This work has been supported by a project of the Principality of Asturias (FC-15-GRUPIN14-053) and a predoctoral grant from the Severo Ochoa Program (BP14-030). We would like to thank Anna Bujnowska for her contribution and Heather Marsh and Nigel Marsh for their help.

The present study was conducted according to the Declaration of Helsinki, which establishes the ethical principles for research involving human beings. The study&#39;s aims, scope and procedure were also approved by the Ethics Committee of the University of Oviedo and University Hospital of Asturias.
1. Parents Report
<ol>
	<li>Before starting the assessment protocol, obtain signed parental consent for the child to be assessed.</li>
	<li>Conduct a structured interview with families of the participants. 
	NOTE: The structured interview has been provided as an appendix.</li>
	<li>Have families and/or teachers of the participant complete the Scale for the Assessment of ADHD13. This scale comprises 20 items that provide information on the presence of symptoms related to attention deficit and hyperactivity/impulsivity that are referred in the Diagnostic and Statistical Manual of Mental Disorders.
	<ol>
		<li>In this section, have the therapist give the following instructions: &#34;Now, in order to get significant information about your child, you must complete this questionnaire referring to the symptoms that might be representative of your child&#39;s behavior. You must classify the frequency with which you observe these 20 symptoms&#34;.</li>
	</ol>
	</li>
</ol>
2. Cognitive Measures
<ol>
	<li>To measure the attentional variables, administer a cognitive scale.
	<ol>
		<li>Administer a Cognitive Scale14 (following the protocol in the manual) for assessing individual intelligence in children and adolescents between the ages of 6 years and 16 years 11 months.</li>
		<li>Analyze in depth the cognitive profile obtained by the scale. 
		NOTE: Considering the information included in the cognitive scales manual, the results from the Wechsler scale could be influenced by ADHD, leading to lower scores in processing speed and working memory in comparison with perceptual reasoning and verbal comprehension.</li>
	</ol>
	</li>
</ol>
3. Executive Measures Using Continuous Performance Tests
<ol>
	<li>Analyze the performance of the children using two CPTs: one based on a Virtual Reality CPT15 and the other consisting of a Traditional CPT16.</li>
	<li>Administer the virtual-reality based CPT15. This is a CPT based on a virtual reality environment that reproduces the conditions of a regular classroom. It evaluates attention, impulsivity, processing speed, and motor activity in children and adolescents between 6 and 16 years of age. The activities that make up the test are preset, and it is not possible to change any specific characteristic of the tasks.
	<ol>
		<li>Double-click on the Virtual Reality CPT app to start the program.</li>
		<li>Enter the username and password provided by the program license.</li>
		<li>Enter the participant information (name, surname and date of birth) and the click on the &#34;Go into the virtual classroom&#34; window.</li>
		<li>Ask the participant to wear the Head Mounted Display (HMD) glasses and headphones, and inform them of the importance of wearing it during the whole test. Have the therapist say: &#34;Now you need to wear these special glasses during the virtual reality tasks, if you don&#39;t see very well or have any issue about that, please tell me and I help you to resolve it&#34;. 
		NOTE: These glasses are connected to the PC, so the therapist can see the images the participants are looking at in order to ensure that they understand the test (Figure 2).</li>
		<li>Ask the participant to hold the button with their dominant hand before starting the virtual attentional tasks. Have the therapist say: &#34;You need to hold and press the button with the same hand you write with&#34;.</li>
		<li>Have the participant explore the virtual environment (a typical classroom) and take the perspective of a student sitting at one of the desks looking at the blackboard for 15 s (Figure 3). Conduct this part by the virtual teacher though these instructions: &#34;Hello, with the glasses that you are wearing, you can see the entire classroom: to the left, to your right, up, and down. You can see everything. Notice all the things in the room, look at the walls and the other people, look at whatever you want&#34;.</li>
		<li>Have the participant follow the virtual teacher, who guides them through the tasks. The first part the participant performs is training, which consists of visually locating balloons and popping them by pressing the button. Have the virtual teacher in this part instruct this part as follows: &#34;Now that you have inspected everything, you&#39;re going to start doing something fun. We have placed some shiny red balloons around you. You need to find the balloons by moving your head. When you find one, look at it closely, and press the button to make it pop. You have to find 4 balloons. Let&#39;s go! The challenge starts now!&#34;</li>
		<li>Have the participant continue to the next step which is the first exercise. This is based on the &#34;x-no&#34; paradigm (traditionally known as &#34;no-go&#34;), where the participant must press the button when he or she does not see or hear the stimulus &#34;apple&#34;. Have the virtual teacher say: &#34;Now, you will to see some drawings on the chalkboard. I will also say a few words to you. You have to pay attention and click the button, AS FAST AS POSSIBLE, when you see or hear anything THAT IS NOT AN APPLE. But be careful! You need to press the button every time you see or hear any other thing. For example, if you hear &#34;CLOUD&#34; or if a drawing of a cloud appears on the chalkboard, you have to press the button. Remember: Never press the button when you see or hear apple! The challenge starts... Now!&#34;. 
		Note: As the activities are preset by the program, it is not possible to change the target-stimulus (in this case, APPLE).</li>
		<li>Have the participant complete the last exercise by following the instructions to press the button whenever he/she sees or hears the number &#34;seven&#34;. This part consists of a &#34;X&#34; paradigm (or &#34;go&#34; task). Say these instructions: &#34;Now you are going to work with numbers. You will see numbers on the chalkboard and you will also hear numbers. You must press the button every time you hear or see the number &#34;SEVEN&#34;. DO NOT press the button for any other number. For example, if you hear or see the number &#34;THREE&#34; DO NOT press the button. Remember: Always press the button when you see or hear &#34;SEVEN&#34;! The test starts now!&#34; 
		NOTE: As the activities are preset by the program, is not possible to change the target-stimulus (in this case, SEVEN).</li>
		<li>Print the report of the test results via the test website adding the name and surname of the child assessed. This report compiles results for the following variables: omissions, commissions, response time, and variability and complement this information by differentiating these measures of sensory modality (visual vs. auditory), presence/ absence of distractors, and task type (go vs. no-go), thereby leading to different execution profiles.</li>
	</ol>
	</li>
	<li>Administer the Traditional CPT16. This is a CPT that can be used in a visual or auditory version, but in this protocol only the visual version is used. This test contains preset tasks. The visual norms for CPT go from 4 years to more than 80, by age and gender.
	<ol>
		<li>Make sure that the participant is relaxed, paying attention to their breathing and ensuring that it is controlled. If it appears that the participant is not controlling their breathing. Indicate as follows: &#34;You should focus on abdominal contraction and controlled breathing out&#34;.</li>
		<li>Open the CPT application and enter the name and birth date of the child, and press the okay button.</li>
		<li>Click on visual tasks window and click the launch button, the computer will start to load the visual tasks.</li>
		<li>Ensure the participant is holding the button (which is connected to a PC) with his/her dominant hand. Repeat the instruction from step 5 of the Virtual Reality CPT: &#34;You need to hold and press the button with the same hand you write with&#34;.</li>
		<li>Inform the participant of the following instructions for the test: &#34;You have to press the button when you see a black square in the upper part which is the target stimulus. However, do not press the button when the black square is in the bottom part&#34; (Figure 4).</li>
		<li>Have the participant perform the training part (which lasts for approximately 3 min) until it is clear the participant understands the task. In the training part of the CPT, the target (stimulus to which the participant has to respond) and the non-target (stimulus to which the participant has to avoid responding) stimulus appear randomly in the screen; the therapist should observe whether the participant presses the button correctly or not. If the participant does not press the button according to the instructions, have the therapist explain the instructions again and then the participant will need to repeat the training section.</li>
		<li>Tell the participant that the task is very long and that she/he must keep still and concentrate on doing the tasks.</li>
		<li>Have the participant complete the CPT activities. It is divided into two sections. The first section of the test (the &#34;Infrequent&#34; or vigilance mode), is characterized by target: non-target ratio of 1:3.5. This is evidenced by a tendency to not press the button. In the second section (the &#34;Frequent&#34; or high response demand mode) presents a target:non-target ratio of 3.5:1, so the child must inhibit the tendency to respond.</li>
		<li>After completion of the CPT, generate the report which compiles the following variables: omissions, RT (response time between the presentation of target stimulus and subject response), commissions, variability, D prime (quality of concentration during the test based on the number of errors in the test) and ADHD Index, attributable to a presence or absence of attention deficit with hyperactivity. Calculate this ADHD Index from the sum of: TR of first half + D prime second half + total variability and is interpreted as attributable to ADHD when the score is lower than -1.80.</li>
	</ol>
	</li>
</ol>
4. Cortical Activation Measures in Fp1 and Fpz/Cz Regions (Hemoencephalography, and Quantified Electroencephalography) 17
<ol>
	<li>Open the Bioexplorer software and choose the design POCKET_HEG_video_1ch_AI_HEGRatio.bxd.
	<ol>
		<li>Press time on button to see the time during the assessment (35 s).</li>
		<li>Inform the participant that he/she cannot move and must be still. The therapist informs the participant about the importance of remaining still during the assessment of blood oxygenation: &#34;Now it is very important that you are still during the assessment of blood oxygenation because if you move, the system will fail, and it will be necessary to measure again. Are you ready?&#34;</li>
		<li>Click on the red button and enter the name of the subject and the cortical point which is going to be measured (Fp1 region for assessment of inhibition capacity and Fpz for the assessment of attention capacity).</li>
		<li>Put the band on the participant&#39;s forehead in a specific area: Fp1 (for assessment of inhibition capacity) and Fpz (for the assessment of attention capacity) as can be seen in Figure 5.</li>
		<li>Make sure that no external light enters the band. Properly adjust the band to the participant&#39;s head in such a way that it is not loose and does not fall off during the evaluation.</li>
		<li>Put the Hemoencephalography-nirHEG (which is connected to the headband) around the participant&#39;s neck, like a necklace.</li>
		<li>Turn on the hardware to connect the band to the PC.</li>
		<li>Measure the blood oxygenation of a specific area through the nir-HEG program for approximately 35 s. Press the green button to start to measure blood oxygenation and 35 s later press the white button to end the assessment.</li>
		<li>Print the output provided by the program and analyze the nir-HEG Ratio of the participant provided by the program. The mean of this tool is 100 (SD = 20) which is used to calibrate the spectrophotometers. An Attention Index (AI) is also obtained through the nir-HEG , which shows the incapability of the participant to increase the ratio and brain activation. This is useful to identify attentional problems and measure capacity of concentration.</li>
	</ol>
	</li>
	<li>Measure the cortical activity levels of the participant using the quantified electroencephalography (Q-EEG), a computerized EEG system that provides levels of cortical activation through the beta/theta ratio. It is used to measure general levels of attention, not taking the performed task. 
	NOTE: The analysis of beta/theta ratio have been carried out according to previous studies12.
	<ol>
		<li>Inform the participant of the correct abdominal breathing required during the test.</li>
		<li>Open the Bioexplorer software and choose the design combined_Theta_Beta.bxd. The screen will appear divided into two windows (the left side shows the cortical activity of FP1 and the right side shows the cortical activity of the CZ)</li>
		<li>Click on the red button and enter the name of the subject and the cortical point which is going to be measured (Fp1 region for assessment of inhibition capacity and Cz region for the assessment of attention capacity).</li>
		<li>Put the red electrode in the Fp1 region and the blue electrode in the Cz region, applying electrode gel (using the information found at: &#8220;http://neurologiclabs.com/neuromonitoring/eeg/&#8221;, to ensure that the electrodes are correctly placed) (see Figure 6).</li>
		<li>Put two more control electrodes (the black and white electrodes) on the participant&#180;s left and right earlobes, applying electrode gel.</li>
		<li>Ensure the participant has her or his eyes open during the assessment. The therapist must watch the participant throughout the assessment. If the participant closes their eyes at any time, end the assessment process and repeat it once the participant is rested.</li>
		<li>Place an electromyography (EMG) sensor on the right forearm to identify the degree of movement.</li>
		<li>Inform the participant that he/she must remain relaxed, trying not to move during the task an breathing slowly. The participant must be concentrated on the computer screen while the theta and beta waves are being emitted. The therapist says: &#34;You must be still and relaxed for 35 s, the only thing you need to do is to watch the theta/beta waves that will be appearing on the computer screen&#34;.</li>
		<li>Press the green button to start to measure cortical activity, and 35 s later press the white button to end the assessment.</li>
		<li>Print the results generated from program and analyze them. If the beta/theta ratio is lower than 50% at Cz, this evidences a deficit of sustained attention. On the other hand, if the ratio is also lower at Fp1, this result is related to an impairment of executive control, attributable to hyperactivity.</li>
	</ol>
	</li>
</ol>

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The authors who are listed above certify there are no financial interests or other conflicts of interest regarding the present study.

Here we present an effective protocol for assessing ADHD from 6-16 years of ages. Given the symptomatic complexity of ADHD and its high prevalence rates, professionals must have reliable and valid instruments to diagnose this disorder. Generally, questionnaires based on behavioral observations are widely used. However, the use of these instruments as the sole assessment measure has certain limitations, including potential subjectivity on the part of the observer18.
As t...

The overall goal of the present protocol is to develop a complete procedure or model of assessment for the diagnosis of Attention Deficit Hyperactivity Disorder, otherwise known as ADHD. ADHD is one of the problems that impacts academic performance. It is understood to be a disorder characterized by problems with attention, inhibitory control and hyperactivity, whose performance is significantly lower than their peers1,2. The latest version of the Diagnostic and Statistical Manual of Mental Disorders (DSM)1 includes different updates from the previous version: ADHD has been categorized as a neurodevelopmental disorder; the age of appearance of the symptoms has been increased so now the symptoms can manifest before 12 years of age; the term ADHD presentation should be used instead of subtype (predominantly hyperactive/impulsive; predominantly inattentive; and combined presentation, and); finally, it has been accepted as a comorbidity with autism spectrum disorders.
There are different estimations of prevalence rates depending on the country or region analyzed3,4,5. An international global systematic3 review observed an average prevalence rate of 5.29%. However, applying criteria from the Diagnostic and Statistical Manual of Mental Disorders4, the percentage ranges from 5.9 to 7.1%. Similarly, a meta-analysis of ADHD in a Spanish population provided an average of 6.8%5. The variations in prevalence rates could be due to the different assessment protocols used.
Although there is a considerable body of research suggesting a neurological basis for ADHD, the origins of this disorder remain unclear. Several studies have associated the ADHD symptomatology to brain cortical hypoactivation, which is related to a deficit in the dopaminergic and noradrenergic systems6. The noradrenergic system modules the selective attention and the activation levels needed to carry out a task. On the other hand, the dopaminergic system is responsible for inhibitory control, both at an executive and motivational level. The low cortical activation related to the dopaminergic and noradrenergic systems is presumed to be the basis for the inhibitory and attentional deficits presented in the ADHD. In this sense, children with ADHD show low cortical activation in the dopaminergic and noradrenergic systems, which is manifested by different profiles of electro cortical activity in a state of rest, evidenced by increased theta -and decreased beta- activity7,8 as well as low levels of blood oxygenation in the Fp1 (front left side of the frontal lobe), and FPz/Cz (central zone of the pre-frontal cortex) regions.
Blood oxygenation is measured using nir-HEG, which uses functional near-infrared spectroscopy to measure color changes in the blood in the brain to indicate oxygen saturation areas; oxygenated blood is bright red whereas de-oxygenated blood is a deep, almost purplish crimson. Cortical activation is measured using quantified electroencephalography (Q-EEG). This is a computerized EEG system that records electrical activity in the brain to provide levels of cortical activation through the beta/theta ratio. It measures attention in general, independently of the task being performed. Other studies have focused on the existence of an executive function (EF) impairment in the ADHD population9, which would explain the difficulty children with ADHD have controlling impulsive responses, resisting interference or distraction, organizing activities in a sequential manner, and sustaining cognitive effort while performing an activity.
Generally, these characteristic symptoms of ADHD have serious consequences which result in difficulties in scholastic, social and familial contexts. Children with ADHD have a higher probability of repeating a grade and/or completing fewer grades at school than children without ADHD. Moreover, dropping out of high school is three times more likely among youth with ADHD10,11.
Considering the modifications and the new categorization of ADHD in the current version of the Diagnostic and Statistical Manual of Mental Disorders 1, results relevant to establish the relationship between cortical activation levels in specific brain areas, executive functions, and diagnosis-related variables7,8,11,12 (i.e., differences between the three types of ADHD presentations).
One of the most common problems in the identification of ADHD is the over diagnosis of the disorder due to the absence of global protocols for assessment. The fact that professionals do not have a general protocol based on objective variables is causing a large percentage of false positive and false negative cases of ADHD. This situation highlights the need for professionals and clinicians to have a clear protocol that considers not only the relevant variables but also the relationships between them.
For this reason, the research group of School Learning, Difficulties and Academic Performance (ADIR) from the University of Oviedo has been working on developing a complete protocol to identifyprofiles of cortical activation and executive control to provide a more objective diagnosis of ADHD than what is currently in use. This protocol is particularly important because it takes into account the fact that cortical activation in the frontal and prefrontal cortex impacts the executive function. The current protocol will be useful for clinicians who are interested in performing a complete assessment that considers the interaction between relevant variables in the diagnosis. To that end, the protocol is based on the assessment model from a recent study proposed by Rodriguez et al. which takes into consideration the interaction between cortical activation and executive variables (Figure 1).
In summary, the purpose of this protocol is to provide a more objective diagnostic procedure for this developmental disorder than is currently available, and to analyze in depth the relationship between activation measures and executive function measures. The procedure will also take into consideration some of the hypothetical determinants of ADHD, both in 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.

<table><tbody><tr><td>EDAH&amp;nbsp;</td><td>TEA Company</td><td></td><td>It is a Scale for the Assessment of ADHD that was administered to families and/or teachers.&lt;br/&gt; &amp;nbsp;It comprises 20 items that provide information on the presence of symptoms relating to attention deficit and hyperactivity/impulsivity, and helps differentiate between the threes subtypes of ADHD. A score above 90% in its subscales indicates attention deficit, hyperactivity/ impulsivity problems, or both.</td></tr><tr><td>Wisc-IV R</td><td>TEA Company</td><td></td><td>The WISC-IV by Wechsler (2005) is a tool that assesses&lt;br/&gt; individual intelligence in children and adolescents between&lt;br/&gt; the ages of 6 years and 16 years 11 months.</td></tr><tr><td>QEEG</td><td>Neurobics pocket</td><td></td><td>Q-EEG (quantified electroencephalogram) is a computerized EEG system,&lt;br/&gt; adapted by Toomin, which provides levels of cortical activation through&lt;br/&gt; the beta/theta ratio. It measures attention in general, independently of the task to be performed.</td></tr><tr><td>NIR-HEG</td><td>Brain trainer company</td><td></td><td>it is a tool used to measure blood oxygenation in expressly selected areas. The nir-HEG employs the translucent property of biological tissue, and low-frequency red and infrared lights with light emitting diodes (LED optodes).&amp;nbsp;</td></tr><tr><td>AULA Nesplora</td><td>Nesplora Company</td><td></td><td>It is a Continuous Performance Test that evaluates attention, impulsivity, processing speed, and motor activity in participants between 6 and 16 years of age.&lt;br/&gt; The task is performed in a virtual reality environment,&lt;br/&gt; which is shown through three-dimensional (3D) glasses&lt;br/&gt; (Head Mounted Display, HMD) equipped with motion&lt;br/&gt; sensors and headphones.&amp;nbsp;</td></tr><tr><td>T.O.V.A (Test of Variables of Attention)</td><td>The T.O.V.A.&amp;nbsp; Company</td><td>T.O.V.A. 8 kit</td><td>T.O.V.A. is an objective, accurate, and FDA cleared continuous performance test&amp;nbsp; (CPT) that measures the key components of attention and inhibitory control.&lt;br/&gt; The T.O.V.A. is used by qualified healthcare professionals as an aid in the assessment&lt;br/&gt; of attention deficits, including attention-deficit/hyperactivity disorder (ADHD), in children and adults.</td></tr></tbody></table>

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 the assessment procedure presented here, it is possible to carry out an effective assessment about ADHD symptomatology in order to design an accurate intervention and make recommendations for parents and teachers. Below are a series of representative results of a participant with ADHD and a participant without ADHD, which will allow professionals to see the differences between the two profiles.
Once clinicians had the info...

Watch this Scientific Journal Video about Using Brain Activation nir-HEG/Q-EEG and Execution Measures CPTs in a ADHD Assessment Protocol at JoVE.com

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.

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 ...

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Research

JoVE Journal

Neuroscience

10.1K Views.  Oviedo University. 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.

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

Measurement of Neurophysiological Signals of Ignoring and Attending Processes in Attention Control

Attention control is the ability to selectively attend to some sensory signals while ignoring others. This ability is thought to involve two processes: enhancement of sensory signals that are to be attended and the attenuation of sensory signals that are to be ignored. The overall strength of attentional modulation is often measured by comparing the amplitude of a sensory neural response to an external input when attended versus when ignored. This method is robust for detecting attentional modulation, but precludes the ability to assess the separate dynamics of attending and ignoring processes. Here, we describe methodology to measure independently the neurophysiological signals of attending and ignoring using the intermodal attention task (IMAT). This task, when combined with electroencephalography, isolates neurophysiological sensory responses in auditory and visual modalities, when either attending or ignoring, with respect to a passive control. As a result, independent dynamics of attending and of a ignoring can be assessed in either modality. Our results using this task indicate that the timing and cortical sources of attending and ignoring effects differ, as do their contributions to the attention modulation effect, pointing to unique neural trajectories and demonstrating sample utility of measuring them separately.

Attention control comprises enhancement of target signals and attenuation of distractor signals. We describe an approach to measure separately but concurrently, the neurophysiology of attending and ignoring in sustained intermodal attention, utilizing a passive control condition during which neither process is continuously engaged.

Attention control is the ability to selectively attend to some sensory signals while ignoring others. This ability is thought to involve two processes: ...

Behavior

Event-related Potentials During Target-response Tasks to Study Cognitive Processes of Upper Limb Use in Children with Unilateral Cerebral Palsy

Unilateral Cerebral Palsy (CP) is a neurodevelopmental disorder that is a very common cause of disability in childhood. It is characterized by unilateral motor impairments that are frequently dominated in the upper limb. In addition to a reduced movement capacity of the affected upper limb, several children with unilateral CP show a reduced awareness of the remaining movement capacity of that limb. This phenomenon of disregarding the preserved capacity of the affected upper limb is regularly referred to as Developmental Disregard (DD). Different theories have been postulated to explain DD, each suggesting slightly different guidelines for therapy. Still, cognitive processes that might additionally contribute to DD in children with unilateral CP have never been directly studied. The current protocol was developed to study cognitive aspects involved in upper limb control in children with unilateral CP with and without DD. This was done by recording event-related potentials (ERPs) extracted from the ongoing EEG during target-response tasks asking for a hand-movement response. ERPs consist of several components, each of them associated with a well-defined cognitive process (e.g., the N1 with early attention processes, the N2 with cognitive control and the P3 with cognitive load and mental effort). Due to its excellent temporal resolution, the ERP technique enables to study several covert cognitive processes preceding overt motor responses and thus allows insight into the cognitive processes that might contribute to the phenomenon of DD. Using this protocol adds a new level of explanation to existing behavioral studies and opens new avenues to the broader implementation of research on cognitive aspects of developmental movement restrictions in children.

Several children with unilateral Cerebral Palsy seem to disregard the preserved capacity of their affected upper limb. This Developmental Disregard is extensively described in the literature but the involved cognitive processes have not been studied. To study underlying cognitive factors of upper limb control, an event-related potential protocol was developed.

Unilateral Cerebral Palsy (CP) is a neurodevelopmental disorder that is a very common cause of disability in childhood. It is characterized by unilateral ...

Correlating Behavioral Responses to fMRI Signals from Human Prefrontal Cortex: Examining Cognitive Processes Using Task Analysis

The aim of this methods paper is to describe how to implement a neuroimaging technique to examine complementary brain processes engaged by two similar tasks. Participants' behavior during task performance in an fMRI scanner can then be correlated to the brain activity using the blood-oxygen-level-dependent signal. We measure behavior to be able to sort correct trials, where the subject performed the task correctly and then be able to examine the brain signals related to correct performance. Conversely, if subjects do not perform the task correctly, and these trials are included in the same analysis with the correct trials we would introduce trials that were not only for correct performance. Thus, in many cases these errors can be used themselves to then correlate brain activity to them. We describe two complementary tasks that are used in our lab to examine the brain during suppression of an automatic responses: the stroop1 and anti-saccade tasks. The emotional stroop paradigm instructs participants to either report the superimposed emotional 'word' across the affective faces or the facial 'expressions' of the face stimuli1,2. When the word and the facial expression refer to different emotions, a conflict between what must be said and what is automatically read occurs. The participant has to resolve the conflict between two simultaneously competing processes of word reading and facial expression. Our urge to read out a word leads to strong 'stimulus-response (SR)' associations; hence inhibiting these strong SR's is difficult and participants are prone to making errors. Overcoming this conflict and directing attention away from the face or the word requires the subject to inhibit bottom up processes which typically directs attention to the more salient stimulus. Similarly, in the anti-saccade task3,4,5,6, where an instruction cue is used to direct only attention to a peripheral stimulus location but then the eye movement is made to the mirror opposite position. Yet again we measure behavior by recording the eye movements of participants which allows for the sorting of the behavioral responses into correct and error trials7 which then can be correlated to brain activity. Neuroimaging now allows researchers to measure different behaviors of correct and error trials that are indicative of different cognitive processes and pinpoint the different neural networks involved.

The goal of our research is to correlate behavior to brain activity. Accurate behavioral measures and imaging techniques allow us to elucidate brain-behavior relationships.

The aim of this methods paper is to describe how to implement a neuroimaging technique to examine complementary brain processes engaged by two similar ...

An Electrophysiology Protocol to Measure Reward Anticipation and Processing in Children

We present a protocol designed to measure the neural correlates of reward in children. The protocol allows researchers to measure both reward anticipation and processing. Its purpose is to create a reward task that is appropriate for young children with and without autism while controlling reward properties between two conditions: social and nonsocial. The current protocol allows for comparisons of brain activity between social and nonsocial reward conditions while keeping the reward itself identical between conditions. Using this protocol, we found evidence that neurotypical children demonstrate enhanced anticipatory brain activity during the social condition. Furthermore, we found that neurotypical children anticipate social reward more robustly than children with autism diagnoses. As the task uses snacks as a reward, it is most appropriate for young children. However, the protocol may be adapted for use with adolescent or adult populations if snacks are replaced by monetary incentives. The protocol is designed to measure electrophysiological events (event-related potentials), but it may be customized for use with eye-tracking or fMRI.

This protocol is designed to measure reward anticipation and processing in young children with and without autism. Specifically, the protocol is designed to study the neural correlates of reward during social and nonsocial conditions while controlling for reward between conditions.

We present a protocol designed to measure the neural correlates of reward in children. The protocol allows researchers to measure both reward anticipation ...

The Adventures of Fundi Intervention Based on the Cognitive and Emotional Processing in Attention Deficit Hyperactive Disorder Patients

Many children with attention deficit hyperactive disorder (ADHD) are known to have executive dysfunction, which weakens their abilities to learn and behave in daily living. This protocol describes the methodology that is required for the intervention (psychotherapy) based on planning, attention, successive, and simultaneous (PASS theory) cognitive processing and fear emotional processing. It provides guiding principles and practical recommendations. A disproportionately high level of fear (dysregulation) increases the vulnerability for dysfunction in learning and behavior. We explain the interplay between emotion and cognition at the neurological level.
A go/no go task (The Adventures of Fundi), which involves decision making, is administered in a PC- mode to a sample of 66 ADHD subjects. The Adventures of Fundi, a computer program, was constructed to induce successive or simultaneous processing when involving the training of planning and selective attention. It aims to improve the executive function with planning and selective attention. If executive function improves, learning improves, and behavior ameliorates. After intervention over 6 months, remission was achieved in 70% of subjects.
The instructor encourages the use of appropriate strategies and points out the ways in which the strategies can be useful in finding the solution to the problem (go/no go). The emphasis is not on rehearsing and adult instructed verbal sequence. The verbalization may reveal the conscious verbalized strategy to solve a task that is not really the strategy being unconsciously used in that case. A self-verbal report is unreliable. This is an inductive learning rather than deductive rule-learning approach central to cognitive PASS training. This inductive training has proved to produce not only near transfer but also far transfer.
Noncognitive factors (emotional factors) must be considered to maximize the benefit of cognitive training. Indirect and metaphorical communication considers the emotional factor.

This protocol illustrates a remedial therapy based on inductive learning and indirect communication (Ericksonian metaphorical hypnosis) that can be applied to children with Attention Deficit Hyperactive Disorder (ADHD). Particularly, this protocol is intended to test the effectiveness of a go/no-go decision task. Neuroscientific rationale is presented throughout the text.

Many children with attention deficit hyperactive disorder (ADHD) are known to have executive dysfunction, which weakens their abilities to learn and ...

A Multimodal Imaging- and Stimulation-based Method of Evaluating Connectivity-related Brain Excitability in Patients with Epilepsy

Resting-state functional connectivity MRI (rs-fcMRI) is a technique that identifies connectivity between different brain regions based on correlations over time in the blood-oxygenation level dependent signal. rs-fcMRI has been applied extensively to identify abnormalities in brain connectivity in different neurologic and psychiatric diseases. However, the relationship among rs-fcMRI connectivity abnormalities, brain electrophysiology and disease state is unknown, in part because the causal significance of alterations in functional connectivity in disease pathophysiology has not been established. Transcranial Magnetic Stimulation (TMS) is a technique that uses electromagnetic induction to noninvasively produce focal changes in cortical activity. When combined with electroencephalography (EEG), TMS can be used to assess the brain's response to external perturbations. Here we provide a protocol for combining rs-fcMRI, TMS and EEG to assess the physiologic significance of alterations in functional connectivity in patients with neuropsychiatric disease. We provide representative results from a previously published study in which rs-fcMRI was used to identify regions with abnormal connectivity in patients with epilepsy due to a malformation of cortical development, periventricular nodular heterotopia (PNH). Stimulation in patients with epilepsy resulted in abnormal TMS-evoked EEG activity relative to stimulation of the same sites in matched healthy control patients, with an abnormal increase in the late component of the TMS-evoked potential, consistent with cortical hyperexcitability. This abnormality was specific to regions with abnormal resting-state functional connectivity. Electrical source analysis in a subject with previously recorded seizures demonstrated that the origin of the abnormal TMS-evoked activity co-localized with the seizure-onset zone, suggesting the presence of an epileptogenic circuit. These results demonstrate how rs-fcMRI, TMS and EEG can be utilized together to identify and understand the physiological significance of abnormal brain connectivity in human diseases.

Resting-state functional-connectivity MRI has identified abnormalities in patients with a wide range of neuropsychiatric disorders, including epilepsy due to malformations of cortical development. Transcranial Magnetic Stimulation in combination with EEG can demonstrate that patients with epilepsy have cortical hyperexcitability in regions with abnormal connectivity.

Resting-state functional connectivity MRI (rs-fcMRI) is a technique that identifies connectivity between different brain regions based on correlations ...

Medicine

Online Transcranial Magnetic Stimulation Protocol for Measuring Cortical Physiology Associated with Response Inhibition

We describe the development of a reproducible, child-friendly motor response inhibition task suitable for online Transcranial Magnetic Stimulation (TMS) characterization of primary motor cortex (M1) excitability and inhibition. Motor response inhibition prevents unwanted actions and is abnormal in several neuropsychiatric conditions. TMS is a non-invasive technology that can quantify M1 excitability and inhibition using single- and paired-pulse protocols and can be precisely timed to study cortical physiology with high temporal resolution. We modified the original Slater-Hammel (S-H) stop signal task to create a &#34;racecar&#34; version with TMS pulses time-locked to intra-trial events. This task is self-paced, with each trial initiating after a button push to move the racecar towards the 800 ms target. GO trials require a finger-lift to stop the racecar just before this target. Interspersed randomly are STOP trials (25%) during which the dynamically adjusted stop signal prompts subjects to prevent finger-lift. For GO trials, TMS pulses were delivered at 650 ms after trial onset; whereas, for STOP trials, the TMS pulses occurred 150 ms after the stop signal. The timings of the TMS pulses were decided based on electroencephalography (EEG) studies showing event-related changes in these time ranges during stop signal tasks. This task was studied in 3 blocks at two study sites (n=38) and we recorded behavioral performance and event-related motor-evoked potentials (MEP). Regression modelling was used to analyze MEP amplitudes using age as a covariate with multiple independent variables (sex, study site, block, TMS pulse condition [single- vs. paired-pulse], trial condition [GO, successful STOP, failed STOP]). The analysis showed that TMS pulse condition (p&#60;0.0001) and its interaction with trial condition (p=0.009) were significant. Future applications for this online S-H/TMS paradigm include the addition of simultaneous EEG acquisition to measure TMS-evoked EEG potentials. A potential limitation is that in children, the TMS pulse sound could&#160;affect behavioral task performance.

We describe an experimental procedure to quantify excitability and inhibition of primary motor cortex during a motor response inhibition task by using Transcranial Magnetic Stimulation throughout the course of a Stop Signal Task.

We describe the development of a reproducible, child-friendly motor response inhibition task suitable for online Transcranial Magnetic Stimulation (TMS) ...

Combined Transcranial Magnetic Stimulation and Electroencephalography of the Dorsolateral Prefrontal Cortex

Transcranial magnetic stimulation (TMS) is a non-invasive method that produces neural excitation in the cortex by means of brief, time-varying magnetic field pulses. The initiation of cortical activation or its modulation depends on the background activation of the neurons of the cortical region activated, the characteristics of the coil, its position and its orientation with respect to the head. TMS combined with simultaneous electrocephalography (EEG) and neuronavigation (nTMS-EEG) allows for the assessment of cortico-cortical excitability and connectivity in almost all cortical areas in a reproducible manner. This advance makes nTMS-EEG a powerful tool that can accurately assess brain dynamics and neurophysiology in test-retest paradigms that are required for clinical trials. Limitations of this method include artifacts that cover the initial brain reactivity to stimulation. Thus, the process of removing artifacts may also extract valuable information. Moreover, the optimal parameters for dorsolateral prefrontal (DLPFC) stimulation are not fully known and current protocols utilize variations from the motor cortex (M1) stimulation paradigms. However, evolving nTMS-EEG designs hope to address these issues. The protocol presented here introduces some standard practices for assessing neurophysiological functioning from stimulation to the DLPFC that can be applied in patients with treatment resistant psychiatric disorders that receive treatment such as transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), magnetic seizure therapy (MST) or electroconvulsive therapy (ECT).

The protocol presented here is for TMS-EEG studies utilizing intracortical excitability test-retest design paradigms. The intent of the protocol is to produce reliable and reproducible cortical excitability measures for assessing neurophysiological functioning related to therapeutic interventions in the treatment of neuropsychiatric diseases such as major depression.

Transcranial magnetic stimulation (TMS) is a non-invasive method that produces neural excitation in the cortex by means of brief, time-varying magnetic ...

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.

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.

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

A Visuospatial Planning Task Coupled with Eye-Tracker and Electroencephalogram Systems

The planning process, characterized by the capability to formulate an organized plan to reach a goal, is essential for human goal-directed behavior. Since planning is compromised in several neuropsychiatric disorders, the implementation of proper clinical and experimental tests to examine planning is critical. Due to the nature of the deployment of planning, in which several cognitive domains participate, the assessment of planning and the design of behavioral paradigms coupled with neuroimaging methods are current challenges in cognitive neuroscience. A planning task was evaluated in combination with an electroencephalogram (EEG) system and eye movement recordings in 27 healthy adult participants. Planning can be separated into two stages: a mental planning stage in which a sequence of steps is internally represented and an execution stage in which motor action is used to achieve a previously planned goal. Our protocol included a planning task and a control task. The planning task involved solving 36 maze trials, each representing a zoo map. The task had four periods: i) planning, where the subjects were instructed to plan a path to visit the locations of four animals according to a set of rules; ii) maintenance, where the subjects had to retain the planned path in their working memory; iii) execution, where the subjects used eye movements to trace the previously planned path as indicated by the eye-tracker system; and iv) response, where the subjects reported the order of the visited animals. The control task had a similar structure, but the cognitive planning component was removed by modifying the task goal. The spatial and temporal patterns of the EEG revealed that planning induces a gradual and lasting rise in frontal-midline theta activity (FM&#952;) over time. The source of this activity was identified within the prefrontal cortex by source analyses. Our results suggested that the experimental paradigm combining EEG and eye-tracker systems was optimal for evaluating cognitive planning.

The study of cognitive planning combining EEG and eye-tracking systems provides a multimodal approach to investigate the neural mechanisms that mediate cognitive control and goal-directed behavior in humans. Here, we describe a protocol for investigating the role of brain oscillations and eye movements in planning performance.

The planning process, characterized by the capability to formulate an organized plan to reach a goal, is essential for human goal-directed behavior. Since ...