectrode Implantation in the Rat Motor Cortex

Medical devices implanted in the brain hold tremendous potential. As part of a Brain Machine Interface (BMI) system, intracortical microelectrodes demonstrate the ability to record action potentials from individual or small groups of neurons. Such recorded signals have successfully been used to allow patients to interface with or control&#160;computers, robotic limbs, and their own limbs. However, previous animal studies have shown that a microelectrode implantation in the brain not only damages the surrounding tissue but can also result in functional deficits. Here, we discuss a series of behavioral tests to quantify potential motor impairments following the implantation of intracortical microelectrodes into the motor cortex of a rat. The methods for open field grid, ladder crossing, and grip strength testing provide valuable information regarding the potential complications resulting from a microelectrode implantation. The results of the behavioral testing are correlated with endpoint histology, providing additional information on the pathological outcomes and impacts of this procedure on the adjacent tissue.

We have shown that a microelectrode implantation in the motor cortex of rats causes immediate and lasting motor deficits. The methods proposed herein outline a microelectrode implantation surgery and three rodent behavioral tasks to elucidate potential changes in the fine or gross motor function due to implantation-caused damage to the motor cortex.

Medical devices implanted in the brain hold tremendous potential. As part of a Brain Machine Interface (BMI) system, intracortical microelectrodes ...

Bioengineering

Transcranial Electrical Brain Stimulation in Alert Rodents

Transcranial electrical brain stimulation can modulate cortical excitability and plasticity in humans and rodents. The most common form of stimulation in humans is transcranial direct current stimulation (tDCS). Less frequently, transcranial alternating current stimulation (tACS) or transcranial random noise stimulation (tRNS), a specific form of tACS using an electrical current applied randomly within a pre-defined frequency range, is used. The increase of noninvasive electrical brain stimulation research in humans, both for experimental and clinical purposes, has yielded an increased need for basic, mechanistic, safety studies in animals. This article describes a model for transcranial electrical brain stimulation (tES) through the intact skull targeting the motor system in alert rodents. The protocol provides step-by-step instructions for the surgical set-up of a permanent epicranial electrode socket combined with an implanted counter electrode on the chest. By placing a stimulation electrode into the epicranial socket, different electrical stimulation types, comparable to tDCS, tACS, and tRNS in humans, can be delivered. Moreover, the practical steps for tES in alert rodents are introduced. The applied current density, stimulation duration, and stimulation type may be chosen depending on the experimental needs. The caveats, advantages, and disadvantages of this set-up are discussed, as well as safety and tolerability aspects.

This protocol describes a surgical set-up for a permanent epicranial electrode socket and an implanted chest electrode in rodents. By placing a second electrode into the socket, different types of transcranial electrical brain stimulation can be delivered to the motor system in alert animals through the intact skull.

Transcranial electrical brain stimulation can modulate cortical excitability and plasticity in humans and rodents. The most common form of stimulation in ...

Chronic Transcranial Electrical Stimulation and Intracortical Recording in Rats

Transcranial electrical stimulation (TES) is a powerful and relatively simple approach to diffusely influence brain activity either randomly or in a closed-loop event-triggered manner. Although many studies are focusing on the possible benefits and side-effects of TES in healthy and pathologic brains, there are still many fundamental open questions regarding the mechanism of action of the stimulation. Therefore, there is a clear need for a robust and reproducible method to test the acute and the chronic effects of TES in rodents. TES can be combined with regular behavioral, electrophysiological, and imaging techniques to investigate neuronal networks in vivo. The implantation of transcranial stimulation electrodes does not impose extra constraints on the experimental design while it offers a versatile, flexible tool to manipulate brain activity. Here we provide a detailed, step-by-step protocol to fabricate and implant transcranial stimulation electrodes to influence brain activity in a temporally constrained manner for months.

This detailed protocol describes transcranial stimulation electrode placement on the temporal bone in order to investigate the short- and long-term effects of transcranial electrical stimulation in freely moving rats.

Transcranial electrical stimulation (TES) is a powerful and relatively simple approach to diffusely influence brain activity either randomly or in a ...

Analyzing Neural Activity and Connectivity Using Intracranial EEG Data with SPM Software

Measuring neural activity and connectivity associated with cognitive functions at high spatial and temporal resolutions is an important goal in cognitive neuroscience. Intracranial electroencephalography (EEG) can directly record electrical neural activity and has the unique potential to accomplish this goal. Traditionally, averaging analysis has been applied to analyze intracranial EEG data; however, several new techniques are available for depicting neural activity and intra- and inter-regional connectivity. Here, we introduce two analytical protocols we recently applied to analyze intracranial EEG data using the Statistical Parametric Mapping (SPM) software: time-frequency SPM analysis for neural activity and dynamic causal modeling of induced responses for intra- and inter-regional connectivity. We report our analysis of intracranial EEG data during the observation of faces as representative results. The results revealed that the inferior occipital gyrus (IOG) showed gamma-band activity at very early stages (110 ms) in response to faces, and both the IOG and amygdala showed rapid intra- and inter-regional connectivity using various types of oscillations. These analytical protocols have the potential to identify the neural mechanisms underlying cognitive functions with high spatial and temporal profiles.

We present two analytical protocols that can be used to analyze intracranial electroencephalography data using the Statistical Parametric Mapping (SPM) software: time-frequency statistical parametric mapping analysis for neural activity, and dynamic causal modeling of induced responses for intra- and inter-regional connectivity.

Measuring neural activity and connectivity associated with cognitive functions at high spatial and temporal resolutions is an important goal in cognitive ...

Mapping Cerebral Blood Flow and Electrical Fields: Electrode Placement in Mice

Placement of Extracranial Stimulating Electrodes and Measurement of Cerebral Blood Flow and Intracranial Electrical Fields in Anesthetized Mice

The detection of cerebral blood flow (CBF) responses to various forms of neuronal activation is critical for understanding dynamic brain function and variations in the substrate supply to the brain. This paper describes a protocol for measuring CBF responses to transcranial alternating current stimulation (tACS). Dose-response curves are estimated both from the CBF change occurring with tACS (mA) and from the intracranial electric field (mV/mm). We estimate the intracranial electrical field based on the different amplitudes measured by glass microelectrodes within each side of the brain. In this paper, we describe the experimental setup, which involves using either bilateral laser Doppler (LD) probes or laser speckle imaging (LSI) to measure the CBF; as a result, this setup requires anesthesia for the electrode placement and stability. We present a correlation between the CBF response and the current as a function of age, showing a significantly larger response at higher currents (1.5 mA and 2.0 mA) in young control animals (12-14 weeks) compared to older animals (28-32 weeks) (p &lt; 0.005 difference). We also demonstrate a significant CBF response at electrical field strengths &lt;5 mV/mm, which is an important consideration for eventual human studies. These CBF responses are also strongly influenced by the use of anesthesia compared to awake animals, the respiration control (i.e., intubated vs. spontaneous breathing), systemic factors (i.e., CO2), and local conduction within the blood vessels, which is mediated by pericytes and endothelial cells. Likewise, more detailed imaging/recording techniques may limit the field size from the entire brain to only a small region. We describe the use of extracranial electrodes for applying tACS stimulation, including both homemade and commercial electrode designs for rodents, the concurrent measurement of the CBF and intracranial electrical field using bilateral glass DC recording electrodes, and the imaging approaches. We are currently applying these techniques to implement a closed-loop format for augmenting the CBF in animal models of Alzheimer's disease and stroke.

Author Spotlight: Stimulation-Based Approach to Improve Cerebral Blood Flow in Alzheimer's Model 

We describe a protocol for assessing dose-response curves for extracranial stimulation in terms of brain electrical field measurements and a relevant biomarker-cerebral blood flow. Since this protocol involves invasive electrode placement into the brain, general anesthesia is needed, with spontaneous breathing preferred rather than controlled respirations.

The detection of cerebral blood flow (CBF) responses to various forms of neuronal activation is critical for understanding dynamic brain function and ...

Performing Behavioral Tasks in Subjects with Intracranial Electrodes

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