Name: investigating pain-related avoidance behavior using a robotic arm-reaching paradigm
Uploaded: 2020-10-03T14:00:00
Description: Watch this Scientific Journal Video about Investigating Pain-Related Avoidance Behavior using a Robotic Arm-Reaching Paradigm at JoVE.com

This research was supported by a Vidi grant from the Netherlands Organization for Scientific Research (NWO), The Netherlands (grant ID 452-17-002) and a Senior Research Fellowship of the Research Foundation Flanders (FWO-Vlaanderen), Belgium (grant ID: 12E3717N) granted to Ann Meulders. The contribution of Johan Vlaeyen was supported by the &#8220;Asthenes&#8221; long-term structural funding Methusalem grant by the Flemish Government, Belgium.
The authors wish to thank Jacco Ronner and Richard Benning from Maastricht University, for programming the experimental tasks, and designing and creating the graphics for the described experiments.

The protocols presented here meet the requirements of the Social and Societal Ethics committee of the KU Leuven (registration number: S-56505), and the Ethics Review Committee Psychology and Neuroscience of Maastricht University (registration numbers: 185_09_11_2017_S1 and 185_09_11_2017_S2_A1).
1. Preparing the laboratory for a test session
<ol>
	<li>Before the test session: Send the participant an e-mail informing him/her about the delivery of pain stimuli, of the general outline of the ex...

Given the key role of avoidance in chronic pain disability1,2,3,4,5, and the limitations faced by traditional avoidance paradigms19, there is a need for methods to investigate (pain-related) avoidance behavior. The robotic arm-reaching paradigm presented here addresses a number of these limitations. We have employed the paradigm in a se...

Avoidance is an adaptive response to pain signaling bodily threat. Yet, when pain becomes chronic, pain and pain-related avoidance lose their adaptive purpose. In line with this, the fear-avoidance model of chronic pain1,2,3,4,5,6,7,8 posits that erroneous interpretations of pain as catastrophic, trigger increases in fear of pain, which motivate avoidance behavior. Excessive avoidance can lead to the development and maintenance of chronic pain disability, due to physical disuse and decreased engagement in daily activities and aspirations1,2,3,4,5,9. Furthermore, given that the absence of pain can be misattributed to avoidance rather than recovery, a self-sustaining cycle of pain-related fear and avoidance can be established10.
Despite recent interest in avoidance in the anxiety literature11,12, research on avoidance in the pain domain is still in its infancy. Previous anxiety research, guided by the influential two-factor theory13, has generally assumed fear to drive avoidance. Correspondingly, traditional avoidance paradigms12 entail two experimental phases, each corresponding to one factor: the first to establish fear (Pavlovian conditioning14 phase), and the second to examine avoidance (Instrumental15 phase). During differential Pavlovian conditioning, a neutral stimulus (conditioned stimulus, CS+; e.g., a circle) is paired with an intrinsically aversive stimulus (unconditioned stimulus, US; e.g., an electric shock), which naturally produces unconditioned responses (URs, e.g., fear). A second control stimulus is never paired with the US (CS-; e.g., a triangle). Following pairings of the CSs with the US, the CS+ will elicit fear in itself (conditioned responses, CRs) in the absence of the US. The CS- comes to signal safety and will not trigger CRs. Afterwards, during instrumental conditioning, participants learn that their own actions (responses, R; e.g., button-press) lead to certain consequences (outcomes; O, e.g., the omission of shock)15,16. If the response prevents a negative outcome, the chance of that response recurring increases; this is referred to as negative reinforcement15. Thus, in the Pavlovian phase of traditional avoidance paradigms, participants first learn the CS-US association. Subsequently, in the instrumental phase, an experimenter-instructed avoidance response (R) is introduced, canceling the US if performed during CS presentation, establishing a R-O association. Thus, the CS becomes a discriminative stimulus (SD), indicating the appropriate moment for, and motivating the performance of, the conditioned R15. Apart from some experiments showing instrumental conditioning of pain reports17 and pain-related facial expressions18, investigations into the instrumental learning mechanisms of pain, in general, are limited.
Although the standard avoidance paradigm, described above, has elucidated many of the processes underlying avoidance, it also has several limitations5,19. First, it does not allow examining the learning, or acquisition, of avoidance itself, because the experimenter instructs the avoidance response. Having participants freely choose between multiple trajectories, and, therefore, learn which responses are painful/safe and which trajectories to avoid/not avoid, more accurately models real-life, where avoidance emerges as a natural response to pain9. Second, in traditional avoidance paradigms, the button-press avoidance response comes at no cost. However, in real life, avoidance can become extremely costly for the individual. Indeed, high-cost avoidance especially disrupts daily functioning5. For example, avoidance in chronic pain can severely limit people&#8217;s social and working lives9. Third, dichotomous responses such as pressing/not pressing a button also do not very well represent real life, where different degrees of avoidance occur. In the following sections, we describe how the robotic arm-reaching paradigm20 addresses these limitations, and how the basic paradigm can be extended to multiple novel research questions.
Acquisition of avoidance 
In the paradigm, participants use a robotic arm to perform arm-reaching movements from a starting point to a target. Movements are employed as the instrumental response because they closely resemble pain-specific, fear-evoking stimuli. A ball virtually represents participants&#8217; movements on-screen (Figure 1), allowing participants to follow their own movements in real-time. During each trial, participants freely choose between three movement trajectories, represented on-screen by three arches (T1&#8211;T3), differing from each other in terms of how effortful they are, and in the likelihood that they are paired with a painful electrocutaneous stimulus (i.e., pain stimulus). Effort is manipulated as deviation from the shortest possible trajectory and increased resistance from the robotic arm. Specifically, the robot is programmed such that resistance increases linearly with deviation, meaning that the more participants deviate, the more force they need to exert on the robot. Furthermore, pain administration is programmed such that the shortest, easiest trajectory (T1) is always paired with the pain stimulus (100% pain/no deviation or resistance). A middle trajectory (T2) is paired with a 50% chance of receiving the pain stimulus, but more effort is required (moderate deviation and resistance). The longest, most effortful trajectory (T3) is never paired with the pain stimulus but requires the most effort to reach the target (0% pain/largest deviation, strongest resistance). Avoidance behavior is operationalized as the maximum deviation from the shortest trajectory (T1) per trial, which is a more continuous measure of avoidance, than for example, pressing or not pressing a button. Furthermore, the avoidance response comes at the cost of increased effort. Moreover, given that participants freely choose between the movement trajectories, and are not explicitly informed about the experimental R-O (movement trajectory-pain) contingencies, avoidance behavior is instrumentally acquired. Online self-reported fear of movement-related pain and pain-expectancy have been collected as measures of conditioned fear toward the different movement trajectories. Pain-expectancy is also an index of contingency awareness and threat appraisal21. This combination of variables allows scrutinizing the interplay between fear, threat appraisals, and avoidance behavior. Using this paradigm, we have consistently demonstrated the experimental acquisition of avoidance20,22,23,24.
Generalization of avoidance 
We have extended the paradigm to investigate generalization of avoidance23&#8212;a possible mechanism leading to excessive avoidance. Pavlovian fear generalization refers to the spreading of fear to stimuli or situations (generalization stimuli, GSs) resembling the original CS+, with fear declining with decreasing similarity to the CS+ (generalization gradient)25,26,27,28. Fear generalization minimizes the need to learn relationships between stimuli anew, allowing swift detection of novel threats in ever-changing environments25,26,27,28. However, excessive generalization leads to fear of safe stimuli (GSs similar to CS-), thus causing unnecessary distress28,29. In line with this, studies using Pavlovian fear generalization consistently show that chronic pain patients excessively generalize pain-related fear30,31,32,33,34, whereas healthy controls show selective fear generalization. Yet, where excessive fear causes discomfort, excessive avoidance can culminate in functional disability, due to avoidance of safe movements and activities, and increased daily activity disengagement1,2,3,4,9. Despite its key role in chronic pain disability, research on the generalization of avoidance is scarce. In the paradigm adapted for studying generalization of avoidance, participants first acquire avoidance, following the procedure described above20. In a subsequent generalization phase, three novel movement trajectories are introduced in the absence of the pain stimulus. These generalization trajectories (G1&#8211;G3) lie on the same continuum as the acquisition trajectories, resembling each of these trajectories, respectively. Specifically, generalization trajectory G1 is situated between T1 and T2, G2 between T2 and T3, and G3 to the right of T3. In this way, generalization of avoidance to novel safe trajectories can be examined. In a previous study, we showed generalization of self-reports, but not avoidance, possibly suggesting different underlying processes for pain-related fear- and avoidance generalization23.
Extinction of avoidance with response prevention 
The primary method of treating high fear of movement in chronic musculoskeletal pain is exposure therapy35&#8212;the clinical counterpart to Pavlovian extinction36, i.e., the reduction of CRs through repeated experience with the CS+ in the absence of the US36. During exposure for chronic pain, patients perform feared activities or movements in order to disconfirm catastrophic beliefs and expectations of harm34,37. Since these beliefs do not necessarily concern pain per se, but rather underlying pathology, movements are not always carried out pain-free in the clinic34. According to inhibitory learning theory38,39, extinction learning does not erase the original fear memory (e.g., movement trajectory-pain); rather, it creates a novel inhibitory extinction memory (e.g., movement trajectory-no pain), which competes with the original fear memory for retrieval40,41. The novel inhibitory memory is more context-dependent than the original fear memory40, deeming the extinguished fear memory susceptible to re-emergence (return of fear)40,41,42. Patients are often prevented from performing even subtle avoidance behaviors during exposure treatment (extinction with response prevention, RPE), to establish genuine fear extinction by preventing the misattribution of safety to avoidance10,43.
Return of avoidance 
Relapse in terms of return of avoidance is still common in clinical populations, even after extinction of fear43,44,45,46. Although multiple mechanisms have been found to result in the return of fear47, little is known about those relating to avoidance22. In this manuscript, we specifically describe spontaneous recovery, i.e., return of fear and avoidance due to the passage of time40,47. The robotic arm-reaching paradigm has been implemented in a 2-day protocol to investigate return of avoidance. During day 1, participants first receive acquisition training in the paradigm, as described above20. In a subsequent RPE phase, participants are prevented from performing the avoidance response, i.e., they can only perform the pain-associated trajectory (T1) under extinction. During day 2, to test for spontaneous recovery, all trajectories are available again, but in the absence of pain stimuli. Using this paradigm, we showed that, one day after successful extinction, avoidance returned22.

<table>
	<tbody>
		<tr>
			<td>1 computer and computer screen</td>
			<td>Intel Corporation</td>
			<td>64-bit Intel Core</td>
			<td>Running the experimental script</td>
		</tr>
		<tr>
			<td>40 inch LCD screen</td>
			<td>Samsung Group</td>
			<td></td>
			<td>Presenting the experimental script</td>
		</tr>
		<tr>
			<td>Blender 2.79</td>
			<td>Blender Foundation</td>
			<td></td>
			<td>3D graphics software for programming the graphics of the experiment</td>
		</tr>
		<tr>
			<td>C#</td>
			<td></td>
			<td></td>
			<td>Programming language used to program the experimental task</td>
		</tr>
		<tr>
			<td>Conductive gel</td>
			<td>Reckitt Benckiser</td>
			<td>K-Y Gel</td>
			<td>Facilitates conduction from the skin to the stimulation electrodes</td>
		</tr>
		<tr>
			<td>Constant current stimulator</td>
			<td>Digitimer Ltd</td>
			<td>DS7A</td>
			<td>Generates electrical stimulation</td>
		</tr>
		<tr>
			<td>HapticMaster</td>
			<td>Motekforce Link</td>
			<td></td>
			<td>Robotic arm</td>
		</tr>
		<tr>
			<td>Matlab</td>
			<td>MathWorks</td>
			<td></td>
			<td>For writing scripts for participant randomization schedule, and for extracting maximum deviation from shortest trajectory per trial</td>
		</tr>
		<tr>
			<td>Qualtrics</td>
			<td>Qualtrics</td>
			<td></td>
			<td>Web survey tool for psychological questionnaires</td>
		</tr>
		<tr>
			<td>Rstudio</td>
			<td>Rstudio Inc.</td>
			<td></td>
			<td>Statistical analyses</td>
		</tr>
		<tr>
			<td>Sekusept Plus</td>
			<td>Ecolab</td>
			<td></td>
			<td>Disinfectant solution for cleaning medical instruments</td>
		</tr>
		<tr>
			<td>Stimulation electrodes</td>
			<td>Digitimer Ltd</td>
			<td>Bar stimulating electrode</td>
			<td>Two reusable stainless steel disk electrodes; 8mm diameter with 30mm spacing</td>
		</tr>
		<tr>
			<td>Tablet</td>
			<td>AsusTek Computer Inc.</td>
			<td>ASUS ZenPad 8.0</td>
			<td>For providing responses to psychological trait questinnaires</td>
		</tr>
		<tr>
			<td>Triple foot switch</td>
			<td>Scythe</td>
			<td>USB-3FS-2</td>
			<td>For providing self-report measures on VAS scale</td>
		</tr>
		<tr>
			<td>Unity 2017</td>
			<td>Unity Technologies</td>
			<td></td>
			<td>Cross-platform game engine for writing the experimental script including presentations of electrocutaneous stimuli</td>
		</tr>
	</tbody>
</table>

investigating pain-related avoidance behavior using a robotic arm-reaching paradigm

Avoidance behavior is a key contributor to the transition from acute pain to chronic pain disability. Yet, there has been a lack of ecologically valid paradigms to experimentally investigate pain-related avoidance. To fill this gap, we developed a paradigm (the robotic arm-reaching paradigm) to investigate the mechanisms underlying the development of pain-related avoidance behavior. Existing avoidance paradigms (mostly in the context of anxiety research) have often operationalized avoidance as an experimenter-instructed, low-cost response, superimposed on stimuli associated with threat during a Pavlovian fear conditioning procedure. In contrast, the current method offers increased ecological validity in terms of instrumental learning (acquisition) of avoidance, and by adding a cost to the avoidance response. In the paradigm, participants perform arm-reaching movements from a starting point to a target using a robotic arm, and freely choose between three different movement trajectories to do so. The movement trajectories differ in probability of being paired with a painful electrocutaneous stimulus, and in required effort in terms of deviation and resistance. Specifically, the painful stimulus can be (partly) avoided at the cost of performing movements requiring increased effort. Avoidance behavior is operationalized as the maximal deviation from the shortest trajectory on each trial. In addition to explaining how the new paradigm can help understand the acquisition of avoidance, we describe adaptations of the robotic arm-reaching paradigm for (1) examining the spread of avoidance to other stimuli (generalization), (2) modeling clinical treatment in the lab (extinction of avoidance using response prevention), as well as (3) modeling relapse, and return of avoidance following extinction (spontaneous recovery). Given the increased ecological validity, and numerous possibilities for extensions and/or adaptations, the robotic arm-reaching paradigm offers a promising tool to facilitate the investigation of avoidance behavior and to further our understanding of its underlying processes.

Acquisition of avoidance behavior is demonstrated by participants avoiding more (showing larger maximal deviations from the shortest trajectory) at the end of an acquisition phase, compared to the beginning of the acquisition phase (Figure 2, indicated by A)20, or as compared to a Yoked control group (Figure 3)23,48.
Acquisition of fear and pain-expecta...

Watch this Scientific Journal Video about Investigating Pain-Related Avoidance Behavior using a Robotic Arm-Reaching Paradigm at JoVE.com

Investigating Pain-Related Avoidance Behavior using a Robotic Arm-Reaching Paradigm

Avoidance is central to chronic pain disability, yet adequate paradigms for examining pain-related avoidance are lacking. Therefore, we developed a paradigm that allows investigating how pain-related avoidance behavior is learned (acquisition), spreads to other stimuli (generalization), can be mitigated (extinction), and how it may subsequently re-emerge (spontaneous recovery).

Avoidance behavior is a key contributor to the transition from acute pain to chronic pain disability. Yet, there has been a lack of ecologically valid ...

Pain-related avoidance behavior majorly contributes to chronic pain disability. It's existing paradigms often like ecological and construct validity by employing an instructed and low or no cost avoidance response. Our paradigm tackles these limitations by allowing investigation of the ways in which avoidance is naturally learned and reinforced and by incorporating a cost study avoidance response.Our paradigm can be uniquely used to explain the processes underlying the learning of pain-related to avoidance behavior, how does behavior becomes disabling in chronic pain, and how it can be mitigated. Place a computer in one room or section for the researcher and place a large television in a separate room or section for the participant. To prepare for a test session, have everyone disinfect their hands upon arrival to the lab.Have the participant sit in a chair with armrest approximately 2.5 meters from the television screen at a comfortable distance of approximately 15 centimeters from the sensor of the robotic arm. After obtaining written informed consent from participant, fill the center of each electrode with conductive electrolyte gel. And use a strap to attach the stimulation electrodes over the triceps tendon of the participant right arm.After explaining the calibration procedure, ask the participant to rate each stimulus on a numerical scale from zero to 10, with zero representing I feel nothing, and 10 representing the worst pain imaginable. Turn on the stimulator. You set the intensity to one milliamp to start, and announce that a pain stimulus is about to be delivered.When the participant acknowledges the announcement, press the orange trigger button on the constant current stimulator to deliver the stimulus. After obtaining the participant's pain rating, apply the stimulus at the next level of intensity as demonstrated gradually increasing the intensity of the pain stimulus in a stepwise manner in one, two, three, and 4 milliamp increments. When the participant reaches a pain intensity that they would describe as significantly painful and demanding some effort to tolerate, terminate the calibration procedure, and document the final pain intensity in milliamps and the pain intensity rating of the participant.Before starting the robotic arm reaching pain-related avoidance task, provide the participant with on-screen standardized written instructions of the task. Program the task such that three arches are presented situated midway through the movement plane, ensure that the shortest arm movement T1 is paired with no deviation or resistance. The middle arm movement T2, is paired with moderate deviation and resistance and the furthest arms movement T3 is paired with the largest deviation and strongest resistance.Instruct the participant to use the dominant hand to operate the robotic arm by moving it's sensor, which is represented by a green ball on the television screen. And to move the sensor from a starting point at the lower left corner of the movement plane, to a target at the upper left corner of the movement plane. Inform the participant that they can freely choose which of the available movement trajectories to perform on each trial.And instruct the participant to provide self-report measures of pain expectancy and fear of movement related pain, on a continuous rating scale by scrolling to the left and right on the scale using two respective foot pedals on a triple foot switch. At the end of the practice phase, after answering any questions leave the room and dim the lights. Observe the participant from the researcher section or room.To execute the acquisition protocol, have the participants press the confirm foot pedal to initiate the experiment. During the avoidance acquisition phase, if the participant performs the shortest movement trajectory T1, program the constant current stimulator to always deliver the pain stimulus, once two thirds of the movement has been completed. If the participant selects the middle movement trajectory T2, present the pain stimulus 50%of the time while ensuring that the participant will have to exert more effort.If the participant performs the furthest most effortful movement trajectory T3, do not present the pain stimulus but ensure that the participant will have to exert the most effort to reach the target. A successfully completed trial will be indicated by the presentation of visual and auditory stop signals. The robotic arm should be programmed to automatically return to its starting position at the end of a trial.After 3000 milliseconds, present the visual and auditory start signals, which indicate that the participant can start the next trial. When testing for generalization of avoidance the onscreen trajectory arches are separated during the acquisition phase to leave room for the generalization trajectory arches. To test for the generalization of avoidance after the acquisition phase, present the three novel generalization movement trajectories G1, G2 and G3 adjacent to the acquisition trajectories.To investigate the extinction of avoidance with response prevention, after the acquisition phase inform the participant that in the upcoming phase, they can only perform T1.During the response prevention phase, visually and optically block T2 and T3 so that only T1 is available. Thus, it is ensured that during the extinction with response prevention phase, the participant only performs the shortest movement trajectory T1.Approximately 24 hours later, attach the stimulation electrodes and provide brief on-screen refresher instructions of the task without including any information regarding the pain stimulus. Then present the three acquisition trajectories in the absence of the pain stimulus.Upon completion of the experiment, detach the stimulation electrodes and thoroughly clean the stimulation electrodes with a disinfectant solution. Then dry the electrodes with soft tissue paper and clean the sensor of the robotic arm with disinfectant wipes or spray. Acquisition of avoidance behavior is demonstrated by participants avoiding pain more at the end of an acquisition phase compared to the beginning of the acquisition phase, or as compared to control group.The acquisition of fear and pain expectancy is evidenced by participants reporting lower fear for and expecting the pain stimulus less during T3 compared to T1 and T2.Generalization of fear and pain expectancy is indicated by participants in the experimental group reporting lower fear two and expecting the pain stimulus less during G3 compared to G1 and G2.The extinction of fear and pain expectancies is evident when participants report lower fear and expect the pain stimulus less during T1 at the end of the response prevention phase compared to the end of the acquisition phase. The spontaneous recovery of avoidance behavior is indicated by participants avoiding more at the beginning of the test of spontaneous recovery compared to the end of the response prevention phase. The spontaneous recovery of fear and pain expectancy is indicated by participants reporting higher fear and pain expectancy for T1, during the beginning of the test of spontaneous recovery compared to the end of the response prevention phase.Moving away from a verse of stimuli is not a pain specific defensive response. This method could also be applied to investigate avoidance of disgust or embarrassment which are relevant for anxiety disorders. Our paradigm enables testing potential differences in avoidance learning, in chronic pain compared to healthy populations.A deeper understanding of the underlying mechanisms of avoidance may optimize or offer new treatment options.

Research

JoVE Journal

Behavior

The Resident-intruder Paradigm: A Standardized Test for Aggression, Violence and Social Stress

This video publication explains in detail the experimental protocol of the resident-intruder paradigm in rats. This test is a standardized method to ...

Examining Recall Memory in Infancy and Early Childhood Using the Elicited Imitation Paradigm

The ability to recall the past allows us to report on details of previous experiences, from the everyday to the significant. Because recall memory is ...

Investigating Motor Skill Learning Processes with a Robotic Manipulandum

Skilled reaching tasks are commonly used in studies of motor skill learning and motor function under healthy and pathological conditions, but can be ...

Psychophysically-anchored, Robust Thresholding in Studying Pain-related Lateralization of Oscillatory Prestimulus Activity

In perceptual studies, it is often important to objectively assess the equality of delivered stimulation across participants or to quantify the ...

Reinstatement of Drug-seeking in Mice Using the Conditioned Place Preference Paradigm

The present protocol describes the Conditioned Place Preference (CPP) as a model of relapse in drug addiction. In this model, animals are first trained to ...

The HoneyComb Paradigm for Research on Collective Human Behavior

Collective human behavior such as group movement frequently shows surprising patterns and regularities, such as the emergence of leadership. Recent ...

Assessment of Stress Effects on Cognitive Flexibility using an Operant Strategy Shifting Paradigm

Stress affects cognitive function. Whether stress enhances or impairs cognitive function depends on several factors, including the 1) type, intensity, and ...

A Novel Pavlovian Fear Conditioning Paradigm to Study Freezing and Flight Behavior

Fear- and anxiety-related behaviors significantly contribute to an organism&#8217;s survival. However, exaggerated defensive responses to perceived threat ...

Using a Murine Model of Psychosocial Stress in Pregnancy as a Translationally Relevant Paradigm for Psychiatric Disorders in Mothers and Infants

The peripartum period is considered a sensitive period where adverse maternal exposures can result in long-term negative consequences for both mother and ...