This work was supported by ERA-NET NEURON/BMBF Germany (TYMON). Publication fees are covered by a grant from the University Hospital D&#252;sseldorf.&#160;The Flanker task used here was modified from the initially programmed version by Prof. C. Beste and his group47.

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</ol>

The authors declare that they have no competing financial interests.

In contrast to non-invasive brain recording techniques like scalp-EEG and MEG, the proposed combined invasive and non-invasive neurophysiological recording framework provides a remarkable opportunity to extract information from cortical and subcortical areas in relation to cognitive-emotional tasks. Such information is reflected by brain oscillatory activity at multiple frequency bands and different levels of organization in relation to brain functioning44. Brain oscillatory patterns that are relevant in our recording framework include: subcortical oscillatory activity (LFPs), changes in cortical-subcortical coherence indicating changes in linear correlation between activities at cortical and subcortical regions on specific frequency bands, subcortical phase-amplitude coupling (PAC) and phase-phase coupling (PPC). In particular, the relevance of PAC and PPC is emphasized as the relation and interaction between oscillations in different frequency bands has been shown to be useful in understanding brain function. In the case of PAC, the phase of a low frequency oscillation is related to the power of a high frequency oscillation thus resulting in synchronization of the amplitude envelope of faster rhythms with the phase of slower rhythms. PPC represents an amplitude independent phase locking between n cycles of high frequency oscillation and m cycles of a low frequency one45. Focusing on the DBS-DOC case example (Example 2), analysis of cortical/subcortical recorded data for the familiar-addressing speech condition revealed modulation of oscillatory activity in the beta and theta band within the central thalamus together with increased thalamocortical coherence in the theta band. In addition, a theta phase - gamma amplitude coupling was apparent within the thalamus locally. These findings not only support the involvement of the thalamus in emotional and cognitive processing but also emphasize functions that are intact in chronic DOC patients and that could be useful in the assessment of conscious states in such patients26.
Methodologically, as exemplified by our two examples, the most relevant steps for recording and analysis of cortical-subcortical brain activity in relation to emotional-cognitive processing include:
1) Design of an experimental paradigm, by taking into consideration the patient needs and constraints in a post-operative setting, ensuring that he/she will be able to carry out the task specified in the study without compromising his/her integrity while maximizing the chance of success in the completion of the experiment.
2) Obtaining signed informed consent from patient, patient&#39;s family members or ethical commission to carry out post-operative recording. In the DBS-DOC case example (Example 2) approval was solely obtained from the ethical commission due to the patient&#39;s unconscious state (coma). In the case of patients with motor disorders consent was obtained directly from the patient.
3) Definition of an appropriate experimental set-up for simultaneous recording of subcortical LPFs and cortical M(EEG) activity. In the case of EEG, we emphasize: Proper choice and set-up of an EEG channel montage and electrode placement on the patient&#39;s scalp. In particular, electrode placement could be challenging due to the presence of bandages on the patient&#39;s head after DBS surgery, so advice of an EEG professional or neurologist is highly recommended for appropriate placement; It is recommended not to carry out any impedance control check in order to prevent any current to be sent directly into the brain of the patient (&#34;off-label&#34; use of EEG-amplifier). Note that the impedance check&#39;s mode in many EEG systems utilizes a small current that passes through all attached electrodes so the resulting voltage and impedances are estimated by Ohm&#39;s law; Selection of an appropriate recording sampling rate and frequency band is mainly determined by factors such as the EEG equipment capabilities, the research question under study and the Nyquist sampling rule, which states that the sampling rate required to eliminate alias frequencies in a bandwidth limited signal (at a value equal to half the Nyquist rate) is two times the highest frequency component present in the signal.
4) Selection of appropriate software tools: All the calculations in the quantitative analysis of the DBS-DOC data (Example 2) were performed by commercial analysis software, open source suites46 and self-customized scripts (see supplementary files). An advantage of open source software tools is the opportunity to customize one&#39;s own analysis pipelines by modifying and combining existing scripts (under the common license attribution). However, in order to do so deeper understanding of the mathematical basis of signal processing and programming are required. Also, data processed by such customized pipeline need to comply with the format required by the specific suite. In the case of commercial software tools, data processing is facilitated by graphical interfaces that make each processing step as intuitive as possible, however users are limited in their capability to modify the algorithms included in the software. As exemplified by the present protocol, a combination of commercial and open source software tools is fruitful as long as the data can be exported (imported) in a compatible way from one system to the other.
5) Limitations and Modifications: The proposed invasive/non-invasive recording framework has limitations in both its use and the recordings provided. As a clinical technique, it is only directed to patients that undergo DBS treatment for a specific medical condition and brain target, consequently the brain areas considered for study will be constrained by the operative plan. The spatial resolution of recordings provided by this technique is at the level of LFP potentials, thus medical translational studies requiring analysis of brain activity at the multiscale level will have to be complemented by animal studies involving recordings at the single cell level. With regard to the DBS-DOC case-example (Example 2), a limitation pertains also to the generalizability of the obtained results as it deals with a single-case study.
Possible modifications and troubleshooting of the Flanker task (Example 1) include enlargement of the response stimulus-interval (&#62;2,000 msec) concerning the inability of patients to react within a specified time interval. This is particularly important in the case of Huntington disease patients, who are characterized by jerky involuntary movements together with cognitive and emotional decline. Also, the task (originally consisting of four blocks of 120 stimuli each) may be shortened due to inability of a patient to continue because of fatigue. In this respect, the physical condition and age would be determinant factors for patient&#39;s selection.
It is concluded that the proposed invasive/non-invasive brain recording approach not only represents a powerful tool for extracting brain oscillatory patterns at the cortico-subcortical level in relation to cognitive and emotion paradigms, but also stresses the importance of time-frequency-phase analyses for extracting brain synchronization patterns at different spatial and temporal resolutions. Future application of this technique includes the study of cortico-subcortical neural correlates of cognitive and sensory processing by targeting not only patients suffering from motor disorders but also psychiatric disorders such as DOC, OCD, depression and dementia.

Invasive neurophysiological recordings in humans date back to seminal studies targeting electrocorticographic recordings from cortical areas and the cerebellum during epilepsy surgery and tumor research1. A critical milestone into further development of such recording procedure has been the introduction of the stereotactic technique that provides safe and efficient access to deep structures of the human brain2. Apart from clinical treatment, brain invasive approaches in humans provide a rather unique opportunity to study brain function in relation to recorded activity patterns modulated by external stimuli, notably the case of intra- and post-operative invasive recordings in patients undergoing deep brain stimulation (DBS) procedures. The applicability and usefulness of DBS has been addressed in various neurological and neuropsychiatric diseases from Parkinson&#39;s disease (PD) to obsessive compulsive disorder (OCD) or conditions like chronic disorders of consciousness (DOC).
In particular, DBS has been applied in the treatment of Parkinson&#39;s disease3,4,5, essential tremor6, primary/generalized segmental dystonia7,8,9, Huntington&#39;s disease10,11, treatment-resistant-depression12,13, nicotine and alcohol addiction14, Alzheimer&#39;s disease15,16, Tourette&#39;s syndrome17 and chronic disorder of consciousness (DOC)18,19,20.
Within the scope of neuropsychiatry, DBS is an approved/CE-marked treatment for obsessive compulsive disorder (OCD) targeting the anterior limb of the internal capsule (ALIC) and is in use targeting the ventral capsule/ventral striatum/ventral caudate (VC/VS),nucleus accumbens (Nac) and the subthalamic nucleus (STN)21. Regarding DBS in OCD22, recent studies emphasize the role of STN into the mechanism of compulsive checking by utilizing memory based-paradigms23,24,25.
Noteworthy, modulation of brain activity under the influence of paradigms with cognitive and emotional connotation has been emphasized in DOC26,27,28,29. Thus, DBS is highlighted not only as a prospective treatment for chronic DOC, but also as a clinical procedure that opens up the possibility of studying the modulation of subcortical activity by recording local field potentials (LFP) from central thalamic regions intra- and post- operatively.
In DBS, neurosurgical implantation of electrodes is based on the stereotactic technique that safely accounts for brain anatomical constraints, while patient&#39;s stimulation is customized through intra-operative impulse-stimulation tests. Post-operative LFP recording is possible after initial implantation of DBS electrodes and before internalization of the impulse generator. In particular, the present protocol is centered on post-operative recordings.
In combination with LFPs, simultaneous recording of cortical brain activity can be achieved for instance by non-invasive electroencephalography (EEG) or magnetoencephalography (MEG)30,31. These two non-invasive methods are supported due to its excellent time resolution. While MEG is less affected than EEG by skull effects32, EEG appears advantageous because it is less affected by artifacts caused by metallic implants and head movements and it can be used at the patient&#39;s bed-side33. By simultaneous recording of cortical-subcortical brain activity (LFP and EEG/MEG) in response to applied emotional-cognitive paradigms, different relationships between brain oscillations and behavior could be established on the basis of time-frequency coupling analyses34. In turn, such patterns could lead to prospective biomarkers of a patient&#39;s individualized cognitive and emotional states and optimization of treatment parameters considering individualized settings.
The following protocol targets invasive and non-invasive neurophysiological recording in humans for the assessment of cognitive and emotional function, specifically at the cortical and subcortical level (EEG and LFPs).
First, the neurophysiological recording steps illustrated in the video, that accompanies the present protocol, correspond to a recording with an example patient with movement disorder that performs the so called Flanker task (Example 1).
Second, steps in the protocol are discussed by focusing on the methodology of analysis and sample results taken from a published DBS example in chronic DOC26 (Example 2).
These two examples highlight the applicability of the proposed protocol to DBS-treated patients with different disorders and various experimental paradigms.

<table><tbody><tr><td>BrainAmp Amplifier</td><td>Brain Products GmbH, Gilching Germany</td><td></td><td>Quantity: 2</td></tr><tr><td>BrainVision Recorder Software</td><td>Brain Products GmbH, Gilching Germany</td><td></td><td>1 License&amp;nbsp;</td></tr><tr><td>BrainVision Analyzer Software&amp;nbsp;</td><td>Brain Products GmbH, Gilching Germany</td><td></td><td>1 License&amp;nbsp;</td></tr><tr><td>Fiber Optic cables and USB connectors</td><td>Brain Products GmbH, Gilching Germany</td><td></td><td>These come with the above listed equipment</td></tr><tr><td>Electrode Input box (64 channels)</td><td>Brain Products GmbH, Gilching Germany</td><td></td><td>Quantity: 1</td></tr><tr><td>EEG gel&amp;nbsp;</td><td>Natus Inc</td><td></td><td>Quantity: 1</td></tr><tr><td>Isopropyl alcohol</td><td>Sch&amp;uuml;lke &amp;amp; Mayr GmbH, Germany</td><td></td><td>Quantity: 1</td></tr><tr><td>Skin preparation gel</td><td>Weaver and Co, USA</td><td></td><td>Quantity: 1</td></tr><tr><td>MATLAB&amp;nbsp;&amp;nbsp;</td><td>Math-Works, Natick, Massachusetts, USA</td><td></td><td>1 License</td></tr><tr><td>FieldTrip toolbox</td><td>http://www.fieldtriptoolbox.org/</td><td></td><td>Open Source</td></tr><tr><td>Macroelectrodes (model 3387 quadripolar DBS lead)</td><td>Medtronic Inc., Minneapolis, MN, USA</td><td></td><td>Quantity: 2</td></tr><tr><td>Sterile percutaneous extension wires (model 3550-05)&amp;nbsp;</td><td>Medtronic Inc., Minneapolis, MN, USA</td><td></td><td>Quantity: 2</td></tr><tr><td>Twist lock cable (model 3550-03)&amp;nbsp;</td><td>Medtronic Inc., Minneapolis, MN, USA</td><td></td><td>Quantity: 2</td></tr><tr><td>custom made connectors to DIN 428092 touch proof connectors</td><td></td><td></td><td>Quantity: 2</td></tr><tr><td>Vercise Lead kit DB -2201&amp;nbsp;</td><td>Boston Scientific</td><td></td><td>Quantity: 2</td></tr><tr><td>Contact extension kit NM-3138&amp;nbsp;</td><td>Boston Scientific</td><td></td><td>Quantity: 2</td></tr><tr><td>O.R. cabel &amp;amp; extension SC-4100 A&amp;nbsp;</td><td>Boston Scientific</td><td></td><td>Quantity: 2</td></tr><tr><td>connector&amp;nbsp;to touch proof&amp;nbsp;</td><td>Twente Medical Systems International B.V.</td><td></td><td>Quantity: 2</td></tr><tr><td>CT scanner Modell PQ2000 (Postoperative CT scans)</td><td>Philips Healthcare GmbH Hamburg</td><td></td><td>Quantity: 1</td></tr><tr><td>Presentation Software (Flanker Task)</td><td>Neurobehavioral systems Inc.</td><td></td><td>1 License&amp;nbsp;</td></tr><tr><td>MEG System</td><td>Elekta Neuromag Inc</td><td></td><td>Alternatively</td></tr><tr><td>High-density EEG sensor net (128 or 256 channels)</td><td>Electrical Geodesics Inc (EGI), USA</td><td></td><td>Alternatively</td></tr></tbody></table>

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.

For the DBS-DOC case (Example 2), we now provide data on target localization for DBS implantation, schematic diagrams of LFP electrode and EEG set up, exemplary recordings of EEG and LFP activity (raw data) and representative analysis results:
Figure 2A shows planned trajectory (black line) projected on an anatomic atlas36, section 30, coronary, 10.7 mm behind the anterior commissure (AC) (red line: AC-PC plane). Red circles mark targeted areas of the lowermost 15 mm (atlas grid size: 10 mm) with iml = internal medullary lamina thalami and Rt = reticular thalamic nucleus. VA = ventroanterior thalamic nucleus, AV = anteroventral thalamic nucleus, AM = anteromedial thalamic nucleus, Fa = fasciculosus nucleus, IthA = interthalamic adhesion.
Figure 2B shows the final electrode in the central thalamus visualized on a 3D atlas37. Two orthogonal planes of section along the axis of the electrode in the right hemisphere after registration of the 3D atlas with the CT scan by means of the atlas38. The four contacts of the electrode (blue circles) were located in the right thalamus (R-Thal). GPi = internal globus pallidus, STN = subthalamic nucleus, ZI = zona incerta, RPT = reticular perithalamic nucleus, RN = red nucleus.
Figure 2C shows a schematic drawing of the DBS electrode. Electrode contacts were re-referenced offline, resulting in three bipolar LFP channels for each hemisphere (LFPL01, LFPL12, LFPL23, LFPR01, LFPR12, and LFPR23). EEG electrode montage (10-20 system) with electrodes used during recording in the DOC case-example (Fz, Cz, Pz, Oz, T4, T3 and Fpz) (Figure 2D)
<img alt="Figure 2" src="/files/ftp_upload/53466/53466fig2.jpg" /> 
Figure 2: Target Localization, LFP Electrode and EEG Set-up (from Example 2). (A) Planned trajectory (black line) projected on an anatomic atlas36, section 30, coronary, 10.7 mm behind AC (red line: AC-PC plane). Red circles mark targeted areas of the lowermost 15 mm (atlas grid size: 10 mm) with iml = internal medullary lamina thalami and Rt = reticular thalamic nucleus. VA = ventroanterior thalamic nucleus, AV = anteroventral thalamic nucleus, AM = &#160;anteromedial thalamic nucleus, Fa = fasciculosus nucleus, IthA = interthalamic adhesion. (B) Final electrode in the central thalamus visualized on a 3D atlas37. Two orthogonal planes of section along the axis of the electrode in the right hemisphere after registration of the 3D atlas with the CT scan by means of an atlas38. The four contacts of the electrode (blue circles) were located in the right thalamus (R-Thal). GPi = internal globus pallidus, STN = subthalamic nucleus, ZI = zona incerta, RPT = reticular perithalamic nucleus, RN = red nucleus. (C) Schematic drawing of the DBS electrode. Electrode contacts were re-referenced offline, resulting in three bipolar LFP channels for each hemisphere. (D) EEG electrode montage (10 - 20 system) with electrodes used in the DOC case-example highlighted in gray. (Figures A and B were modified with permission from26, Figure C was modified with permission from Medtronic). <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53466/53466fig2large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
Figure 3A shows exemplary EEG recordings corresponding to bipolar channels: T4Cz, T3Cz, PzCz, OzPz and FzPz in the case of the neutral non-addressing condition (left) and the familiar addressing condition (right).
Figure 3B displays exemplary LFP recordings corresponding to bipolar channels: LFPL23 and LFPR23 in the case of the non-addressing condition (left) and the familiar addressing condition (right).
<img alt="Figure 3" src="/files/ftp_upload/53466/53466fig3.jpg" /> 
Figure 3: Exemplary Recordings (from Example 2). (A) Figure shows EEG recordings.The figure illustrates EEG traces corresponding to bipolar channels (see 4.2 for details about channel re-referencing). (B) Figure shows LFP recordings.The figure illustrates LFP traces corresponding to bipolar channels in the case of left and right hemispheres (see 4.2 for details about channel re-referencing). <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53466/53466fig3large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
Analysis of stimulus-locked modulation of oscillatory activity within central thalamus revealed a right-sided significant (p = 0.044) increase of beta power (12-25 Hz) within the first second (0.45-0.55 sec) when contrasting neutral addressing vs. familiar-addressing conditions (Figure 4A).
Coherence analysis between channels PzCz (EEG) and LFPR23 (right hemisphere) revealed a significant difference between conditions in the theta band. Also, the imaginary part of coherence showed deviation from zero indicating a phase delay between LFP and EEG (Figure 4B). Local analysis revealed significant (p = 0.01) theta-gamma PAC (with max. at 5-to-75 Hz) for the right local LFP channel (LFPR23-LFPR23) in the familiar-addressing condition (Figure 4C).
Analysis of power change corresponding to LFP23 revealed an early beta increase within the first second (green box) and a late theta modulation (red box) (Figure 4D, Top). It is also noticeable that Gamma around 40 Hz (green circle/ellipse) is followed by a broader and higher gamma up to 80 Hz (Figure 4D, Top). A significant theta increase in the familiar-addressing condition at 4-6.5 Hz and time period 2.6-2.8 sec&#160;(red circle), (p = 0.048) on LFPL23 as well as an increased trend on LFPR23 were revealed (Figure 4D, Bottom).
<img alt="Figure 4 A and B" src="/files/ftp_upload/53466/53466fig4AB.jpg" /> 
Figure 4: Time-frequency Power Analysis and EEG-LFP Coherence (from Example 2). (A) Local oscillatory power contrasting neutral versus familiar-addressing condition for the first second; Color code represents t-values. Top: left channel LFPL23; Bottom: right channel LFPR23. Significant beta increase (p = 0.044) at 12-25 Hz, 0.45-0.55 sec (red circle). (Modified with permission from26). (B) Familiar-addressing condition (red line) and neutral non-addressing condition (blue line). Coherence was calculated on independent 1 sec segments from epochs with duration 0-4 sec and averaged across all segments. Top (left): Coherence with channel LFPL23 left hemisphere, Top (right): Coherence with channel LFPR23 right hemisphere. Significant difference between conditions (p = 0.044) is indicated by red circle/stars for coherence with channel PzCz, 5-6 Hz. Bottom: Imaginary part of coherence between LFPR23 right hemisphere and channel Cz (green circle) shows deviation from zero meaning a phase delay between LFP and EEG (thus effect not due to volume conduction).&#160;(Modified with permission from26) <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53466/53466fig4ABlarge.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

<img alt="Figure 4C" src="/files/ftp_upload/53466/53466fig4C.jpg" /> 
Figure 4C: Phase Amplitude Coupling (PAC) (from Example 2). PAC for phase frequencies 3-22 Hz and amplitude frequencies 35-80 Hz. Colors encode normalized direct phase-amplitude cross-frequency coupling (ndPAC). Spurious coupling is set to 0 (p = 0.01). Conditions: left: neutral, right: familiar-addressing. Top: PAC of right local LFP channel LFPR23-LFPR23 showing PAC in familiar addressing condition with max. at 5-75 Hz (red circle). Bottom: PAC of right LFP-EEG combination with LFPR23-EEGPzCz. (Modified with permission from26) <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53466/53466fig4Clarge.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 4D" src="/files/ftp_upload/53466/53466fig4D.jpg" /> 
Figure 4D: LFP Time-frequency Analysis (from Example 2). Time frequency plots of local power changes at LFP23. TOP: Power difference from baseline in the familiar-addressing condition over the period of the trial (0-4 sec). Left: broad frequency band 5-80 Hz, right: gamma band; top row: left hemisphere (LFPL23), bottom row: right hemisphere (LFPR23). BOTTOM: Statistical contrast between conditions illustrating significant theta increase in the familiar-addressing condition at 4-6.5 Hz and time period 2.6-2.8 sec (red circle), p = 0.048 on LFPL23 and increase (trend) on LFPR23. Color map encodes t-values; top: left hemisphere (LFPL23), bottom: right hemisphere (LFPR23). (Modified with permission from26) <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53466/53466fig4Dlarge.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

Watch this Scientific Journal Video about Combined Invasive Subcortical and Non-invasive Surface Neurophysiological Recordings for the Assessment of Cognitive and Emotional Functions in Humans at JoVE

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

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 ...

combined-invasive-subcortical-non-invasive-surface-neurophysiological

Nanyang Technological University

Research

JoVE Journal

Behavior

10.7K Views.  Medical Faculty, Heinrich-Heine-University. 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. 

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

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.

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 ...

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), ...

Neuroscience

Simultaneous Monitoring of Wireless Electrophysiology and Memory Behavioral Test as a Tool to Study Hippocampal Neurogenesis

Brainwaves amplitude obtained from electroencephalography (EEG) has been well-recognized as a basis for cognitive capacity, memory, and learning on animals and humans. Adult neurogenesis mechanism is also linked to memory and learning improvement. Traditionally, researchers used to assess learning and memory parameters in rodent models by behavioral tasks. Therefore, the simultaneous monitoring of behavioral changes and EEG is particularly interesting in correlating data between brain activity and task-related behaviors. However, most of the equipment required to perform both studies are either complex, expensive, or uses a wired setup network that hinders the natural animals&#8217; movement. In this study, EEG was recorded with a wireless electrophysiology device along with the execution of a novel object recognition task (NORT). The animal&#8217;s behavior was monitored simultaneously by a video tracking system. Both recordings were analyzed offline by their timestamps which were synched to link EEG signals with the animal&#8217;s actions. Subjects consist of adult Wistar rats after medium-term environmental enrichment treatment. Six skull screw electrodes were fixed in pairs on both hemispheres over frontal, central, and parietal regions and were referenced to an electrode located posterior of the nasal bone. NORT protocol consists of exposing the animal to two identical objects for 10 min. After 2 h and 24 h, one of the objects was replaced with a novel one. Exploration time for each object was monitored by a behavioral tracking software (BTS) and EEG data recording. The analysis of the EEG synced with behavioral data consists of estimations of alpha and beta relative band power and comparisons between novel object recognition versus familiar object exploration, between three experimental stages. In this manuscript, we have discussed electrodes manufacturing process, epidural electrodes implantation surgery, environmental enrichment protocol, NORT protocol, BTS setup, EEG &#8211; BTS coupling for simultaneous monitoring in real-time, and EEG data analysis based on automatic events detection.

The protocol presented here provides information on the simultaneous electroencephalography (EEG) and behavioral assessment in real-time. We have discussed all steps involved in this protocol as an attractive solution for researchers in many fields of neuroscience, particularly in learning and memory areas.

Brainwaves amplitude obtained from electroencephalography (EEG) has been well-recognized as a basis for cognitive capacity, memory, and learning on ...

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 ...

Acute In Vivo Electrophysiological Recordings of Local Field Potentials and Multi-unit Activity from the Hyperdirect Pathway in Anesthetized Rats

Converging evidence shows that many neuropsychiatric diseases should be understood as disorders of large-scale neuronal networks. To better understand the pathophysiological basis of these diseases, it is necessary to precisely characterize in which way the processing of information is disturbed between the different neuronal parts of the circuit. Using extracellular in vivo electrophysiological recordings, it is possible to accurately delineate neuronal activity within a neuronal network. The application of this method has several advantages over alternative techniques, e.g., functional magnetic resonance imaging and calcium imaging, as it allows a unique temporal and spatial resolution and does not rely on genetically engineered organisms. However, the use of extracellular in vivo recordings is limited since it is an invasive technique that cannot be universally applied. In this article, a simple and easy to use method is presented with which it is possible to simultaneously record extracellular potentials such as local field potentials and multiunit activity at multiple sites of a network. It is detailed how a precise targeting of subcortical nuclei can be achieved using a combination of stereotactic surgery and online analysis of multi-unit recordings. Thus, it is demonstrated, how a complete network such as the hyperdirect cortico-basal ganglia loop can be studied in anesthetized animals in vivo.

Acute In Vivo Electrophysiological Recordings of Local Field Potentials and Multi-unit Activity from the Hyperdirect Pathway in Anesthetized Rats

In this study, the methodology is presented on how to perform multi-site in vivo electrophysiological recordings from the hyperdirect pathway under urethane anesthesia.

Converging evidence shows that many neuropsychiatric diseases should be understood as disorders of large-scale neuronal networks. To better understand the ...

Visual Evoked Potential Recordings in Mice Using a Dry Non-invasive Multi-channel Scalp EEG Sensor

For scalp EEG research environments with laboratory mice, we designed a dry-type 16 channel EEG sensor which is non-invasive, deformable, and re-usable because of the plunger-spring-barrel structural facet and mechanical strengths resulting from metal materials. The whole process for acquiring the VEP responses in vivo from a mouse consists of four steps: (1) sensor assembly, (2) animal preparation, (3) VEP measurement, and (4) signal processing. This paper presents representative measurements of VEP responses from multiple mice with a submicro-voltage signal resolution and sub-hundred millisecond temporal resolution. Although the proposed method is safer and more convenient compared to other previously reported animal EEG acquiring methods, there are remaining issues including how to enhance the signal-to-noise ratio and how to apply this technique with freely moving animals. The proposed method utilizes easily available resources and shows a repetitive VEP response with a satisfactory signal quality. Therefore, this method could be utilized for longitudinal experimental studies and reliable translational research exploiting non-invasive paradigms.

We designed a dry-type 16 channel EEG sensor which is non-invasive, deformable, and re-usable. This paper describes the whole process from manufacturing the proposed EEG electrode to signal processing of visual evoked potential (VEP) signals measured on a mouse scalp using a dry non-invasive multi-channel EEG sensor.

For scalp EEG research environments with laboratory mice, we designed a dry-type 16 channel EEG sensor which is non-invasive, deformable, and re-usable ...

Simultaneous Recordings of Cortical Local Field Potentials, Electrocardiogram, Electromyogram, and Breathing Rhythm from a Freely Moving Rat

Monitoring the physiological dynamics of the brain and peripheral tissues is necessary for addressing a number of questions about how the brain controls body functions and internal organ rhythms when animals are exposed to emotional challenges and changes in their living environments. In general experiments, signals from different organs, such as the brain and the heart, are recorded by independent recording systems that require multiple recording devices and different procedures for processing the data files. This study describes a new method that can simultaneously monitor electrical biosignals, including tens of local field potentials in multiple brain regions, electrocardiograms that represent the cardiac rhythm, electromyograms that represent awake/sleep-related muscle contraction, and breathing signals, in a freely moving rat. The recording configuration of this method is based on a conventional micro-drive array for cortical local field potential recordings in which tens of electrodes are accommodated, and the signals obtained from these electrodes are integrated into a single electrical board mounted on the animal's head. Here, this recording system was improved so that signals from the peripheral organs are also transferred to an electrical interface board. In a single surgery, electrodes are first separately implanted into the appropriate body parts and the target brain areas. The open ends of all of these electrodes are then soldered to individual channels of the electrical board above the animal's head so that all of the signals can be integrated into the single electrical board. Connecting this board to a recording device allows for the collection of all of the signals into a single device, which reduces experimental costs and simplifies data processing, because all data can be handled in the same data file. This technique will aid the understanding of the neurophysiological correlates of the associations between central and peripheral organs.

This study introduces a method for the simultaneous recording of local field potentials in the brain, electrocardiograms, electromyograms, and breathing signals of a freely moving rat. This technique, which reduces experimental costs and simplifies data analysis, will contribute to the understanding of the interactions between the brain and peripheral organs.

Monitoring the physiological dynamics of the brain and peripheral tissues is necessary for addressing a number of questions about how the brain controls ...

Subdural Soft Electrocorticography (ECoG) Array Implantation and Long-Term Cortical Recording in Minipigs

Neurological impairments and diseases can be diagnosed or treated using electrocorticography (ECoG) arrays. In drug-resistant epilepsy, these help delineate the epileptic region to resect. In long-term applications such as brain-computer interfaces, these epicortical electrodes are used to record the movement intention of the brain, to control the robotic limbs of paralyzed patients. However, current stiff electrode grids do not answer the need for high-resolution brain recordings and long-term biointegration. Recently, conformable electrode arrays have been proposed to achieve long-term implant stability with high performance. However, preclinical studies for these new implant technologies are needed to validate their long-term functionality and safety profile for their translation to human patients. In this context, porcine models are routinely employed in developing medical devices due to their large organ sizes and easy animal handling. However, only a few brain applications are described in the literature, mostly due to surgery limitations and integration of the implant system on a living animal.
Here, we report the method for long-term implantation (6 months) and evaluation of soft ECoG arrays in the minipig model. The study first presents the implant system, consisting of a soft microfabricated electrode array integrated with a magnetic resonance imaging (MRI)-compatible polymeric transdermal port that houses instrumentation connectors for electrophysiology recordings. Then, the study describes the surgical procedure, from subdural implantation to animal recovery. We focus on the auditory cortex as an example target area where evoked potentials are induced by acoustic stimulation. We finally describe a data acquisition sequence that includes MRI of the whole brain, implant electrochemical characterization, intraoperative and freely moving electrophysiology, and immunohistochemistry staining of the extracted brains.
This model can be used to investigate the safety and function of novel design of cortical prostheses; mandatory preclinical study to envision translation to human patients.

Subdural Soft Electrocorticography ECoG Array Implantation and Long-Term Cortical Recording in Minipigs

Here, we present a method for the long-term performance and safety assessment of soft subdural electrode arrays in a minipig model, describing surgical method and tools, postoperative magnetic resonance imaging, electrophysiology of the auditory cortex, electrochemical properties of the implant, and postmortem immunochemistry.

Neurological impairments and diseases can be diagnosed or treated using electrocorticography (ECoG) arrays. In drug-resistant epilepsy, these help ...

Bioengineering

Conducting Concurrent Electroencephalography and Functional Near-Infrared Spectroscopy Recordings with a Flanker Task

Concurrent EEG and fNIRS recordings offer an excellent opportunity to gain a full understanding of the neural mechanism of cognitive processing by inspecting the relationship between the neural and hemodynamic signals. EEG is an electrophysiological technology that can measure the rapid neuronal activity of the cortex, whereas fNIRS relies on the hemodynamic responses to infer brain activation. The combination of EEG and fNIRS neuroimaging techniques can identify more features and reveal more information associated with the functioning of the brain. In this protocol, fused EEG-fNIRS measurements were performed for concurrent recordings of evoked-electrical potentials and hemodynamic responses during a Flanker task. In addition, the critical steps for setting up the hardware and software system as well as the procedures for data acquisition and analysis were provided and discussed in detail. It is expected that the present protocol can pave a new avenue for improving the understanding of the neural mechanisms underlying various cognitive processes by using the EEG and fNIRS signals.

The present protocol describes how to perform concurrent EEG and fNIRS recordings and how to inspect the relationship between the EEG and fNIRS data.&#160;

Concurrent EEG and fNIRS recordings offer an excellent opportunity to gain a full understanding of the neural mechanism of cognitive processing by ...

Concurrent EEG and Functional MRI Recording and Integration Analysis for Dynamic Cortical Activity Imaging

Electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) are two of the fundamental noninvasive methods for identifying brain activity. Multimodal methods have sought to combine the high temporal resolution of EEG with the spatial precision of fMRI, but the complexity of this approach is currently in need of improvement. The protocol presented here describes the recently developed spatiotemporal fMRI-constrained EEG source imaging method, which seeks to rectify source biases and improve EEG-fMRI source localization through the dynamic recruitment of fMRI sub-regions. The process begins with the collection of multimodal data from concurrent EEG and fMRI scans, the generation of 3D cortical models, and independent EEG and fMRI processing. The processed fMRI activation maps are then split into multiple priors, according to their location and surrounding area. These are taken as priors in a two-level hierarchical Bayesian algorithm for EEG source localization. For each window of interest (defined by the operator), specific segments of the fMRI activation map will be identified as active to optimize a parameter known as model evidence. These will be used as soft constraints on the identified cortical activity, increasing the specificity of the multimodal imaging method by reducing cross-talk and avoiding erroneous activity in other conditionally active fMRI regions. The method generates cortical maps of activity and time-courses, which may be taken as final results, or used as a basis for further analyses (analyses of correlation, causation, etc.) While the method is somewhat limited by its modalities (it will not find EEG-invisible sources), it is broadly compatible with most major processing software, and is suitable for most neuroimaging studies.

An EEG-fMRI multimodal imaging method, known as the spatiotemporal fMRI-constrained EEG source imaging method, is described here. The presented method employs conditionally-active fMRI sub-maps, or priors, to guide EEG source localization in a manner that improves spatial specificity and limits erroneous results.

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

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