Ogrim G. has nothing to disclose. Kropotov J.D. was the head of the laboratory at the Institute of the Human Brain, St. Petersburg when and where the WinEEG program was developed. He has no economic interests in the system.

Diagnoses in psychiatry are based on observed behavior. In most cases, a specified number of symptoms must be observed in different settings for 6 months or more. An important part of the diagnostic process is to exclude somatic etiology. In addition, other psychiatric diagnoses must be considered. Quite often the symptoms of interest can be part of another diagnostic category. If several symptoms overlap with other disorders, the clinician must decide if this second disorder is a comorbid or differential diagnosis.
The clinical tools available are diagnostic interviews, rating scales, medical and developmental history, psychological tests and direct observations. Most of these methods are quite subjective; heavily influenced by the informant as well as the professional. Rating scales from parents and teachers usually show quite modest correlations (r = 0.3 - 0.5).
In the representative results, we argue that the underlying mechanisms in ADHD probably differ from patient to patient. Lack of (language) understanding, problems with self-motivation, sensitivity to external distractors, etc. can all lead to symptoms of inattention. The EEG based methods described in this paper can help solve some of these challenges. The problem of subjective interpretations is absent. The ERP methods described seem to reveal underlying psychological operations like working memory, action inhibition, monitoring, response preparation, etc. involving specific brain structures. Deficits in these mechanisms are not limited to specific diagnostic categories. We believe that in the future, treatment (medication, neurofeedback, cognitive training, tDCS, ...) will focus on such cognitive and/or emotional operations and their underlying brain mechanisms and not on the current diagnostic categories.
A purpose of a diagnosis is to determine the best treatments. To evaluate the effects of treatment, self-reported and observed improvements are of course decisive. Such reports can to some degree represent placebo effects, however, and should be supported by (partial) normalization of underlying brain dysfunctions reflected in for example changes in ERP components. This combination of subjective and objective measures of treatment effects are important in both clinic and research.
For reasons as those mentioned above, it is no surprise that people with the same diagnoses often do not respond to the same medical treatments. In personalized medicine diagnoses are supplemented with empirically based measures of response prediction to pinpoint the best treatment for the individual patient. In this paper we have described our research on prediction of stimulant medication response in pediatric ADHD. To find reliable predictors of positive response to antidepressant medication is perhaps even more important as the time needed to evaluate responses is long, as is the titration period. The procedures described in this paper could contribute to the ongoing EEG and ERP based research on prediction of medication effects in depression53.
The EEG based methods described are non-invasive and affordable, and well suited for research as well as for clinical work.

In 2008, initiated by NIMH, the Research Domain Criteria (RDoC) project1 was published, aiming to find a biologically valid framework for the understanding of mental disorders. In 2013, the U.S. Food and Drug Administration (FDA) approved of the first EEG-based biomarker of ADHD to help assess ADHD in patients from 6 to 17 years of age. The Neuropsychiatric EEG-Based Assessment Aid (NEBA) System records EEG for 15-20 min. It is based on the computation of the theta/beta ratio found to be higher in children and adolescents with ADHD than in typically developing children2. Recent publications find that this ratio does not captures all ADHD3.
A large number of publications in clinical neuroscience demonstrate that impaired cognitive control represents a common feature of many psychiatric disorders including ADHD, schizophrenia, depression, and OCD4,5. Theoretically, cognitive control consists of hypothetical operations allowing people to adjust flexibly to goals and contexts. Two different categories of cognitive control, proactive and reactive control, have been described6. Our primary focus is on the reactive mode of cognitive control. Proactive cognitive control includes working memory (i.e., maintaining sensory and motor events for seconds). Reactive cognitive control includes monitoring, detection of conflict7,8, and action inhibition (for review see9,10).
The GO/NOGO paradigm is sensitive to cognitive control11,12,13,14,15. GO stimuli elicit positive fluctuations from parietal brain areas. (P3 GO). The anteriorly distributed positive N2 and P3 NOGO waves, elicited by NOGO stimuli, are associated with detection of conflict and action inhibition16,17,18,19. The N2 wave has been understood as an indicator of inhibition of action, but updated research shows that the N2 wave is associated with infrequent GO stimuli and detection of conflict20. Action inhibition is linked to the P3 NOGO wave at frontal-central sites.
The N2/P3 dichotomy may not be correct. It has been questioned by a view that ERP waves, in particular those representing cognitive control, are sums of several sources that may overlap in locations and time14,21.
To disentangle the sources of ERP waves, several methods of blind source separation have been used15,22,23,24. In studies at the Institute of the Human Brain, St. Petersburg, N2d NOGO wave has been decomposed. Hidden components were detected. These components had distinct topographies and functional meanings. Only one of them was associated with detection of conflict14,15,25,26. In most adult studies of ADHD, P3 NOGO is smaller in comparison to matched healthy controls27,28,29,30,31,32.
The brain operations taking place during tasks of cognitive control do not seem to be correctly explained by the N2/P3 dichotomy when ERPs in GO/NOGO paradigms are analyzed14,15. Several approaches aiming to disentangle hidden components from ERP waves have been used (for review see21). Some studies have used independent component analysis (ICA) for ERPs in patient groups such as patients with schizophrenia29, and adults with ADHD33,34, attempting to discriminate patients from controls without diagnoses.
In (Yeredor, 2010,25 p.75), a new method is suggested and adapted for ERPs. It is a method of blind source separation, based on a procedure of joint diagonalization of cross-variance matrixes. To study the functional meanings of such latent components applying this method in the cued GO/NOGO paradigm, a study from the Institute of the Human Brain was recently implemented26. In this study the action inhibition operations and the conflict detection operations were independently manipulated by modifications of the cued GO/NOGO task. A hidden component, thought to reflect detection of conflict, was found. A N2-like response and frontal topography characterized this component35. In trials requiring inhibition of prepared actions a central topography and P3-like response was seen.
In this publication the studies reported have used the traditional ERP method. Application of ICA, or the procedure of joint diagonalization of cross-variance matrixes25 (page 75) has so far not been done. In general, the results based on the different methods agree with each other, but the methods for discovering latent components seem to be more purely associated with distinct neuropsychological functions. The aim of this paper is to offer a detailed description of the WinEEG method. The focus is on ERPs, but EEG spectra and behavioral data from the GO/NOGO task are also included in the studies described to illustrate the WinEEG method.

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	<tbody>
		<tr>
			<td>amplifier +</td>
			<td><a href="http://www.mitsar-medical.com/" target="_blank">www.mitsar-medical.com</a></td>
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			<td></td>
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		<tr>
			<td>Body harness, different sizes</td>
			<td>Electro-Cap International, Inc</td>
			<td>E3 SM; E3 M; E3 L</td>
			<td></td>
		</tr>
		<tr>
			<td>Ear electrodes 9 mm sockets</td>
			<td>Electro-Cap International, Inc</td>
			<td>E5-9S</td>
			<td></td>
		</tr>
		<tr>
			<td>Electrocaps 19 channel different sizes</td>
			<td>Electro-Cap International, Inc</td>
			<td>E1 SM; E1 M; E1 M/SM</td>
			<td></td>
		</tr>
		<tr>
			<td>Electrocaps 19 channel different sizes</td>
			<td>Electro-Cap International, Inc</td>
			<td>E1 L/M; E1 L</td>
			<td></td>
		</tr>
		<tr>
			<td>Electrogel for electrocaps</td>
			<td>Electro-Cap International, Inc</td>
			<td>E9; E10</td>
			<td></td>
		</tr>
		<tr>
			<td>HBi database</td>
			<td><a href="http://www.hbimed.com/" target="_blank">www.hbimed.com</a></td>
			<td></td>
			<td></td>
		</tr>
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			<td>Head size measure band</td>
			<td>Electro-Cap International, Inc</td>
			<td>E 12</td>
			<td></td>
		</tr>
		<tr>
			<td>Needle syringe kit</td>
			<td>Electro-Cap International, Inc</td>
			<td>E7</td>
			<td></td>
		</tr>
		<tr>
			<td>Nuprep EEG and ECG skin prep gel</td>
			<td>Electro-Cap International, Inc</td>
			<td>R7</td>
			<td></td>
		</tr>
		<tr>
			<td>Ten20 EEG conductive paste</td>
			<td>Electro-Cap International, Inc</td>
			<td>R5-4T</td>
			<td></td>
		</tr>
		<tr>
			<td>WinEEG program</td>
			<td><a href="http://www.mitsar-medical.com/" target="_blank">www.mitsar-medical.com</a></td>
			<td></td>
			<td></td>
		</tr>
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event related potentials (erps) and other eeg based methods for extracting biomarkers of brain dysfunction: examples from pediatric attention deficit/hyperactivity disorder (adhd)

Neuropsychiatric diagnoses like ADHD are based on subjective methods like interviews, rating scales and observations. There is a need for more brain-based supplements. Stimulant medication is the most common treatment for ADHD. Clinically useful predictors of response have so far not been reported. The aim of this paper is to describe the EEG based methods we apply to extract potential biomarkers for brain dysfunction. Examples relate to biomarkers for pediatric ADHD, and prediction of medication response. The main emphasis is on Event Related Potentials (ERPs).
A nineteen channel EEG is recorded during a 3 min eyes-opened task, a 3 min eyes-closed task, and a 20 min cued visual GO/NOGO task (VCPT). ERPs are recorded during this task. The goal of the ERP protocol is to extract biomarkers of assumed brain dysfunctions that significantly differentiate between a patient group and healthy controls. The protocol includes recording during standard conditions and artifact correction. ERP waves can be used or transformed into latent components. The components of the patient group are compared with controls, empathizing components that, when compared, show relatively high effect sizes. Sub-groups of the patients are selected on the basis of the cluster analysis in the space of the components. Treatment procedure (such as medication, tDCS or neurofeedback protocol) can be applied and the changes in components related to treatment in the subgroups are observed, forming the basis for clinical recommendations.
The methods described were applied in a study of 87 pediatric ADHD patients. The index of medication response discriminated significantly between responders and non-responders with a large, and clinically meaningful effect size (d = 1.84). In an ongoing study comparing ADHD children with matched controls, several variables discriminate significantly between patients and controls. The global index will exceed d = .8. The EEG based methods described here could be clinically meaningful.

Prediction of medication response in pediatric ADHD 
ADHD is a common neuropsychiatric childhood disorder36. It is characterized by symptoms of inattention accompanied by symptoms of hyperactivity and impulsivity. Impairment in school, home, and leisure settings are common. In school aged children, the estimated prevalence is 5% to 7%. Comorbidities are common. Medical treatment, using stimulants based on methylphenidate (MPH) or dextroamphetamine (DEX), are widely used. Positive effects of stimulant medication (reductions in restlessness, hyperactivity and impulsivity and improved attention) are reported in 70% of the patients. Shifting from medication based on MPH to DEX can increase positive effects to 80%37,38. Frontal-striatal circuits seem to be activated by stimulants39.
There is no generally accepted definition of a medication response that is clinically meaningful. Applying rating scales, comparing baseline scores with scores on medication, is the most commonly used method. In some studies, a 25% or 50% reduction of scores is used as definition of response. In other studies, scores not exceeding 1 SD above population mean are used40,41. Clinically, an overall decision based on all relevant available data is used. To evaluate side effects, such as loss of appetite, insomnia, increased irritability, or anxiety, is important37,42.
The use of rating scales can be criticized for several reasons. Small correlations (0.30-0.50) between teacher and parent scores are reported in several studies48. The search for clinically useful predictors of response is motivated by a large number of non-responders, informants that do not agree, and the fact that everyone can have some modest effects of improved attention when small doses of stimulants are used. Published research on predictors of response include ADHD subtype, demographics, comorbid disorders, gene variables, scores on rating scales, neuropsychological test results, and EEG/ERP variables43,44,45,46. Our 2016 publication47 summarizes studies that have applied ERPs to predict medication response.
In previous studies, we analyze d data from the cued visual GO/NOGO task (i.e., attention test data, EEG spectra, and ERPs). In one study, we found 3 variables contributing significantly to the prediction of side-effects. These variables were combined to an index that was considered clinically meaningful42. In a study on clinical effects, applying the same methods, the prediction index was also considered clinically useful48. The effects of a single dose of stimulant medication on medication responders (REs) and non-responders (non-REs) was investigated in a third study47. The test procedure was completed twice, the first test with no medication, and the second test an hour after having received a trial dose. Based on rating scales and interviews after a 4-week medication trial, the patients were classified as REs or non-REs. Our focus was on changes in cognitive ERPs and attention test scores. We found that the effects on the P3 NOGO component was significantly different in the two groups, with a large effect size (d = 1.76). A significant increase of the component amplitude was seen in REs but not in non-REs. Predictions of response based on two tests was improved compared with predictions based only on test 1.
In our latest study, we developed two global indexes, one for prediction of clinical gains and one for prediction of side-effects. As described above we combined variables that discriminated significantly between compared groups with a modest or large effect size. Each variable was weighted in accordance with the effect size. We examined variables from all three WinEEG domains: EEG spectra, ERPs and behavior. The following variables were combined: Test 1: P3NOGO amplitude and theta/alpha ratio; differences between Test 2 and Test 1: Omission errors, reaction time variability, contingent negative variation (CNV) and P3NOGO amplitude. The effect size of the global scale was d = 1.86. Accuracy was 0.92. Prediction of side-effects was based on 4 variables: Test 1: RT, Test 2: novelty component, alpha peak frequency, and reaction time changes (Test 2 - Test 1). The global scale d was 1.08 and accuracy was 0.7849.
Some preliminary results 
In an ongoing study, we compare a group of 61 ADHD patients age 9-12 years and a group of 67 age-matched healthy controls (HC). The final statistical analyses have so far not been completed. Below we are presenting the preliminary results obtained from WinEEG assessment.
Behaviorally, the ADHD group showed an inattention pattern with statistically (at p&#60;0.001) more omission errors in comparison to the healthy controls (HC) group (13.7% vs. 4.8%) accompanied by an attention lapses pattern expressed in statistically higher (p&#60;0.001) variability of reaction time (151 ms vs. 125 ms).
The main results of comparing ERP waveforms between the two groups are shown in Figure 5 and Figure 6. Figure 5 demonstrates the ERP correlates of dysfunction of proactive cognitive control in ADHD group. Two indexes of proactive cognitive control (P3 cue wave and CNV wave) are reduced in the ADHD group in comparison to the HC group. Figure 6 demonstrates the ERP correlates of dysfunction of reactive cognitive control in the ADHD group. Two indexes of reactive cognitive control (N2 NOGO and P3 NOGO) are reduced in the ADHD group in comparison to the HC group.
<img alt="Figure 5" class="xfigimg" src="/files/ftp_upload/60710/60710fig5.jpg" /> 
Figure 5: Grand average ERP wave patterns (a) and the corresponding maps (b) in proactive cognitive control in ADHD and healthy control (HC) groups. (a) ERPs measured at P3 in ADHD group (green line) and HC group (red line) and their difference (ADHD-HC) wave (blue line). Blue vertical bars below the curves indicate level of statistical significance of the difference (small bars - p&#60;0.05, middle bars - p&#60;0.01, large bars - p&#60;0.001). Arrows indicate the classical waves - P3 cue and CNV (contingent negative variation). (b) Maps at the maximums of amplitudes of P3 and CNV waves for the two groups. <a href="https://www.jove.com/files/ftp_upload/60710/60710fig5large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 6" class="xfigimg" src="/files/ftp_upload/60710/60710fig6.jpg" /> 
Figure 6: Grand average ERP wave patterns (a) and the corresponding maps (b) in reactive cognitive control in ADHD and healthy control (HC) groups. (a) ERPs measured at Fz and Cz ADHD group (green line) and HC group (red line) and their difference (ADHD-HC) wave (blue line). Blue vertical bars below the curves indicate the level of statistical significance of the difference (small bars - p&#60;0.05, middle bars - p&#60;0.01, large bars - p&#60;0.001). Arrows indicate the classical waves - N2 NOGO and P3 NOGO. (b) Maps at the maximums of amplitudes of N2 NOGO and P3 NOGO waves for the two groups. <a href="https://www.jove.com/files/ftp_upload/60710/60710fig6large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
As one can see the ADHD group shows hypo-functioning of multiple operations of cognitive control. These operations occur in different time windows and in different spatial locations. A particular patient might have only one hypo-functioning indicating the source of the individual disorder and the ways of its correction.
Clinical significance 
To compute a clinically useful biomarker for a heterogenous diagnosis such as ADHD, several variables that differ significantly between ADHD and controls need to be combined. The effect size (d) of an index should be above d = .8. An important next step will be applying this index when ADHD is compared with clinical controls.

Watch this Scientific Journal Video about Event Related Potentials ERPs and other EEG Based Methods for Extracting Biomarkers of Brain Dysfunction: Examples from Pediatric Attention Deficit/Hyperactiv

Event Related Potentials ERPs and other EEG Based Methods for Extracting Biomarkers of Brain Dysfunction: Examples from Pediatric Attention Deficit/Hyperactivity Disorder ADHD

EEG-methods are applied for extracting biomarkers of brain dysfunctions. The focus is on multi-channel event-related potentials (ERPs) recorded in a cued GO/NOGO task. Non-brain artifacts are corrected and ERPs are compared with the normative data. Examples relate to biomarkers for ADHD diagnosis and prediction of medication response.

Event Related Potentials (ERPs) and other EEG Based Methods for Extracting Biomarkers of Brain Dysfunction: Examples from Pediatric Attention Deficit/Hyperactivity Disorder (ADHD)

Neuropsychiatric diagnoses like ADHD are based on subjective methods like interviews, rating scales and observations. There is a need for more brain-based ...

event-related-potentials-erps-other-eeg-based-methods-for-extracting

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15.4K Views.  Østfold Hospital Trust. EEG-methods are applied for extracting biomarkers of brain dysfunctions. The focus is on multi-channel event-related potentials (ERPs) recorded in a cued GO/NOGO task. Non-brain artifacts are corrected and ERPs are compared with the normative data. Examples relate to biomarkers for ADHD diagnosis and prediction of medication response.

Video: Event Related Potentials ERPs and other EEG Based Methods for Extracting Biomarkers of Brain Dysfunction: Examples from Pediatric Attention Deficit/Hyperactivity Disorder ADHD

High Density Event-related Potential  Data Acquisition in Cognitive Neuroscience

Functional magnetic resonance imaging (fMRI) is currently the standard method of evaluating brain function in the field of Cognitive Neuroscience, in part because fMRI data acquisition and analysis techniques are readily available. Because fMRI has excellent spatial resolution but poor temporal resolution, this method can only be used to identify the spatial location of brain activity associated with a given cognitive process (and reveals virtually nothing about the time course of brain activity). By contrast, event-related potential (ERP) recording, a method that is used much less frequently than fMRI, has excellent temporal resolution and thus can track rapid temporal modulations in neural activity. Unfortunately, ERPs are under utilized in Cognitive Neuroscience because data acquisition techniques are not readily available and low density ERP recording has poor spatial resolution. In an effort to foster the increased use of ERPs in Cognitive Neuroscience, the present article details key techniques involved in high density ERP data acquisition. Critically, high density ERPs offer the promise of excellent temporal resolution and good spatial resolution (or excellent spatial resolution if coupled with fMRI), which is necessary to capture the spatial-temporal dynamics of human brain function.

Event-related potential (ERP) recording is under utilized in Cognitive Neuroscience because data acquisition techniques are not readily available and this method often has poor spatial resolution. To foster the increased use of ERPs in Cognitive Neuroscience, the present article details key techniques involved in high density ERP data acquisition.

Functional magnetic resonance imaging (fMRI) is currently the standard method of evaluating brain function in the field of Cognitive Neuroscience, in part ...

Combining Computer Game-Based Behavioural Experiments With High-Density EEG and Infrared Gaze Tracking

Experimental paradigms are valuable insofar as the timing and other parameters of their stimuli are well specified and controlled, and insofar as they yield data relevant to the cognitive processing that occurs under ecologically valid conditions. These two goals often are at odds, since well controlled stimuli often are too repetitive to sustain subjects' motivation. Studies employing electroencephalography (EEG) are often especially sensitive to this dilemma between ecological validity and experimental control: attaining sufficient signal-to-noise in physiological averages demands large numbers of repeated trials within lengthy recording sessions, limiting the subject pool to individuals with the ability and patience to perform a set task over and over again. This constraint severely limits researchers' ability to investigate younger populations as well as clinical populations associated with heightened anxiety or attentional abnormalities. Even adult, non-clinical subjects may not be able to achieve their typical levels of performance or cognitive engagement: an unmotivated subject for whom an experimental task is little more than a chore is not the same, behaviourally, cognitively, or neurally, as a subject who is intrinsically motivated and engaged with the task. A growing body of literature demonstrates that embedding experiments within video games may provide a way between the horns of this dilemma between experimental control and ecological validity. The narrative of a game provides a more realistic context in which tasks occur, enhancing their ecological validity (Chaytor &amp; Schmitter-Edgecombe, 2003). Moreover, this context provides motivation to complete tasks. In our game, subjects perform various missions to collect resources, fend off pirates, intercept communications or facilitate diplomatic relations. In so doing, they also perform an array of cognitive tasks, including a Posner attention-shifting paradigm (Posner, 1980), a go/no-go test of motor inhibition, a psychophysical motion coherence threshold task, the Embedded Figures Test (Witkin, 1950, 1954) and a theory-of-mind (Wimmer &amp; Perner, 1983) task. The game software automatically registers game stimuli and subjects' actions and responses in a log file, and sends event codes to synchronise with physiological data recorders. Thus the game can be combined with physiological measures such as EEG or fMRI, and with moment-to-moment tracking of gaze. Gaze tracking can verify subjects' compliance with behavioural tasks (e.g. fixation) and overt attention to experimental stimuli, and also physiological arousal as reflected in pupil dilation (Bradley et al., 2008). At great enough sampling frequencies, gaze tracking may also help assess covert attention as reflected in microsaccades - eye movements that are too small to foveate a new object, but are as rapid in onset and have the same relationship between angular distance and peak velocity as do saccades that traverse greater distances. The distribution of directions of microsaccades correlates with the (otherwise) covert direction of attention (Hafed &amp; Clark, 2002).

Procedures for recording high-density EEG and gaze data during computer game-based cognitive tasks are described. Using a video game to present cognitive tasks enhances ecological validity without sacrificing experimental control.

Experimental paradigms are valuable insofar as the timing and other parameters of their stimuli are well specified and controlled, and insofar as they ...

Mapping Cortical Dynamics Using Simultaneous MEG/EEG and Anatomically-constrained Minimum-norm Estimates: an Auditory Attention Example

Magneto- and electroencephalography (MEG/EEG) are neuroimaging techniques that provide a high temporal resolution particularly suitable to investigate the cortical networks involved in dynamical perceptual and cognitive tasks, such as attending to different sounds in a cocktail party. Many past studies have employed data recorded at the sensor level only, i.e., the magnetic fields or the electric potentials recorded outside and on the scalp, and have usually focused on activity that is time-locked to the stimulus presentation. This type of event-related field / potential analysis is particularly useful when there are only a small number of distinct dipolar patterns that can be isolated and identified in space and time. Alternatively, by utilizing anatomical information, these distinct field patterns can be localized as current sources on the cortex. However, for a more sustained response that may not be time-locked to a specific stimulus (e.g., in preparation for listening to one of the two simultaneously presented spoken digits based on the cued auditory feature) or may be distributed across multiple spatial locations unknown a priori, the recruitment of a distributed cortical network may not be adequately captured by using a limited number of focal sources.
Here, we describe a procedure that employs individual anatomical MRI data to establish a relationship between the sensor information and the dipole activation on the cortex through the use of minimum-norm estimates (MNE). This inverse imaging approach provides us a tool for distributed source analysis. For illustrative purposes, we will describe all procedures using FreeSurfer and MNE software, both freely available. We will summarize the MRI sequences and analysis steps required to produce a forward model that enables us to relate the expected field pattern caused by the dipoles distributed on the cortex onto the M/EEG sensors. Next, we will step through the necessary processes that facilitate us in denoising the sensor data from environmental and physiological contaminants. We will then outline the procedure for combining and mapping MEG/EEG sensor data onto the cortical space, thereby producing a family of time-series of cortical dipole activation on the brain surface (or "brain movies") related to each experimental condition. Finally, we will highlight a few statistical techniques that enable us to make scientific inference across a subject population (i.e., perform group-level analysis) based on a common cortical coordinate space.

We use magneto- and electroencephalography (MEG/EEG), combined with anatomical information captured by magnetic resonance imaging (MRI), to map the dynamics of the cortical network associated with auditory attention.

Magneto- and electroencephalography (MEG/EEG) are neuroimaging techniques that provide a high temporal resolution particularly suitable to investigate the ...

Applications of EEG Neuroimaging Data: Event-related Potentials, Spectral Power, and Multiscale Entropy

When considering human neuroimaging data, an appreciation of signal variability represents a fundamental innovation in the way we think about brain signal. Typically, researchers represent the brain's response as the mean across repeated experimental trials and disregard signal fluctuations over time as "noise". However, it is becoming clear that brain signal variability conveys meaningful functional information about neural network dynamics. This article describes the novel method of multiscale entropy (MSE) for quantifying brain signal variability. MSE may be particularly informative of neural network dynamics because it shows timescale dependence and sensitivity to linear and nonlinear dynamics in the data.

Neuroimaging researchers typically consider the brain's response as the mean activity across repeated experimental trials and disregard signal variability over time as "noise". However, it is becoming clear that there is signal in that noise. This article describes the novel method of multiscale entropy for quantifying brain signal variability in the time domain.

When considering human neuroimaging data, an appreciation of signal variability represents a fundamental innovation in the way we think about brain ...

Extracting Visual Evoked Potentials from EEG Data Recorded During fMRI-guided Transcranial Magnetic Stimulation

Transcranial Magnetic Stimulation (TMS) is an effective method for establishing a causal link between a cortical area and cognitive/neurophysiological effects. Specifically, by creating a transient interference with the normal activity of a target region and measuring changes in an electrophysiological signal, we can establish a causal link between the stimulated brain area or network and the electrophysiological signal that we record. If target brain areas are functionally defined with prior fMRI scan, TMS could be used to link the fMRI activations with evoked potentials recorded. However, conducting such experiments presents significant technical challenges given the high amplitude artifacts introduced into the EEG signal by the magnetic pulse, and the difficulty to successfully target areas that were functionally defined by fMRI. Here we describe a methodology for combining these three common tools: TMS, EEG, and fMRI. We explain how to guide the stimulator&#39;s coil to the desired target area using anatomical or functional MRI data, how to record EEG during concurrent TMS, how to design an ERP study suitable for EEG-TMS combination and how to extract reliable ERP from the recorded data. We will provide representative results from a previously published study, in which fMRI-guided TMS was used concurrently with EEG to show that the face-selective N1 and the body-selective N1 component of the ERP are associated with distinct neural networks in extrastriate cortex. This method allows us to combine the high spatial resolution of fMRI with the high temporal resolution of TMS and EEG and therefore obtain a comprehensive understanding of the neural basis of various cognitive processes.

This paper describes a method for collecting and analyzing electroencephalography (EEG) data during concurrent transcranial magnetic stimulation (TMS) guided by activations revealed with functional magnetic resonance imaging (fMRI). A method for TMS artifact removal and extraction of event related potentials is described as well as considerations in paradigm design and experimental setup.

Transcranial Magnetic Stimulation (TMS) is an effective method for establishing a causal link between a cortical area and cognitive/neurophysiological ...

Somatosensory Event-related Potentials from Orofacial Skin Stretch Stimulation

Cortical processing associated with orofacial somatosensory function in speech has received limited experimental attention due to the difficulty of providing precise and controlled stimulation. This article introduces a technique for recording somatosensory event-related potentials (ERP) that uses a novel mechanical stimulation method involving skin deformation using a robotic device. Controlled deformation of the facial skin is used to modulate kinesthetic inputs through excitation of cutaneous mechanoreceptors. By combining somatosensory stimulation with electroencephalographic recording, somatosensory evoked responses can be successfully measured at the level of the cortex. Somatosensory stimulation can be combined with the stimulation of other sensory modalities to assess multisensory interactions. For speech, orofacial stimulation is combined with speech sound stimulation to assess the contribution of multi-sensory processing including the effects of timing differences. The ability to precisely control orofacial somatosensory stimulation during speech perception and speech production with ERP recording is an important tool that provides new insight into the neural organization and neural representations for speech.

This paper introduces a method for obtaining somatosensory event-related potentials following orofacial skin stretch stimulation. The current method can be used to evaluate the contribution of somatosensory afferents to both speech production and speech perception.

Cortical processing associated with orofacial somatosensory function in speech has received limited experimental attention due to the difficulty of ...

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 ...

How to Find Effects of Stimulus Processing on Event Related Brain Potentials of Close Others when Hyperscanning Partners

The partners of each pair must be able to pass the McGill Friendship Questionnaire without communicating. Each partner is then seated in front of a screen in one of two adjacent rooms. These rooms are separated by a glass window through which participants communicate to maintain feelings of togetherness while being fitted with the EEG cap. After checking for adequate EEG signals, the glass is covered by a curtain to prevent visual communication. Then, partners must be silent but are instructed to try to feel in the presence of their partner during the entire experiment. Just before it starts, participants are told that each of them will be presented with one image at a time and that these images will occur at the same time for both of them on their own screen. They are also instructed that, for each trial, the simultaneous images will always be different. However, unbeknownst to them, trials are randomized: only half of them are consistent with this instruction and actually include two different images. These trials form the DSC, that is, the different-stimuli condition. The other half of the trials are inconsistent with the instruction. They include two identical images and form the ISC (identical-stimuli condition). After the experiment, participants are sorted into two groups: those who reported that they felt in the presence of their partner during the majority of the trials and those who reported they did not. The impact of the stimulus processing of the partner is found by subtracting the mean voltages of the ERPs of the ISC (inconsistent with the instructions) from the ERPs of the DSC (consistent with the instructions) in at least two time windows (TWs): firstly, in the 75 to 150 ms TW, where the absolute values of these subtractions are greater, especially at right frontal sites, in those who felt in the presence of their partner than in those who did not; secondly, in the LPP time window (i.e., from 650 to 950 ms post onset), where ERPs are significantly less positive in the DSC than in the ISC in those in whom the raw results of the early (75-150ms) subtractions are negative.

This protocol describes key steps involved in assessing the sensitivity of the brain of one person to the stimulus processing of a close other by selecting pairs of partners, recording their electroencephalogram (EEG) simultaneously and computing their event-related brain potentials (ERPs).

The partners of each pair must be able to pass the McGill Friendship Questionnaire without communicating. Each partner is then seated in front of a screen ...

Using Brain Activation (nir-HEG/Q-EEG) and Execution Measures (CPTs) in a ADHD Assessment Protocol

Attention Deficit Hyperactivity Disorder (ADHD) is a problem that impacts academic performance and has serious consequences that result in difficulties in scholastic, social and familial contexts. One of the most common problems in the identification of this disorder relates to the apparent over diagnosis of the disorder due to the absence of global protocols for assessment. The research group of School Learning, Difficulties and Academic Performance (ADIR) from the University of Oviedo, has developed a complete protocol that suggests the existence of certain patterns of cortical activation and executive control for identifying ADHD more objectively. This protocol takes into consideration some of the hypothetical determinants of ADHD, including the relationship between activation of selected areas of the brain, and differences in performance on various aspects of executive functioning such as omissions, commissions or response times, using innovative tools of Continuous Performance Testing (based on Virtual Reality CPT and Traditional CPT) and brain activation measures (two different tools, based on Hemoencephalography- nirHEG; and Quantified Electroencephalography --Q-EEG, respectively). This model of assessment aims to provide an effective assessment of ADHD symptomatology in order to design an accurate intervention and make appropriate recommendations for parents and teachers.

Using Brain Activation nir-HEG/Q-EEG and Execution Measures CPTs in a ADHD Assessment Protocol

This work presents a new protocol for the assessment of Attention Deficit Hyperactivity Disorder (ADHD) by providing a more objective diagnostic procedure for this developmental disorder based on the use of innovative tools. It also analyzes the relationship between activation measures and executive function measures.

Attention Deficit Hyperactivity Disorder (ADHD) is a problem that impacts academic performance and has serious consequences that result in difficulties in ...

Single Synapse Indicators of Glutamate Release and Uptake in Acute Brain Slices from Normal and Huntington Mice

Synapses are highly compartmentalized functional units that operate independently on each other. In Huntington&#39;s disease (HD) and other neurodegenerative disorders, this independence might be compromised due to insufficient glutamate clearance and the resulting spill-in and spill-out effects. Altered astrocytic coverage of the presynaptic terminals and/or dendritic spines as well as a reduced size of glutamate transporter clusters at glutamate release sites have been implicated in the pathogenesis of diseases resulting in symptoms of dys-/hyperkinesia. However, the mechanisms leading to the dysfunction of glutamatergic synapses in HD are not well understood. Improving and applying synapse imaging we have obtained data shedding new light on the mechanisms impeding the initiation of movements. Here, we describe the principle elements of a relatively inexpensive approach to achieve single synapse resolution by using the new genetically encoded ultrafast glutamate sensor iGluu, wide-field optics, a scientific CMOS (sCMOS) camera, a 473 nm laser and a laser positioning system to evaluate the state of corticostriatal synapses in acute slices from age appropriate healthy or diseased mice. Glutamate transients were constructed from single or multiple pixels to obtain estimates of i) glutamate release based on the maximal elevation of the glutamate concentration [Glu] next to the active zone and ii) glutamate uptake as reflected in the time constant of decay (TauD) of the perisynaptic [Glu]. Differences in the resting bouton size and contrasting patterns of short-term plasticity served as criteria for the identification of corticostriatal terminals as belonging to the intratelencephalic (IT) or the pyramidal tract (PT) pathway. Using these methods, we discovered that in symptomatic HD mice ~40% of PT-type corticostriatal synapses exhibited insufficient glutamate clearance, suggesting that these synapses might be at risk to excitotoxic damage. The results underline the usefulness of TauD as a biomarker of dysfunctional synapses in Huntington mice with a hypokinetic phenotype.

We present a protocol to evaluate the balance between glutamate release and clearance at single corticostriatal glutamatergic synapses in acute slices from adult mice. This protocol uses the fluorescent sensor iGluu for glutamate detection, a sCMOS camera for signal acquisition and a device for focal laser illumination.