This work was supported by departmental grants from the Multidisciplinary Pain Center (PCT), Anesthesiology and Critical Care Medicine departments of the Antwerp University Hospital (UZA), Belgium. In addition, an educational grant (Dehousse mandaat) was received from the University of Antwerp (UA). The authors want to thank Dr. Tom Schepens for his expert help during revision of this article.

This single-center cohort study was performed in accordance with the ethical standards of ICH-GCP and the Declaration of Helsinki after it was approved by the institutional review board and ethics committee of the Antwerp University Hospital, Belgium (study identifier: 16/33/334). The study was registered at Clinicaltrials.gov (NCT02916004) before its initiation.
All included patients were sedated in accordance with the standard hospital sedation protocol before study enrollment. The patients were titrated to a Richmond Agitation-Sedation Scale (RASS) set by the ICU physician. Patients were sedated to a RASS - 4 prior to study inclusion. All patients were routinely titrated to a Behavior Pain Scale (BPS) of 3 by the ICU analgosedation protocol.
Note: Determining therapeutic measures solely on the basis of the excitability of the recorded pain reflexes is not recommended. When interpreting the measurements, possible effects on the efferent branch of the reflex arc must be considered. Patients who are sedated or anesthetized have a higher pain reflex threshold than non-sedated patients. For reflex assessment, higher currents may be required. Monitoring of physiological parameters (heart rate, blood pressure, breathing rate) is recommended.
1. Safety Precautions
<ol>
	<li>Verify potential confounders for noise control (other devices, alternating mattress).</li>
	<li>Verify if the ambient temperature is in the normal range.</li>
</ol>
2. Positioning of the Subject
<ol>
	<li>Position the patient in the bed to maintain angles of 120&#176; of flexion of the hip and 130 - 160&#176; at the knee.</li>
	<li>Place the palmar side of the wrist upwards.</li>
	<li>Ensure that the non-measured eye is closed during reflex recording.</li>
</ol>
3. Preparation of the Skin for Electrode Application
Note: This will reduce electrode impedance.
<ol>
	<li>Clip or shave hair at the application sites.</li>
	<li>Check the application sites, they must be clean and dry. If necessary, remove any body lotion by cleaning the skin with soap and water and rub the skin gently with a dry wash cloth or gauze.</li>
	<li>Abrade the application sites with available abrasive material. Use the skin preparation paper over a large area rather than only a single swipe.</li>
	<li>Apply each electrode immediately after skin preparation.</li>
</ol>
4. Placement of the Electrodes for Pupil Dilation Reflex (PDR) Assessment
Note: Please see the Figures for an overview of electrodes application. Magnetic and electrical fields may appear as background noise or other artefacts in the measurement trace. Maximal acceptable noise level using the followings protocol is set from values higher than 10 &#181;V. High noise level is defined when the maximum amplitude in the area before the stimulation (&#8216;noise area&#8217;, i.e., -130 ms up to -10 ms before stimulation) exceeds this adjustable threshold (&#8216;maximum acceptable noise level&#8217;). Noise values are not used to calculate the threshold and the stimulation is repeated with the current intensity until an EMG signal with no noise is determined. To limit the occurrence of artefacts, verify the device has been updated to the latest version. Artefacts can be reduced by optimal electrode placement and skin preparation.
<ol>
	<li>Use Ag-AgCl electrodes with highly conductive wet gel to ensure an optimal signal during reflex recording.</li>
	<li>Maintain an inter-electrode distance of 30 mm (center-to-center).</li>
	<li>Place two stimulation electrodes for PDR recording, at the wrist on the skin area innervated by the median nerve, keeping the palmar side of the wrist facing upwards.</li>
</ol>
5. Placement of the Electrodes for Nociceptive Flexion Reflex (NFR) Assessment
Note: Please see the Figures for an overview of electrodes application.
<ol>
	<li>Use two stimulation electrodes at the ankle and place the electrodes distal to the lateral malleolus, stimulating the sural nerve area.</li>
	<li>Use two registration electrodes for EMG recording at the biceps femoris muscle. Place the electrodes four finger breadths above the popliteal fossa, posterior to the iliotibial band on the ipsilateral leg.</li>
	<li>Use one reference electrode, placed at the quadriceps tendon.</li>
</ol>
6. Safety Check
<ol>
	<li>Identify the materials: battery status (PDR tool), accessibility of a plug connection nearby (NFR evaluation monitor), lead wires, and connections to the labeled device sockets.</li>
	<li>Identify the patient: patient number, medical history, current medications, behavior pain scale, and sedation depth.</li>
</ol>
7. Pupillary Dilation Reflex Assessment: Getting Started
<ol>
	<li>Attach the lead wire to the stimulation electrodes at the wrist. Verify that the black-labeled part is attached to the most distal electrode.&#160;</li>
	<li>Turn the infrared camera on.</li>
	<li>Select the measurement protocol: &#8216;pupillary pain index&#8217; (PPI) through menu selection on the touch screen display.&#160;Perform an impedance control indicated by the colored symbols, if necessary repeat the preparation procedure.</li>
	<li>Clean the camera and eye cab with water and disinfect them.</li>
</ol>
8. Pupillary Dilation Reflex Assessment: Installation
<ol>
	<li>Open the eyelid and place the camera in an optimal position.
	<ol>
		<li>Let the rubber eyecup rest on the orbit, enclosing the whole eye.</li>
		<li>Verify whether pupil detection has been set correctly and adjust the camera if necessary. The operator may have to raise the eyelid more.</li>
		<li>Center the pupil in the middle of the screen and verify the position by pursuing a pupil completely colored green.</li>
	</ol>
	</li>
	<li>Close the contralateral eye, decreasing the consensual light response.</li>
	<li>Wait for a least 5 seconds to start the measurement, ensuring a stabilization period necessary for pupil accommodation (dark measurement environment).</li>
</ol>
9. Pupillary Dilation Reflex Assessment: Measurement
<ol>
	<li>Start the test by pushing the trigger button. Hold the button until the pupil assessment is complete (a few seconds). Ensure that the entire measurement cycle is executed by 2 audible signals (first at the start, second when the test is finished)
	<ol>
		<li>Do not move the camera during measurement; a countdown is shown on the screen when stimulation intensity is increasing automatically from 10 mA up to maximum 60 mA.</li>
	</ol>
	</li>
	<li>Identify the results automatically displayed after 15 seconds on the screen 
	Baseline pupil size (mm) before noxious stimulation (yellow horizontal line). 
	Maximal pupil size (mm) after noxious stimulation (white horizontal line). 
	Different levels of noxious stimulations by colored bands and values. 
	Maximal pupil variation (% and mm). 
	PPI score</li>
	<li>Save the measurement results by pressing the icon after pupil assessment.</li>
</ol>
10. Nociception Flexion Reflex Assessment: Getting Started
<ol>
	<li>Attach the lead wires for stimulation, recording and reference. Verify whether the black-labeled parts are attached to the most distal electrodes; white is for reference value recording at the knee.</li>
	<li>Turn the device on when connected to a power supply. Identify the USB flash drive if data storage is desired.</li>
</ol>
11. Nociceptive Flexion Reflex Assessment: Installation
<ol>
	<li>Press the settings button to go to the configuration menu to verify the stimulation settings and the threshold determination procedure for reflex measurement in unconscious sedated patients.
	<ol>
		<li>Verify Measurement technique is on threshold tracking.</li>
		<li>Verify the Stimulus type is determined as RIII reflex.</li>
		<li>Select off when asked for NRS input.</li>
		<li>Choose Peak Z Score as Evaluation criterion.</li>
		<li>Use &#62;100 number of stimuli.</li>
		<li>Initiate stimulation at 1 mA intensity, with minimum and maximum step size of 0.5 mA.</li>
		<li>Verify the Interstimulus interval is defined as 8 s with a reflex range of 90 &#8211; 180 ms.</li>
	</ol>
	</li>
</ol>
12. Nociceptive Flexion Reflex Assessment: Measurement
<ol>
	<li>Start the measurement, i.e., automatic reflex threshold tracking.</li>
	<li>Reduce impedances when &#8216;High noise level&#8217; appears by repeating the skin preparation protocol.</li>
	<li>Identify reflex features.
	<ol>
		<li>Identify the currents applied to the patient and number of stimulations.</li>
		<li>Identify the raw EMG displayed 200 ms before to 300 ms after stimulation via the EMG electrode on the thigh.</li>
		<li>Identify the reflex range and the reflex threshold value. The parameter is shown numerically (value in mA).</li>
	</ol>
	</li>
</ol>

The authors have nothing to disclose.

This paper describes the application of two nociceptive reflex devices for objective (patient-independent) pain assessment in adult ICU patients. Moreover, the evaluation of the PDR and the NFR characteristics are described.
Pain and delirium are common in hospitalized patients, often in combination, and may adversely affect outcome parameters. In the ICU, opioids are frequently administered, sometimes in combination with other sedative agents, to protect patients against stressful stimuli suc...

Many critically ill patients in the Intensive Care Unit (ICU) are prone to experience pain during daily care or during diagnostic or therapeutic procedures. Substandard nociceptive evaluation and consequent suboptimal pain management may increase stress and anxiety1. Persistent pain not only increases circulating catecholamines, compromises tissue perfusion and reduces oxygen delivery2 but also activates catabolic hypermetabolism, thus contributing to hyperglycemia, lipolysis and muscle loss. All of these elements impair the healing process and increase the risk of infections3,4,5,6.
As stated by the International Association for the Study of Pain (IASP), clinicians must use pain assessment tools that are valid for all patients, and self-reports remain the golden standard for pain evaluation. However, there are many situations in which patients are unable to communicate, especially because of critical illness or when they are mechanically ventilated (MV). The increased interest in ICU patient-related outcome measures has amplified the need for structured and reliable techniques for nociceptive assessment when a patient is unable to report pain and discomfort. Attempts to address this need have been hampered by the lack of specific, reproducible and feasible monitoring tools. In recent years, considerable effort has been directed toward providing physicians with more objective nociceptive parameters. However, many studies executed in the ICU have focused on the use of vital signs as possible surrogates for pain assessment and underlie not to use blood pressure or heart rate as a specific parameter for pain7,8.
As reported in previous research, untreated pain significantly compromises patient outcomes and should therefore always be assessed independently of vital signs, and assessments should not be influenced by a patient&#39;s inability to communicate7,8,9,10,11,12. This approach of objective nociceptive assessment has gained considerable support due to the known negative consequences of pain. Especially in ICU patients, physiological and psychological effects can be substantial and long-lasting and may significantly decrease health-related quality of life13,14.
Currently, no objective pain monitoring protocol exists that can readily be applied to a large group of critically ill patients. The implementation of objective assessment tools in ICU patients could optimize pain management and thus prevent the development of central sensitization syndromes. Moreover, opioid-induced hyperalgesia (OIH), chronification of pain, and long-lasting pain-related morbidity may decrease. Finally, the application of nociceptive reflex evaluation tools may provide a unique translational platform on which new pharmacological analgesic compounds can be tested.
The aim of the proposed methodology is to provide an overview of the technical requirements and provide a precise description of the protocols used to assess nociceptive reflexes in non-communicative ICU patients. Overall, we aim to provide a comprehensive guide for the use of objective pain measurement tools in the ICU and in other circumstances in which sedated or unconscious patients need to be assessed.
Critically ill unconscious adults admitted to the ICU were screened for study inclusion from October 2016 until December 2017. All were mechanically ventilated and received a strict analgosedation protocol containing propofol/remifentanil or propofol/sufentanil, which are the two most commonly used schemes in our hospital. A history of ophthalmologic surgery, known pupil reflex disorders, Horner or Adie&#39;s syndrome, previous eye trauma, cranial nerve lesions or acute intracranial hypertension caused by traumatic brain injury, tumor compression or bleeding, fulminant stroke, known (poly)neuropathy related to diabetes or other neurological conditions known to influence reflex activity, intra- or extracorporeal treatment (pacemaker, intra-aortic balloon pump, extracorporeal life support), chronic opioid use (&#62;3 months), age &#60;18 years, and the use of topical interfering eye drops (atropine, phenylephrine), &#945;2 adrenergic agonists15, the use of other analgosedation protocols than described by the inclusion criteria or neuromuscular blocking agents were defined as exclusion criteria.
The demographic variables and medical data of the enrolled subjects, including the Simplified Acute Physiology Score II (SAPS II),16 were extracted from the digital patient data management system (e.g., Metavision).
Pain Assessment
ICU patients were screened for study inclusion, which required a medical history and admission diagnosis to assess the inclusion and exclusion criteria mentioned above. Physiological reflexes were assessed in the ICU environment under real-life conditions: no specific modifications were made regarding temperature or noise control. Reflex assessment was executed during daytime working hours at the individual patient room of approximately 20 &#176;C. All generated data (reflex characteristics) can be stored by each of the two devices when this function is enabled on the touch screen display.
Measurement of the Pupil Dilation Reflex
A pupillometry device was used for pupil dilation reflex (PDR) assessment using infrared video recording for quantitative pupil size evaluation. For the application of standardized nociceptive stimulation, two low-impedance Ag-AgCl electrodes were placed on the skin area innervated by the median nerve on the left arm after skin preparation (Figure 1). The current was fixed at 60 milliamp&#232;res (mA) with a maximum acceptable resistance of 5 kOhms, defining a voltage limitation of 300 volts (V).
PDR assessment was performed using an inbuilt pupillary pain index (PPI) measurement protocol that generates an automatic electric stimulation pattern for dynamic pupil reflex evaluation. Standardized noxious stimulation was applied with increasing intensity (from 10 mA to 60 mA with incremental steps of 10 mA, a duration of 1 s, and a pulse width of 200 &#181;s) until pupillary dilation greater than 13% ([maximal diameter - minimal diameter]/maximal diameter * 100) or maximal stimulation at 60 mA was achieved. When the defined criteria were reached, stimulation was automatically interrupted, and a PPI score was displayed (Table 1). Baseline pupil size (before standardized noxious stimulation), pupil reflex amplitude (PRA), stimulation intensity and the PPI score were recorded. The duration of PDR measurement was between 2 and 16 seconds depending on the number of required stimulations.
Several studies have suggested the use of pupillometry in non-communicative ICU adults. Paulus et al. demonstrated that PDR evaluation may predict analgesia requirements during endotracheal aspiration17. Moreover, this method may be able to reveal different levels of analgesia and could have discriminatory properties regarding different types of noxious procedures18,19. Recently, scientific interest has been directed toward the use of specific protocols for PDR assessment because of their low stimulation currents. The PPI protocol suggested in our approach has been previously investigated in anesthetized adults, revealing a significant correlation between PDR and opioid administration20. Furthermore, Sabourdin et al.21 demonstrated that PDR can be used to guide individual intraoperative remifentanil administration and therefore reduce intraoperative opioid consumption and postoperative rescue analgesia requirements.
Measurement of the Nociceptive Flexion Reflex
To assess the role of primary afferent fibers in the transmission of nociceptive signals from peripheral nociceptors to the sympathetic chain, the nociceptive flexion reflex (NFR) was evaluated. Reflex elicitation is mediated after A-delta fibers are activated by a complex interaction between neurons located in the dorsal horn of the spinal cord22. Rhudy and colleagues described the RIII reflex, a late response of the NFR with high-threshold nociceptive characteristics measured electromyographically (EMG) over the biceps femoris muscle after nociceptor activation.23
Increasing electrical stimulations are performed via cutaneous Ag-AgCl electrodes at the lateral malleolus, triggering the solely sensory sural nerve. The reflex response is evaluated in time and amplitude through EMG recording (Figure 2; Reprinted with permission of PH Dr med. Jan Baars, Managing Director, Dolosys GmbH.).
Following Willer et al., using the described reflex registration setup, the required stimulation intensity to elicit the NFR (threshold tracking) can be used as an objective nociceptive assessment correlating with subjective pain scores24,25,26,27,28. Subsequently, numerous studies have been conducted to identify reflex characteristics (mainly reflex threshold and amplitude) and their correlation with pain intensity sensation in conscious adults. These studies revealed that the reflex threshold and response amplitude is closely related to pain intensity27,29,30.Furthermore, standardized NFR scoring criteria, such as the reflex peak and the mean reflex EMG activity, can be used as reliable criteria for defining this NFR23,31,32. According to recent research, the defined reflex characteristics contributing to the NFR, despite their empirically derived origin, showed good test-retest reliabilities33,34. The duration of NFR recording, taking into account the (variable) step size range (0.5 mA - 2 mA), interstimulus interval of 8 seconds with an interval randomization of 20% to avoid possible habituation and reflex range between 90 - 180 ms after stimulation35, was between 5 and 15 minutes depending on the necessary stimulation intensity to elicit the NFR and therefore the number of required stimulations (maximum of 100 mA).

<table><tbody><tr><td>Neurolight Algiscan</td><td>ID Med, Marseille, France&amp;nbsp;</td><td>Pupillometre 13235</td><td>Infra red camera for pupil dilation reflex measurement</td></tr><tr><td>Paintracker</td><td>Dolosys GmbH, Belin, Germany</td><td>Paintracker V1 2497</td><td>Nociception flexion reflex assessment tool</td></tr><tr><td>Red DotTrace Prep</td><td>3M, Ontario, Canada</td><td>CV-0001-7353-0</td><td>Skin surface preparation tape</td></tr><tr><td>Electrodes - BlueSensor N</td><td>Ambu, Ballerup, Denmark</td><td>BlueSensor N N-00-S/25&amp;nbsp;</td><td>Low-impedance Ag-AgCl skin electrodes</td></tr></tbody></table>

objective nociceptive assessment in ventilated icu patients: a feasibility study using pupillometry and the nociceptive flexion reflex

The concept of objective nociceptive assessment and optimal pain management have gained increasing attention. Despite the known negative short- and long-term consequences of unresolved pain or excessive analgosedation, adequate nociceptive monitoring remains challenging in non-communicative, critically ill adults. In the intensive care unit (ICU), routine nociceptive evaluation is carried out by the attending nurse using the Behavior Pain Scale (BPS) in mechanically ventilated patients. This assessment is limited by medication use (e.g., neuromuscular blocking agents) and the inherent subjective character of nociceptive evaluation by third parties.
Here, we describe the use of two nociceptive reflex testing devices as tools for objective pain evaluation: the pupillary dilation reflex (PDR) and nociception flexion reflex (NFR). These measurement tools are non-invasive and well tolerated, providing clinicians and researchers with objective information regarding two different nociceptive processing pathways: (1)&#160;the pain-related autonomic reactivity&#160;and (2) the ascending component of the somatosensory system. The use of PDR and NFR measurements are currently limited to specialized pain clinics and research institutions because of impressions that these are technically demanding or time-consuming procedures, or even because of a lack of knowledge regarding their existence.
By focusing on the two abovementioned nociceptive reflex assessments, this study evaluated their feasibility as a physiological pain measurement method in daily practice. Pursuing novel technologies for evaluating the analgesia level in unconscious patients may further improve individual pharmacological treatment and patient related outcome measures. Therefore, future research must include large well-designed clinical trials in a real-life environment.

We used both reflex assessments in a total of 40 critically ill ventilated subjects (38% females) at the ICU department using the previously described protocol. Patients with various indications for analgo-sedation were included: 58% for primary respiratory insufficiency, 23% due to multiple organ failure, 10% of the patients had a septic shock, and 9% were defined as being sedated for other reasons (e.g., cardiogenic reasons). All measurements were performed by the same investig...

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Objective Nociceptive Assessment in Ventilated ICU Patients: A Feasibility Study Using Pupillometry and the Nociceptive Flexion Reflex

Pain assessment in anesthetized patients who cannot communicate with the outside world in any way remains challenging despite the development of innovative objective pain evaluation tools. In this project, the pupillary dilation reflex and the nociception flexion reflex are assessed in critically ill, mechanically ventilated adult patients.

The concept of objective nociceptive assessment and optimal pain management have gained increasing attention. Despite the known negative short- and ...

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8.7K Views.  Antwerp University Hospital (UZA), University of Antwerp (UA). Pain assessment in anesthetized patients who cannot communicate with the outside world in any way remains challenging despite the development of innovative objective pain evaluation tools. In this project, the pupillary dilation reflex and the nociception flexion reflex are assessed in critically ill, mechanically ventilated adult patients.

Video: Objective Nociceptive Assessment in Ventilated ICU Patients: A Feasibility Study Using Pupillometry and the Nociceptive Flexion Reflex

Assessment and Evaluation of the High Risk Neonate: The NICU Network Neurobehavioral Scale

There has been a long-standing interest in the assessment of the neurobehavioral integrity of the newborn infant. The NICU Network Neurobehavioral Scale (NNNS) was developed as an assessment for the at-risk infant. These are infants who are at increased risk for poor developmental outcome because of insults during prenatal development, such as substance exposure or prematurity or factors such as poverty, poor nutrition or lack of prenatal care that can have adverse effects on the intrauterine environment and affect the developing fetus. The NNNS assesses the full range of infant neurobehavioral performance including neurological integrity, behavioral functioning, and signs of stress/abstinence. The NNNS is a noninvasive neonatal assessment tool with demonstrated validity as a predictor, not only of medical outcomes such as cerebral palsy diagnosis, neurological abnormalities, and diseases with risks to the brain, but also of developmental outcomes such as mental and motor functioning, behavior problems, school readiness, and IQ. The NNNS can identify infants at high risk for abnormal developmental outcome and is an important clinical tool that enables medical researchers and health practitioners to identify these infants and develop intervention programs to optimize the development of these infants as early as possible. The video shows the NNNS procedures, shows examples of normal and abnormal performance and the various clinical populations in which the exam can be used.

The NICU Network Neurobehavioral Scale (NNNS) was developed as an assessment for the at-risk infant. The purpose of this article is to describe the NNNS, provide video examples of the NNNS procedures and discuss the ways in which the exam has been used.

There has been a long-standing interest in the assessment of the neurobehavioral integrity of the newborn infant.  The NICU Network Neurobehavioral Scale ...

Behavior

Use of the Operant Orofacial Pain Assessment Device (OPAD) to Measure Changes in Nociceptive Behavior

We present an operant system for the detection of pain in awake, conscious rodents. The Orofacial Pain Assessment Device (OPAD) assesses pain behaviors in a more clinically relevant way by not relying on reflex-based measures of nociception. Food fasted, hairless (or shaved) rodents are placed into a Plexiglas chamber which has two Peltier-based thermodes that can be programmed to any temperature between 7 &deg;C and 60 &deg;C. The rodent is trained to make contact with these in order to access a reward bottle. During a session, a number of behavioral pain outcomes are automatically recorded and saved. These measures include the number of reward bottle activations (licks) and facial contact stimuli (face contacts), but custom measures like the lick/face ratio (total number of licks per session/total number of contacts) can also be created. The stimulus temperature can be set to a single temperature or multiple temperatures within a session. The OPAD is a high-throughput, easy to use operant assay which will lead to better translation of pain research in the future as it includes cortical input instead of relying on spinal reflex-based nociceptive assays.

Use of the Operant Orofacial Pain Assessment Device OPAD to Measure Changes in Nociceptive Behavior

We present a user-friendly, high-throughput operant system for the evaluation of pain behaviors in awake, conscious rodents. The Orofacial Pain Assessment Device (OPAD) can assess pain through a reward/conflict paradigm thus providing a more humane way of testing. This protocol will yield more clinically relevant and translational data from rodents.

We present an operant  system for the detection of pain in awake, conscious rodents. The Orofacial  Pain Assessment Device (OPAD) assesses pain behaviors ...

Methods to Quantify Pharmacologically Induced Alterations in Motor Function in Human Incomplete SCI

Spinal cord injury (SCI) is a debilitating disorder, which produces profound deficits in volitional motor control. Following medical stabilization, recovery from SCI typically involves long term rehabilitation. While recovery of walking ability is a primary goal in many patients early after injury, those with a motor incomplete SCI, indicating partial preservation of volitional control, may have the sufficient residual descending pathways necessary to attain this goal. However, despite physical interventions, motor impairments including weakness, and the manifestation of abnormal involuntary reflex activity, called spasticity or spasms, are thought to contribute to reduced walking recovery. Doctrinaire thought suggests that remediation of this abnormal motor reflexes associated with SCI will produce functional benefits to the patient. For example, physicians and therapists will provide specific pharmacological or physical interventions directed towards reducing spasticity or spasms, although there continues to be little empirical data suggesting that these strategies improve walking ability.
In the past few decades, accumulating data has suggested that specific neuromodulatory agents, including agents which mimic or facilitate the actions of the monoamines, including serotonin (5HT) and norepinephrine (NE), can initiate or augment walking behaviors in animal models of SCI. Interestingly, many of these agents, particularly 5HTergic agonists, can markedly increase spinal excitability, which in turn also increases reflex activity in these animals. Counterintuitive to traditional theories of recovery following human SCI, the empirical evidence from basic science experiments suggest that this reflex hyper excitability and generation of locomotor behaviors are driven in parallel by neuromodulatory inputs (5HT) and may be necessary for functional recovery following SCI. 
The application of this novel concept derived from basic scientific studies to promote recovery following human SCI would appear to be seamless, although the direct translation of the findings can be extremely challenging. Specifically, in the animal models, an implanted catheter facilitates delivery of very specific 5HT agonist compounds directly onto the spinal circuitry. The translation of this technique to humans is hindered by the lack of specific surgical techniques or available pharmacological agents directed towards 5HT receptor subtypes that are safe and effective for human clinical trials. However, oral administration of commonly available 5HTergic agents, such as selective serotonin reuptake inhibitors (SSRIs), may be a viable option to increase central 5HT concentrations in order to facilitate walking recovery in humans. Systematic quantification of how these SSRIs modulate human motor behaviors following SCI, with a specific focus on strength, reflexes, and the recovery of walking ability, are missing.
This video demonstration is a progressive attempt to systematically and quantitatively assess the modulation of reflex activity, volitional strength and ambulation following the acute oral administration of an SSRI in human SCI. Agents are applied on single days to assess the immediate effects on motor function in this patient population, with long-term studies involving repeated drug administration combined with intensive physical interventions.

This video demonstrates modulation of reflex activity, volitional strength and ambulation through clinical and quantitative assessments in individuals with motor incomplete SCI as a result of acute oral administration of a serotonin reuptake inhibitor (SSRI).

Spinal cord injury (SCI) is a debilitating disorder, which produces profound deficits in volitional motor control. Following medical stabilization, ...

Quantitative Assessment of Cortical Auditory-tactile Processing in Children with Disabilities

Objective and easy measurement of sensory processing is extremely difficult in nonverbal or vulnerable pediatric patients. We developed a new methodology to quantitatively assess children&#39;s cortical processing of light touch, speech sounds and the multisensory processing of the 2 stimuli, without requiring active subject participation or causing children discomfort. To accomplish this we developed a dual channel, time and strength calibrated air puff stimulator that allows both tactile stimulation and sham control. We combined this with the use of event-related potential methodology to allow for high temporal resolution of signals from the primary and secondary somatosensory cortices as well as higher order processing. This methodology also allowed us to measure a multisensory response to auditory-tactile stimulation.

Objective and easy measurement of sensory processing is extremely difficult in nonverbal or vulnerable pediatric patients. We developed a new methodology to quantitatively assess infants and children&#39;s cortical processing of light touch, speech sounds, and the multisensory processing of the 2 stimuli, without requiring active subject participation or causing discomfort in vulnerable patients.

Objective and easy measurement of sensory processing is extremely difficult in nonverbal or vulnerable pediatric patients. We developed a new methodology ...

Acute and Chronic Tactile Sensory Testing after Spinal Cord Injury in Rats

Spinal cord injury (SCI) impairs sensory systems causing allodynia1-8. To identify cellular and molecular causes of allodynia, sensitive and valid sensory testing in rat SCI models is needed. However, until recently, no single testing approach had been validated for SCI so that standardized methods have not been implemented across labs. Additionally, available testing methods could not be implemented acutely or when severe motor impairments existed, preventing studies of the development of SCI-induced allodynia3. Here we present two validated sensory testing methods using von Frey Hair (VFH) monofilaments which quantify changes in tactile sensory thresholds after SCI4-5. One test is the well-established Up-Down test which demonstrates high sensitivity and specificity across different SCI severities when tested chronically5. The other test is a newly-developed dorsal VFH test that can be applied acutely after SCI when allodynia develops, prior to motor recovery4-5. Each VFH monofilament applies a calibrated force when touched to the skin of the hind paw until it bends. In the up-down method, alternating VFHs of higher or lower forces are used on the plantar L5 dermatome to delineate flexor withdrawal thresholds. Successively higher forces are applied until withdrawal occurs then lower force VFHs are used until withdrawal ceases. The tactile threshold reflects the force required to elicit withdrawal in 50% of the stimuli. For the new test, each VFH is applied to the dorsal L5 dermatome of the paw while the rat is supported by the examiner. The VFH stimulation occurs in ascending order of force until at least 2 of 3 applications at a given force produces paw withdrawal. Tactile sensory threshold is the lowest force to elicit withdrawal 66% of the time. Acclimation, testing and scoring procedures are described. Aberrant trials that require a retest and typical trials are defined. Animal use was approved by Ohio State University Animal Care and Use Committee.

We describe two tactile sensory testing methods for acute or chronic periods of spinal cord injury in rats. These validated procedures can detect the development and maintenance of allodynia-like sensations.

Spinal cord injury (SCI) impairs sensory systems causing allodynia1-8. To identify cellular and molecular causes of allodynia, sensitive and valid sensory ...

Neurodevelopmental Reflex Testing in Neonatal Rat Pups

Neurodevelopmental reflex testing is commonly used in clinical practice to assess the maturation of the nervous system. Neurodevelopmental reflexes are also referred to as primitive reflexes. They are sensitive and consistent with later outcomes. Abnormal reflexes are described as an absence, persistence, reappearance, or latency of reflexes, which are predictive indices of infants that are at high risk for neurodevelopmental disorders. Animal models of neurodevelopmental disabilities, such as cerebral palsy, often display aberrant developmental reflexes, as would be observed in human infants. The techniques described assess a variety of neurodevelopmental reflexes in neonatal rats. Neurodevelopmental reflex testing offers the investigator a testing method that is not otherwise available in such young animals. The methodology presented here aims to assist investigators in examining developmental milestones in neonatal rats as a method of detecting early-onset brain injury and/or determining the effectiveness of therapeutic interventions. The methodology presented here aims to provide a general guideline for investigators.

Behavioral testing is the gold standard for determining outcomes following brain injury, and can identify the presence of developmental disabilities in infants and children. Neurodevelopmental reflexes are an early indicator of these abnormalities. A host of easily accomplished developmental reflex tests in the neonatal rodent were developed and described here.

Neurodevelopmental reflex testing is commonly used in clinical practice to assess the maturation of the nervous system. Neurodevelopmental reflexes are ...

Pupillary Response as Assessment of Effective Seizure Induction by Electroconvulsive Therapy

Electroconvulsive therapy (ECT) is reported to be effective for severe neuropsychiatric disorders. In ECT, electrical stimulation is applied to the brain, inducing seizure activity. Adequate seizure induction with ECT is associated with seizure duration, symmetrical high amplitude waveforms during slow-wave activity, postictal suppression, and activation of the sympathetic nervous system. Sympathetic nervous system activation is influenced by anesthetic agents or cardiovascular drugs during ECT. Pupillary responses can reflect sympathetic nervous activity or the degree of brain damage. Pupillary response measurement can be conducted in a simple, precise, and objective way using an automated infrared pupillometer, enabling the measurement of pupil diameter (mm) to two decimal places. The white light used for measuring light reflexes is not overly bright, and patients do not typically report discomfort. Pupillary light reflexes were measured before anesthesia induction and immediately after electrical stimulation using this equipment. Pupil diameter is typically enlarged after brain damage or sympathetic nervous activation. Adequate seizure induction using ECT could induce pupillary enlargement immediately after electrical stimulation. In the current method, the constriction ratio of pupil size was calculated automatically and compared with seizure quality. Pupillary responses immediately after electrical stimulation may provide a useful assessment of the efficacy of seizure induction with ECT.

Pupillary responses (light reflex) were measured for assessment of adequate seizure induction by electroconvulsive therapy using an automated infrared pupillometer immediately after electrical stimulation. Constriction ratio was calculated and compared with seizure quality.

Electroconvulsive therapy (ECT) is reported to be effective for severe neuropsychiatric disorders. In ECT, electrical stimulation is applied to the brain, ...

SECONDs Administration Guidelines: A Fast Tool to Assess Consciousness in Brain-injured Patients

Establishing an accurate diagnosis is crucial for patients with disorders of consciousness (DoC) following a severe brain injury. The Coma Recovery Scale-Revised (CRS-R) is the recommended behavioral scale for assessing the level of consciousness among these patients, but its long duration&#160;of administration is a major hurdle in clinical settings. The Simplified Evaluation of CONsciousness Disorders (SECONDs) is a shorter scale that was developed to tackle this issue. It consists of six mandatory items&#160;(observation, command-following, visual pursuit, visual fixation, oriented behaviors, and arousal)&#160;and two conditional items&#160;(communication and localization to pain). The score ranges between 0 and 8 and corresponds to a specific diagnosis (i.e., coma, unresponsive wakefulness syndrome, minimally conscious state minus/plus, or emergence from the minimally conscious state). A first validation study on patients with prolonged DoC showed high concurrent validity and intra- and inter-rater reliability. The SECONDs requires less training than the CRS-R and its administration lasts about 7 minutes (interquartile range: 5-9 minutes). An additional index score allows the more precise tracking of a patient&#39;s behavioral fluctuation or evolution over time. The SECONDs is therefore a fast and valid tool for assessing the level of consciousness in patients with severe brain injury. It can easily be used by healthcare staff and implemented in time-constrained clinical settings, such as intensive care units, to help&#160;decrease misdiagnosis rates and to optimize treatment decisions. These administration guidelines provide detailed instructions for administering the SECONDs in a standardized and reproducible manner, which is an essential requirement for achieving a reliable diagnosis.

These guidelines can be used for the administration of the Simplified Evaluation of CONsciousness Disorders (SECONDs), a short behavioral tool developed to diagnose brain-injured patients in time-constrained settings. This scale examines command-following, communication, visual pursuit, fixation, pain localization, oriented movements and arousal.

Establishing an accurate diagnosis is crucial for patients with disorders of consciousness (DoC) following a severe brain injury. The Coma Recovery ...

Assessment of Nerve Injury-Induced Mechanical Hypersensitivity in Rats Using an Orofacial Operant Pain Assay

Pain has sensory and affective components. Unlike traditional, reflex-based pain assays, operant pain assays can produce more clinically relevant results by addressing the cognitive and motivational aspects of pain in rodents. This paper presents a protocol for assessing mechanical hypersensitivity following chronic constriction injury of the infraorbital nerves (CCI-ION) in rats using an orofacial operant pain system. Before CCI-ION surgery, rats were trained in an orofacial pain assessment device (OPAD) to drink sweetened condensed milk while making facial contact with the metal spiked bars and lick-tube.
In this assay, rats can choose between receiving milk as a positive reinforcer or escaping an aversive mechanical stimulus that is produced by a vertical row of small pyramid-shaped spikes on each side of the reward access hole. Following 2 weeks of training in the OPAD and before the CCI-ION surgery, baseline mechanical sensitivity data were recorded for 5 days for each rat during a 10 min testing session. During a session, the operant system automatically records the number of reward bottle activations (licks) and facial contacts, contact duration, and latency to the first lick, among other measures.
Following baseline measurements, rats underwent either CCI-ION or sham surgery. In this protocol, mechanical hypersensitivity was quantified by measuring the number of licks, latency to the first lick, the number of contacts, and the ratio of licks to facial contacts (L/F). The data showed that CCI-ION resulted in a significant decrease in the number of licks and the L/F ratio and an increase in the latency to the first lick, indicating mechanical hypersensitivity. These data support the use of operant-based pain assays to assess mechanical pain sensitivity in preclinical pain research.

This protocol describes the assessment of mechanical hypersensitivity in a rat model of neuropathic orofacial pain using an operant-based orofacial pain assessment device.

Pain has sensory and affective components. Unlike traditional, reflex-based pain assays, operant pain assays can produce more clinically relevant results ...

Electrophysiological Measurement of Noxious-evoked Brain Activity in Neonates Using a Flat-tip Probe Coupled to Electroencephalography

Pain is an unpleasant sensory and emotional experience. In non-verbal patients, it is very difficult to measure pain, even with pain assessment tools. Those tools are subjective or determine secondary physiological indicators which also have certain limitations particularly when exploring the effectiveness of analgesia. As cortical processing is essential for pain perception, brain activity measures may provide a useful approach to assess pain in infants. Here we present a method to assess nociception with electrophysiological brain activity recordings optimized for the use in newborn infants. To produce highly standardized and reproducible noxious stimuli we applied mechanical stimulation with a flat-tip probe, e.g., PinPrick, which is not skin-breaking and does not cause behavioral distress. The noxious-evoked potential allows the objective measurement of nociception in non-verbal patients. This method can be used in newborn infants as early as 34 weeks of gestational age. Moreover, it could be applied in different situations such as measuring the efficacy of analgesic or anesthetic drugs.

Measuring pain in non-verbal patients is a challenge. In this study we combine EEG recording with stimulation using a flat-tip probe to detect noxious-evoked brain activity in an objective manner.

Pain is an unpleasant sensory and emotional experience. In non-verbal patients, it is very difficult to measure pain, even with pain assessment tools. ...