We thank the Perth Children&#8217;s Hospital Foundation for their generous support in purchasing the EEG equipment used in this project.&#160;We thank Gardar Thorvardsson (Kvikna) and Ieesha Sparks (Temple Medical and Scientific) for their support in the technical aspects of the study project.

The study was approved by the Child and Adolescent Health Service (CAHS) Human Research Ethics Committee (HREC, Approval Number RGS0000004988) and adhered to the tenets of the Declaration of Helsinki.
1. Identification of patients for inclusion in the study
<ol>
	<li>At the time of referral determine the infant&#39;s eligibility to be enrolled in the study. Any infant with suspected HIE requiring transport is eligible for the study.</li>
	<li>Use the standardized diagnostic criteria12 to identify suspected HIE infants:
	<ol>
		<li>Check if the gestational age is &#62;35 weeks.</li>
		<li>Check if it is &#60;6 h post birth.</li>
		<li>Check for evidence of asphyxia as defined by the presence of the following four criteria:
		<ol>
			<li>Check for any acute perinatal event that may result in HIE (e.g., abruption of placenta, cord prolapse, severe FHR abnormality).</li>
			<li>Check if the Apgar score is &#60;6 at 10 min or if there is a continued need for resuscitation with positive pressure ventilation +/- chest compressions at 10 min of age.</li>
			<li>Check if the cord pH is &#60;7.0 or BE is &#62;12 mmol/L within 60 min of birth (if able to do gas).</li>
			<li>If cord pH is not available, check if arterial pH is &#60;7.0 or BE is &#62;12 mmol/L within 60 min of birth (if able to do gas).</li>
		</ol>
		</li>
	</ol>
	</li>
</ol>
2. Obtaining consent from the parents
<ol>
	<li>On arrival, approach parents for verbal consent for the use of the device and a survey on the acceptability of its use.</li>
	<li>Provide the parent information sheet, which contains all the necessary information for informed consent.</li>
	<li>Ensure the parent(s) understand the information and have the opportunity to ask any questions.</li>
	<li>Obtain written consent within 72 h of the verbal consent.</li>
</ol>
3. Requesting consent from the transport doctor and nurse
<ol>
	<li>Request consent from the transport doctor and nurse to send them surveys about their experience using aEEG in transport.</li>
</ol>
4. aEEG application
<ol>
	<li>Insert aEEG electrode pins into the baby&#39;s scalp per standard guidelines13.</li>
	<li>Measure and locate the anatomical landmarks: Sagittal suture and ear tragus.</li>
	<li>Align the electrode measuring tape (Figure 1) vertically on the head and parallel to the face.</li>
	<li>Match the letters/symbols on the positioning aid until the same letter/symbol in both locations (Figure 1).</li>
	<li>Mark the positions with a surgical pen on each side of the tape (Figure 2).
	<ol>
		<li>Let the hair part naturally or part it vertically away from the marked position using sterile water and swab sticks. Dry it with gauze.</li>
		<li>Clean skin with 1% chlorhexidine/alcohol swabs and let it dry.</li>
		<li>Hold the skin tight and insert the needle at 30&#176; angle, with the sensor wire upwards.</li>
		<li>Secure the subdermal needle electrode in place using steristrips and the Chevron method14 (Figure 3).</li>
		<li>Repeat the previous steps for the other needle insertions.</li>
		<li>If the scalp is very hairy, use skin preparation swabs around the needle insertion site and allow drying prior to taping.</li>
		<li>Point the needles and wires in the same direction.</li>
		<li>Place the reference electrode on the chest (anterior or posterior), the back of the shoulder, or the nape area of the neck.</li>
	</ol>
	</li>
	<li>Connect the electrodes to the aEEG amplifier using the C3/C4 and P3/P4 configurations (see Figure 4).</li>
</ol>
5. Setting up EEG amplifier and tablet
<ol>
	<li>Connect the amplifier to the tablet computer using an ethernet cable; an overview of the connections can be seen in Figure 5.</li>
	<li>Turn on the tablet and log in.</li>
	<li>Enter the Acquire Pro application. The default neonatal configuration will be automatically applied.</li>
	<li>Change the default settings of impedance from 5 K&#8486; to 10 K&#8486;.</li>
	<li>Press Start Recording, and a patient ID will automatically be created.</li>
	<li>Press the EEG tab to observe the live trace.</li>
	<li>Secure the clinical tablet to the cot. Transport the infant in either a Mansell neocot or a Voyager transport incubator (Figure 6 and Figure 7). The location of the tablet on the cot depends on which cot is taken on the transport (see Figure 8).</li>
	<li>If using an aircraft, dismount the tablet from the cot and hold it in the hands.</li>
</ol>
6. aEEG monitoring during transport.
<ol>
	<li>During the transport, note any movements that may contribute to artifact, clinical change, or seizure on the tablet software. Use buttons that can be pressed on the tablet to label important events, including seizure, patient care, loading/unloading, take-off, and landing.</li>
	<li>For continuous clinical events such as seizures, a label will be added for the duration they occur. When the event finishes, press the button a second time. For non-continuous events, press the button only once for a time stamp.</li>
	<li>On arrival at the receiving hospital, transfer the baby to the intensive care bed. Disconnect scalp electrodes from the study amplifier and transfer them onto the NICU aEEG monitor, where the recording can be continued per unit protocol. 
	NOTE: Treating clinicians must be blinded to the aEEG trace and acute decisions must not be made based on the traces.</li>
</ol>
7. Data interpretation
<ol>
	<li>Record demographic and transport information in addition to electroencephalogram.</li>
	<li>Download aEEG traces using the Centrum application.</li>
	<li>Ensure that the aEEG traces are reviewed by the CPI and two independent assessors with between 5-20 years&#39; experience of reading neonatal aEEG.</li>
	<li>Blind the assessors to the clinical information and traces.</li>
	<li>Separate traces into 15 min segments and review the number of artifact segments. A segment of the trace is considered an artifact if two of the three &#39;experts&#39; agree. An arbitrary value of 100 &#181;V has been chosen at which movement artifact is said to occur.</li>
	<li>Download raw data from each trace at a rate of 8 Hz from the C3-C4 electrodes. 
	NOTE: Impedance (Z) is the resistance of current flow and measures the quality of skin electrode placement and lead motion artifact. Low, equal, and stable impedance ensures optimal aEEG. The software system records impedance as a discrete notification set at &#62;10 K&#8486;. The magnitude and number are recorded for each trace.</li>
	<li>Complete staff and parent surveys after the transport using an electronic data capture tablet application. 
	NOTE: The study aims to recruit and collect data from 20 patients with suspected HIE.</li>
</ol>
8. Analysis
<ol>
	<li>Record and present demographic, transport, and aEEG descriptives using median (interquartile range; IQR).</li>
	<li>Present the artifact as a percent of the total trace. Describe movement artifact as the mean (standard deviation; SD) percent of the total trace.</li>
	<li>Present Z as a mean number (range) and Z magnitude as median (IQR) as kiloohms (K&#8486;).</li>
	<li>Define traces as total and movement artifacts free and absent of Z 80% of the time. 
	NOTE: Representative results presented in this methodology are expressed as a median and interquartile range and comparison of medians using the Mann-Whitney U test.</li>
</ol>

Using a Portable Amplitude-Integrated Electroencephalogram for Infant Transport

<ol>
	<li>Kurinczuk, J. J., White-Koning, M., Badawi, N. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Epidemiology+of+neonatal+encephalopathy+and+hypoxic-ischaemic+encephalopathy.">Epidemiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy.</a> Early Hum Dev. 86 (6), 329-338 (2010).</li><li>. Midwives Notification System, Government of Western Australia, Department of Health Available from: <a target="_blank" href="https://www.health.wa.gov.au/Reports-and-publications/Western-Australias-Mothers-and-Babies-summary-information/data?report=mns_birth_y">https://www.health.wa.gov.au/Reports-and-publications/Western-Australias-Mothers-and-Babies-summary-information/data?report=mns_birth_y</a> (2023)</li><li>Shankaran, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Whole-body+hypothermia+for+neonates+with+hypoxic-ischemic+encephalopathy.">Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy.</a> N Engl J Med. 353 (15), 1574-1584 (2005).</li><li>Thoresen, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Time+is+brain:+Starting+therapeutic+hypothermia+within+three+hours+after+birth+improves+motor+outcome+in+asphyxiated+newborns.">Time is brain: Starting therapeutic hypothermia within three hours after birth improves motor outcome in asphyxiated newborns.</a> Neonatology. 104 (3), 228-233 (2013).</li><li>Wall&#248;e, L., Hjort, N. L., Thoresen, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Start+cooling+as+soon+as+possible.">Start cooling as soon as possible.</a> Acta Paediatr. 108 (4), 771 (2019).</li><li>Skranes, J. H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Amplitude-integrated+electroencephalography+improves+the+identification+of+infants+with+encephalopathy+for+therapeutic+hypothermia+and+predicts+neurodevelopmental+outcomes+at+2+years+of+age.">Amplitude-integrated electroencephalography improves the identification of infants with encephalopathy for therapeutic hypothermia and predicts neurodevelopmental outcomes at 2 years of age.</a> J Pediatr. 187, 34-42 (2017).</li><li>Shalak, L. F., Laptook, A. R., Velaphi, S. C., Perlman, J. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Amplitude-integrated+electroencephalography+coupled+with+an+early+neurologic+examination+enhances+prediction+of+term+infants+at+risk+for+persistent+encephalopathy.">Amplitude-integrated electroencephalography coupled with an early neurologic examination enhances prediction of term infants at risk for persistent encephalopathy.</a> Pediatrics. 111 (2), 351-357 (2003).</li><li>Hellstrom-Westas, L., Rosen, I., Svenningsen, N. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Predictive+value+of+early+continuous+amplitude+integrated+eeg+recordings+on+outcome+after+severe+birth+asphyxia+in+full+term+infants.">Predictive value of early continuous amplitude integrated eeg recordings on outcome after severe birth asphyxia in full term infants.</a> Arch Dis Child Fetal Neonatal Ed. 72 (1), F34-F38 (1995).</li><li>Davies, A., Wassink, G., Bennet, L., Gunn, A. J., Davidson, J. O. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Can+we+further+optimize+therapeutic+hypothermia+for+hypoxic-ischemic+encephalopathy.">Can we further optimize therapeutic hypothermia for hypoxic-ischemic encephalopathy.</a> Neural Regen Res. 14 (10), 1678 (2019).</li><li>Davis, J. W., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Outcomes+to+5+years+of+outborn+versus+inborn+infants+&amp;lt;32+weeks+in+western+australia:+A+cohort+study+of+infants+born+between+2005+and+2018.">Outcomes to 5 years of outborn versus inborn infants &amp;lt;32 weeks in western australia: A cohort study of infants born between 2005 and 2018.</a> Arch Dis Child Fetal Neonatal Ed. 108 (5), 499-504 (2023).</li><li>Schomer, D. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Ambulatory+EEG+monitoring,+reviewing,+and+interpreting.">Ambulatory EEG monitoring, reviewing, and interpreting.</a> J Clin Neurophysiol. 38 (2), 77-86 (2021).</li><li>Hypoxic ischaemic encephalopathy (HIE). Neonatology Available from: <a target="_blank" href="https://cahs.health.wa.gov.au/~/media/HSPs/CAHS/Documents/Health-Professionals/Neonatology-guidelines/Hypoxic-Ischaemic-Encephalopathy.pdf?thn=0">https://cahs.health.wa.gov.au/~/media/HSPs/CAHS/Documents/Health-Professionals/Neonatology-guidelines/Hypoxic-Ischaemic-Encephalopathy.pdf?thn=0</a> (2018)</li><li>Brainz Monitor: Low impedance needle electrodes. Neonatology Available from: <a target="_blank" href="https://cahs.health.wa.gov.au/-/media/HSPs/CAHS/Documents/Health-Professionals/Neonatology-guidelines/Brainz-Monitor-Low-Impedance-Needle-Electrodes.pdf?thn=0">https://cahs.health.wa.gov.au/-/media/HSPs/CAHS/Documents/Health-Professionals/Neonatology-guidelines/Brainz-Monitor-Low-Impedance-Needle-Electrodes.pdf?thn=0</a> (2021)</li><li>Found, P. W. H., Baines, D. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Efficacy+of+securing+cannulae+with+different+taping+methods).">Efficacy of securing cannulae with different taping methods).</a> Anaesth Intensive Care. 28 (5), 547-551 (2000).</li><li>Stephens, C. M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Electroencephalography+quality+and+application+times+in+a+pediatric+emergency+department+setting:+A+feasibility+study.">Electroencephalography quality and application times in a pediatric emergency department setting: A feasibility study.</a> Pediatr Neurol. 148, 82-85 (2023).</li><li>Variane, G. F. T., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Remote+monitoring+for+seizures+during+therapeutic+hypothermia+in+neonates+with+hypoxic-ischemic+encephalopathy.">Remote monitoring for seizures during therapeutic hypothermia in neonates with hypoxic-ischemic encephalopathy.</a> JAMA Netw Open. 6 (11), e2343429 (2023).</li><li>Bruns, N., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Application+of+an+amplitude-integrated+EEG+monitor+(cerebral+function+monitor)+to+neonates.">Application of an amplitude-integrated EEG monitor (cerebral function monitor) to neonates.</a> J Vis Exp. (127), e55985 (2017).</li><li>Dilena, R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Consensus+protocol+for+eeg+and+amplitude-integrated+eeg+assessment+and+monitoring+in+neonates.">Consensus protocol for eeg and amplitude-integrated eeg assessment and monitoring in neonates.</a> Clin Neurophysiol. 132 (4), 886-903 (2021).</li><li>Moghadam, S. M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=An+automated+bedside+measure+for+monitoring+neonatal+cortical+activity:+A+supervised+deep+learning-based+electroencephalogram+classifier+with+external+cohort+validation.">An automated bedside measure for monitoring neonatal cortical activity: A supervised deep learning-based electroencephalogram classifier with external cohort validation.</a> Lancet Digit Health. 4 (12), e884-e892 (2022).</li></ol>

The authors have no example conflicts of interest to disclose.&#160;Kvikna ehf. Reykjavik, Iceland and Temple&#160;Medical and Scientific,&#160;Sydney, New South Wales, Australia had no input into the design, analysis, or interpretation of the study but funded publication fees.

This novel study describes the application and early data acquisition of aEEG in infants with suspected HIE who require transport soon after birth. aEEG application during neonatal transport has not been reported previously. aEEG has been used under novel circumstances, such as remote monitoring under telehealth neurocritical care consultation in Brazil and the Paediatric ED15,16. 
The aEEG needle application is similar to that used ...

Impaired oxygen delivery or blood flow to the brain around the time of birth can cause brain injury (hypoxic ischemic encephalopathy; HIE). This is a leading cause of death and disability in full-term babies1. HIE is reported to have a worldwide incidence of 2 per 1000 deliveries, which is likely to be higher in low to middle-income countries. In Western Australia, approximately 50 babies are born each year who have a clinical diagnosis of HIE (32308 live births in 2022, an incidence of approximately 1.5 per 10002).
HIE is diagnosed with criteria based on the circumstances of birth, changes in the infant&#39;s blood acid balance (from umbilical cord or baby after birth), and changes in neurological status3. The treatment for moderate or severe HIE is whole-body hypothermia of 33-34 &#176;C. The earlier this is commenced, the likely greater the benefit to the baby&#39;s neurological outcome3,4,5. Amplitude-integrated EEG (aEEG) is an essential part of assessment and monitoring, which in many regions is only available in tertiary centers. Electrodes (EEG safety DIN connector or DIN 42802 with 1.5 mm diameter pin) are inserted into the scalp to measure and record brain electrical activity. Electrodes are then connected to an amplifier, which is in turn connected to a clinical tablet computer to display and record brainwave activity. aEEG can provide information on brain wave activity and be used to assist with the diagnosis of HIE6. The combination of neurological examination and aEEG may enhance the ability to identify infants with moderate or severe HIE7,8,9.
The Newborn Emergency Transport Service of Western Australia (NETS WA) provides intensive care transport to approximately 1100 sick babies per year. Healthcare staff in local hospitals can contact NETS WA through a free phone number and are immediately connected via a conference call with a neonatal specialist doctor and nurse to request a transfer. The NETS team travels either by specialized road ambulance or fixed-wing aircraft with a purpose-built intensive care transport equipment cot. On arrival of the transport team to the referring hospital, the baby is assessed, and treatment is continued or escalated. The team then transfers the infant to a tertiary neonatal intensive care unit (NICU) in the state capital (Perth). In Western Australia, owing to the often-large distances between referring hospitals and centralized specialist services10 (a maximum distance of 1381 miles), aEEG may not applied for up to many hours after birth, leading to a delay in treatment.
Many monitoring systems have been designed for the intensive care unit but owing to their size and power requirement, they are impractical for the transport environment. Ward-based equipment is prone to movement artifacts, which may record insufficient quality data in the transport environment. Ambulatory EEG amplifier technology, designed primarily to be worn by patients at home, can connect to a computer tablet with EEG detection software and be applied to a newborn during transport11. This can be carried by the neonatal transport team to a baby with suspected HIE. The software is capable of being viewed remotely via a portable internet uplink and web-based viewer. Currently, there are no reports on the suitability or readability of aEEG in the transport environment.
Applying and monitoring aEEG in the transport of infants with HIE has not been previously reported, and there are no existing protocols for its use. There is no evidence to support feasibility or utility in the transport environment. We present a protocol for aEEG use in neonatal transport. It aims to assess whether aEEG in babies with HIE who require transport after birth is feasible and can provide readable clinical information.

<table><tbody><tr><td>Stratus EEG Centrum, Acquire Pro Software for&lt;br/&gt; Microsoft Windows</td><td>Stratus Software Solutions LLC&lt;br/&gt; Kvikna Medical Lyngh&amp;aacute;ls 9 110 Reykjavik Iceland</td><td>Version 4.2</td><td></td></tr><tr><td>Trackit T4PCU24+8</td><td>Lifelines Neuro&lt;br/&gt; 7 Clarendon Court&lt;br/&gt; Over Wallop&lt;br/&gt; StockBridge&lt;br/&gt; Hants, UK</td><td>SN: T4-170046&lt;br/&gt; Issue: 4 C169</td><td></td></tr><tr><td>Ultra Subdermal Needle Electrode</td><td>Natus&lt;br/&gt; 3150 Pleasant View Road&lt;br/&gt; Middleton&lt;br/&gt; WI 53562&lt;br/&gt; USA</td><td>019-476600</td><td>14 mm x 0.38 mm&lt;br/&gt; SST Needle&lt;br/&gt; DIN 42802 connector</td></tr></tbody></table>

amplitude-integrated eeg in infants at risk of hypoxic-ischemic encephalopathy: a feasibility study in road and air transport in western australia

Infants at risk of HIE require early identification and initiation of therapeutic hypothermia (TH). Earlier treatment with TH is associated with better outcomes. aEEG is frequently used when making the decision whether to commence TH. As this is often limited to tertiary centers, TH may be delayed if the infant requires transport to a center that provides it. We aimed to provide a method for the application of amplitude-integrated electroencephalogram (aEEG) and to determine the feasibility of acquiring clinically meaningful information during transport. All infants &#8805;35 weeks, at risk of HIE at referral, were eligible for inclusion. Scalp electrodes were placed in the C3-C4; P3-P4 position on the infant&#39;s scalp and connected to the aEEG amplifier. The aEEG amplifier was, in turn, connected to a clinical tablet computer with EEG software to collect and analyze aEEG information. Recordings were reviewed by the chief principal investigator and two independent reviewers (blinded) for background trace and artifact. Predefined criteria for data quality were set to movement artifacts and software impedance notifications. Surveys were completed by healthcare staff and parents for acceptability and ease of use.

Between 1st September 2022 and 5th June 2023, 25 babies were transported in Western Australia with possible HIE and were eligible for inclusion. Of the total, 20 infants were consented, recruited, and successfully had aEEG applied during their transport. A total of 5 patients were not recruited and 3 were missed for consent. In one case, the device had started an automatic software update and was unusable; in one case, the baby was not at risk of HIE and was deemed ineligible for recruitment. Of the...

Author Spotlight: Assessing the Feasibility of Using Amplitude-Integrated EEG During Neonatal Transport

Here, we present a feasibility study to assess a portable amplitude-integrated electroencephalogram (aEEG) recording system during the transport of infants with suspected hypoxic ischemic encephalopathy (HIE).

Amplitude-Integrated EEG in Infants at Risk of Hypoxic-Ischemic Encephalopathy: A Feasibility Study in Road and Air Transport in Western Australia

Infants at risk of HIE require early identification and initiation of therapeutic hypothermia (TH). Earlier treatment with TH is associated with better ...

amplitude-integrated-eeg-infants-at-risk-hypoxic-ischemic

Research

JoVE Journal

Medicine

565 Views.  Government of Western Australia, Child and Adolescent Health Service. We wilden de haalbaarheid beoordelen van het gebruik van een amplitude-geïntegreerd elektro-encefalogram tijdens neonataal transport. Aan de hand van klinische criteria bepaalden we of het tijdens het transport verkregen spoor leesbaar was. Dit helpt de clinicus bij de diagnose en prognose van baby's die vervoer nodig hebben na mogelijke verstikking van de geboorte of hypoxische ischemische encefalopathie.Monitoring op afstand, geautomatiseerde appara...

Video: Auteur in de schijnwerpers: beoordeling van de haalbaarheid van het gebruik van amplitude-geïntegreerd EEG tijdens neonataal transport

Making Sense of Listening: The IMAP Test Battery

The ability to hear is only the first step towards making sense of the range of information contained in an auditory signal. Of equal importance are the abilities to extract and use the information encoded in the auditory signal. We refer to these as listening skills (or auditory processing AP). Deficits in these skills are associated with delayed language and literacy development, though the nature of the relevant deficits and their causal connection with these delays is hotly debated.
When a child is referred to a health professional with normal hearing and unexplained difficulties in listening, or associated delays in language or literacy development, they should ideally be assessed with a combination of psychoacoustic (AP) tests, suitable for children and for use in a clinic, together with cognitive tests to measure attention, working memory, IQ, and language skills. Such a detailed examination needs to be relatively short and within the technical capability of any suitably qualified professional. Current tests for the presence of AP deficits tend to be poorly constructed and inadequately validated within the normal population. They have little or no reference to the presenting symptoms of the child, and typically include a linguistic component. Poor performance may thus reflect problems with language rather than with AP. To assist in the assessment of children with listening difficulties, pediatric audiologists need a single, standardized child-appropriate test battery based on the use of language-free stimuli.
We present the IMAP test battery which was developed at the MRC Institute of Hearing Research to supplement tests currently used to investigate cases of suspected AP deficits. IMAP assesses a range of relevant auditory and cognitive skills and takes about one hour to complete. It has been standardized in 1500 normally-hearing children from across the UK, aged 6-11 years. Since its development, it has been successfully used in a number of large scale studies both in the UK and the USA. IMAP provides measures for separating out sensory from cognitive contributions to hearing. It further limits confounds due to procedural effects by presenting tests in a child-friendly game-format. Stimulus-generation, management of test protocols and control of test presentation is mediated by the IHR-STAR software platform. This provides a standardized methodology for a range of applications and ensures replicable procedures across testers. IHR-STAR provides a flexible, user-programmable environment that currently has additional applications for hearing screening, mapping cochlear implant electrodes, and academic research or teaching.

A test battery (IMAP) for performing an in-depth assessment of auditory and cognitive abilities contributing to listening skills is described. It is quick to administer, child-friendly and free from linguistic confounds. Stimulus generation and protocol management are controlled via a software platform (IHR-STAR) to ensure replicable procedures.

The ability to hear is only the first step towards making sense of the range of information contained in an auditory signal. Of equal importance are the ...

A Strategy to Identify de Novo Mutations in Common Disorders such as Autism and Schizophrenia

There are several lines of evidence supporting the role of de novo mutations as a mechanism for common disorders, such as autism and schizophrenia. First, the de novo mutation rate in humans is relatively high, so new mutations are generated at a high frequency in the population. However, de novo mutations have not been reported in most common diseases. Mutations in genes leading to severe diseases where there is a strong negative selection against the phenotype, such as lethality in embryonic stages or reduced reproductive fitness, will not be transmitted to multiple family members, and therefore will not be detected by linkage gene mapping or association studies. The observation of very high concordance in monozygotic twins and very low concordance in dizygotic twins also strongly supports the hypothesis that a significant fraction of cases may result from new mutations. Such is the case for diseases such as autism and schizophrenia. Second, despite reduced reproductive fitness1 and extremely variable environmental factors, the incidence of some diseases is maintained worldwide at a relatively high and constant rate. This is the case for autism and schizophrenia, with an incidence of approximately 1% worldwide. Mutational load can be thought of as a balance between selection for or against a deleterious mutation and its production by de novo mutation. Lower rates of reproduction constitute a negative selection factor that should reduce the number of mutant alleles in the population, ultimately leading to decreased disease prevalence. These selective pressures tend to be of different intensity in different environments. Nonetheless, these severe mental disorders have been maintained at a constant relatively high prevalence in the worldwide population across a wide range of cultures and countries despite a strong negative selection against them2. This is not what one would predict in diseases with reduced reproductive fitness, unless there was a high new mutation rate. Finally, the effects of paternal age: there is a significantly increased risk of the disease with increasing paternal age, which could result from the age related increase in paternal de novo mutations. This is the case for autism and schizophrenia3. The male-to-female ratio of mutation rate is estimated at about 4&#x2013;6:1, presumably due to a higher number of germ-cell divisions with age in males. Therefore, one would predict that de novo mutations would more frequently come from males, particularly older males4. A high rate of new mutations may in part explain why genetic studies have so far failed to identify many genes predisposing to complexes diseases genes, such as autism and schizophrenia, and why diseases have been identified for a mere 3% of genes in the human genome. Identification for de novo mutations as a cause of a disease requires a targeted molecular approach, which includes studying parents and affected subjects. The process for determining if the genetic basis of a disease may result in part from de novo mutations and the molecular approach to establish this link will be illustrated, using autism and schizophrenia as examples.

Molecular genetic strategy for finding de novo mutations causing common disorders such as autism and schizophrenia.

There are several lines of evidence supporting the role of de novo mutations as a mechanism for common disorders, such as autism and schizophrenia. First, ...

Infant Auditory Processing and Event-related Brain Oscillations

Rapid auditory processing and acoustic change detection abilities play a critical role in allowing human infants to efficiently process the fine spectral and temporal changes that are characteristic of human language. These abilities lay the foundation for effective language acquisition; allowing infants to hone in on the sounds of their native language. Invasive procedures in animals and scalp-recorded potentials from human adults suggest that simultaneous, rhythmic activity (oscillations) between and within brain regions are fundamental to sensory development; determining the resolution with which incoming stimuli are parsed. At this time, little is known about oscillatory dynamics in human infant development. However, animal neurophysiology and adult EEG data provide the basis for a strong hypothesis that rapid auditory processing in infants is mediated by oscillatory synchrony in discrete frequency bands. In order to investigate this, 128-channel, high-density EEG responses of 4-month old infants to frequency change in tone pairs, presented in two rate conditions (Rapid: 70 msec ISI and Control: 300 msec ISI) were examined. To determine the frequency band and magnitude of activity, auditory evoked response averages were first co-registered with age-appropriate brain templates. Next, the principal components of the response were identified and localized using a two-dipole model of brain activity. Single-trial analysis of oscillatory power showed a robust index of frequency change processing in bursts of Theta band (3 - 8 Hz) activity in both right and left auditory cortices, with left activation more prominent in the Rapid condition. These methods have produced data that are not only some of the first reported evoked oscillations analyses in infants, but are also, importantly, the product of a well-established method of recording and analyzing clean, meticulously collected, infant EEG and ERPs. In this article, we describe our method for infant EEG net application, recording, dynamic brain response analysis, and representative results.

High-density electroencephalography (dEEG) is being used increasingly to study brain development and plasticity in the early years of life. Here we present an application of sophisticated analysis techniques that builds on traditional EEG recording to understand the oscillatory dynamics of rapid auditory processing in the infant brain.

Rapid auditory processing and acoustic change detection abilities play a critical role in allowing human infants to efficiently process the fine spectral ...

Behavior

Assessing Teratogenic Changes in a Zebrafish Model of Fetal Alcohol Exposure

Fetal alcohol syndrome (FAS) is a severe manifestation of embryonic exposure to ethanol. It presents with characteristic defects to the face and organs, including mental retardation due to disordered and damaged brain development. Fetal alcohol spectrum disorder (FASD) is a term used to cover a continuum of birth defects that occur due to maternal alcohol consumption, and occurs in approximately 4% of children born in the United States. With 50% of child-bearing age women reporting consumption of alcohol, and half of all pregnancies being unplanned, unintentional exposure is a continuing issue2. In order to best understand the damage produced by ethanol, plus produce a model with which to test potential interventions, we developed a model of developmental ethanol exposure using the zebrafish embryo. Zebrafish are ideal for this kind of teratogen study3-8. Each pair lays hundreds of eggs, which can then be collected without harming the adult fish. The zebrafish embryo is transparent and can be readily imaged with any number of stains. Analysis of these embryos after exposure to ethanol at different doses and times of duration and application shows that the gross developmental defects produced by ethanol are consistent with the human birth defect. Described here are the basic techniques used to study and manipulate the zebrafish FAS model.

In order to understand the molecular mechanisms of the ethanol-induced developmental damage, we have developed a zebrafish model of ethanol exposure and are exploring the physical, cellular, and genetic alterations that occur after ethanol exposure1. We then seek to find potential interventions and rapidly test them in this animal model.

Fetal alcohol syndrome (FAS) is a severe manifestation of embryonic exposure to ethanol. It presents with characteristic defects to the face and organs, ...

Non-invasive Optical Measurement of Cerebral Metabolism and Hemodynamics in Infants

Perinatal brain injury remains a significant cause of infant mortality and morbidity, but there is not yet an effective bedside tool that can accurately screen for brain injury, monitor injury evolution, or assess response to therapy. The energy used by neurons is derived largely from tissue oxidative metabolism, and neural hyperactivity and cell death are reflected by corresponding changes in cerebral oxygen metabolism (CMRO2). Thus, measures of CMRO2 are reflective of neuronal viability and provide critical diagnostic information, making CMRO2 an ideal target for bedside measurement of brain health.
Brain-imaging techniques such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) yield measures of cerebral glucose and oxygen metabolism, but these techniques require the administration of radionucleotides, so they are used in only the most acute cases.
Continuous-wave near-infrared spectroscopy (CWNIRS) provides non-invasive and non-ionizing radiation measures of hemoglobin oxygen saturation (SO2) as a surrogate for cerebral oxygen consumption. However, SO2 is less than ideal as a surrogate for cerebral oxygen metabolism as it is influenced by both oxygen delivery and consumption. Furthermore, measurements of SO2 are not sensitive enough to detect brain injury hours after the insult 1,2, because oxygen consumption and delivery reach equilibrium after acute transients 3. We investigated the possibility of using more sophisticated NIRS optical methods to quantify cerebral oxygen metabolism at the bedside in healthy and brain-injured newborns. More specifically, we combined the frequency-domain NIRS (FDNIRS) measure of SO2 with the diffuse correlation spectroscopy (DCS) measure of blood flow index (CBFi) to yield an index of CMRO2 (CMRO2i) 4,5.
With the combined FDNIRS/DCS system we are able to quantify cerebral metabolism and hemodynamics. This represents an improvement over CWNIRS for detecting brain health, brain development, and response to therapy in neonates. Moreover, this method adheres to all neonatal intensive care unit (NICU) policies on infection control and institutional policies on laser safety. Future work will seek to integrate the two instruments to reduce acquisition time at the bedside and to implement real-time feedback on data quality to reduce the rate of data rejection.

We combined frequency-domain near-infrared spectroscopy measures of cerebral hemoglobin oxygenation with diffuse correlation spectroscopy measures of cerebral blood flow index to estimate an index of oxygen metabolism. We tested the utility of this measure as a bedside screening tool to evaluate the health and development of the newborn brain.

Perinatal brain injury remains a significant cause of infant mortality  and morbidity, but there is not yet an effective bedside tool that can  accurately ...

Preterm EEG: A Multimodal Neurophysiological Protocol

Since its introduction in early 1950s, electroencephalography (EEG) has been widely used in the neonatal intensive care units (NICU) for assessment and monitoring of brain function in preterm and term babies. Most common indications are the diagnosis of epileptic seizures, assessment of brain maturity, and recovery from hypoxic-ischemic events. EEG recording techniques and the understanding of neonatal EEG signals have dramatically improved, but these advances have been slow to penetrate through the clinical traditions. The aim of this presentation is to bring theory and practice of advanced EEG recording available for neonatal units. 
In the theoretical part, we will present animations to illustrate how a preterm brain gives rise to spontaneous and evoked EEG activities, both of which are unique to this developmental phase, as well as crucial for a proper brain maturation. Recent animal work has shown that the structural brain development is clearly reflected in early EEG activity. Most important structures in this regard are the growing long range connections and the transient cortical structure, subplate. Sensory stimuli in a preterm baby will generate responses that are seen at a single trial level, and they have underpinnings in the subplate-cortex interaction. This brings neonatal EEG readily into a multimodal study, where EEG is not only recording cortical function, but it also tests subplate function via different sensory modalities. Finally, introduction of clinically suitable dense array EEG caps, as well as amplifiers capable of recording low frequencies, have disclosed multitude of brain activities that have as yet been overlooked.
In the practical part of this video, we show how a multimodal, dense array EEG study is performed in neonatal intensive care unit from a preterm baby in the incubator. The video demonstrates preparation of the baby and incubator, application of the EEG cap, and performance of the sensory stimulations.

This video explains the background theory of the neonatal EEG activity and the sensory responses, followed by a live demonstration of their recording in neonatal intensive care unit.

Since its introduction in early 1950s, electroencephalography (EEG) has been widely used in the neonatal intensive care units (NICU) for assessment and ...

Neuroscience

Carotid Artery Infusions for Pharmacokinetic and Pharmacodynamic Analysis of Taxanes in Mice

When proposing the use of a drug, drug combination, or drug delivery into a novel system, one must assess the pharmacokinetics of the drug in the study model. As the use of mouse models are often a vital step in preclinical drug discovery and drug development1-8, it is necessary to design a system to introduce drugs into mice in a uniform, reproducible manner. Ideally, the system should permit the collection of blood samples at regular intervals over a set time course. The ability to measure drug concentrations by mass-spectrometry, has allowed investigators to follow the changes in plasma drug levels over time in individual mice1, 9, 10. In this study, paclitaxel was introduced into transgenic mice as a continuous arterial infusion over three hours, while blood samples were simultaneously taken by retro-orbital bleeds at set time points. Carotid artery infusions are a potential alternative to jugular vein infusions, when factors such as mammary tumors or other obstructions make jugular infusions impractical. Using this technique, paclitaxel concentrations in plasma and tissue achieved similar levels as compared to jugular infusion. In this tutorial, we will demonstrate how to successfully catheterize the carotid artery by preparing an optimized catheter for the individual mouse model, then show how to insert and secure the catheter into the mouse carotid artery, thread the end of the catheter out through the back of the mouse&#8217;s neck, and hook the mouse to a pump to deliver a controlled rate of drug influx. Multiple low volume retro-orbital bleeds allow for analysis of plasma drug concentrations over time.

This method was developed with the goal of delivering a steady drug solution via the carotid artery, to assess the pharmacokinetics of novel drugs in mouse models.

When proposing the use of a drug, drug combination, or drug delivery into a novel system, one must assess the pharmacokinetics of the drug in the study ...

Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo

Due to the high level of heterogeneity and mutations inherent in human cancers, single agent therapies, or combination regimens which target the same pathway, are likely to fail. Emphasis must be placed upon the inhibition of pathways that are responsible for intrinsic and/or adaptive resistance to therapy. An active field of investigation is the development and testing of DNA repair inhibitors that promote the action of, and prevent resistance to, commonly used chemotherapy and radiotherapy. We used a novel protocol to evaluate the effectiveness of BRCA2 inhibition as a means to sensitize tumor cells to the DNA damaging drug cisplatin. Tumor cell metabolism (acidification and respiration) was monitored in real-time for a period of 72 hr to delineate treatment effectiveness on a minute by minute basis. In combination, we performed an assessment of metastatic frequency using a chicken embryo chorioallantoic membrane (CAM) model of extravasation and invasion. This protocol addresses some of the weaknesses of commonly used in vitro and in vivo methods to evaluate novel cancer therapy regimens. It can be used in addition to common methods such as cell proliferation assays, cell death assays, and in vivo murine xenograft studies, to more closely discriminate amongst candidate targets and agents, and select only the most promising candidates for further development.

Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo

Here, real-time monitoring of tumor cell metabolism, combined with an in vivo chicken embryo chorio-allantoic membrane (CAM) model of metastasis, are used to evaluate novel anti-cancer targets/agents for their ability to sensitize tumor cells to DNA damaging chemotherapeutics.

Due to the high level of heterogeneity and mutations inherent in human cancers, single agent therapies, or combination regimens which target the same ...

Application of an Amplitude-integrated EEG Monitor (Cerebral Function Monitor) to Neonates

Amplitude-integrated EEG (aEEG) is an easily accessible technique to monitor the electrocortical activity in preterm and term infants in neonatal intensive care units (NICUs). This method was first used to monitor newborns after asphyxia, providing information about future neurological outcomes. The aEEG is also helpful to select newborns who benefit from cooling. The aEEG monitoring of preterm infants is becoming more widespread, as various studies have shown that neurodevelopmental outcome is related to early aEEG tracings. Here, we demonstrate the application of the aEEG monitoring system and present typical patterns that depend upon gestational age and pathophysiological conditions. Furthermore, we mention pitfalls in the interpretation of the aEEG, as this method requires accurate fixation and localization of the electrodes. Additionally, the raw EEG can be used to detect neonatal seizures or to identify aEEG application problems. In conclusion, aEEG is a safe and generally well-tolerated method for the bedside monitoring of neonatal cerebral function; it can even provide information about long-term outcome.

Application of an Amplitude-integrated EEG Monitor Cerebral Function Monitor to Neonates

Here, we show how to apply amplitude-integrated electroencephalography to monitor cerebral function in neonates.

Amplitude-integrated EEG (aEEG) is an easily accessible technique to monitor the electrocortical activity in preterm and term infants in neonatal ...

Real-Life EEG and ECG Synchronization in Infant-Caregiver Interactions

Home-Based EEG Hyperscanning for Infant-Caregiver Social Interactions

Prior hyperscanning studies that record the brain activities of caregivers and children concurrently have primarily been conducted within the confines of the laboratory, thus limiting the generalizability of results to real-life settings. Here, a comprehensive protocol for capturing synchronized electroencephalography (EEG), electrocardiography (ECG), and behavioral recordings from infant-caregiver dyads during various interactive tasks at home is proposed. This protocol demonstrates how to synchronize the different data streams and report EEG data retention rates and quality checks. Additionally, critical issues and possible solutions with respect to the experimental setup, tasks, and data collection in home settings are discussed. The protocol is not limited to infant-caregiver dyads but can be applied to various dyadic constellations. Overall, we demonstrate the flexibility of EEG hyperscanning setups, which allow experiments to be conducted outside of the laboratory to capture participants' brain activities in more ecologically valid environmental settings. Yet, movement and other types of artifacts still constrain the experimental tasks that can be performed in the home setting.

Author Spotlight: Capturing Infant-Caregiver Interactions Through Synchronized Multimodal Data Collection

This protocol describes how synchronized electroencephalography, electrocardiography, and behavioral recordings were captured from infant-caregiver dyads in a home setting.

Prior hyperscanning studies that record the brain activities of caregivers and children concurrently have primarily been conducted within the confines of ...

Amplitude-Integrated EEG in Infants at Risk of Hypoxic-Ischemic Encephalopathy: A Feasibility Study in Road and Air Transport in Western Australia

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