EVALUATION AND CHARACTERISATION OF THE THERMAL GRILL APPARATUS FOR SPINAL CORD INJURY PATIENTS

Transcription

1 EVALUATION AND CHARACTERISATION OF THE THERMAL GRILL APPARATUS FOR SPINAL CORD INJURY PATIENTS by Diane Kostka A thesis submitted in conformity with the requirements for the degree of Master of Health Science in Clinical Engineering Graduate Department of Institute of Biomaterials and Biomedical Engineering University of Toronto Copyright by Diane Kostka 2011

2 Evaluation and Characterisation of the Thermal Grill apparatus for Spinal Cord Injury patients. Diane Kostka Master of Health Science in Clinical Engineering Institute of Biomaterials and Biomedical Engineering University of Toronto 2011 Abstract Patients suffering from central neuropathic pain have thermal sensory deficits within the painful area. Prior research proposed that the loss of thermal sensation in regions of central neuropathic pain may reflect similar central nervous system interaction between warm and cold sensory inputs that underlie the Thermal Grill Illusion (TGI) in which burning pain is felt while reduced warm/cold sensations are reported. This work presents a portable and reliable device that was used to systematically evaluate the characteristics of the TGI in healthy individuals. The results suggest that the spatial distribution of the warm and cool stimuli significantly affected the quality of perceived TGI. Additionally, simultaneous tactile and thermal stimulation was shown to be significantly less painful than thermal stimulation alone. A high correlation was also seen in the subject s TG intensity scores and their cold pain threshold. These results are useful for future TGI studies for central neuropathic pain. ii

3 Acknowledgements I am deeply grateful to Dr. Milos Popovic for giving me the confidence to explore my research interests and the guidance to avoid getting lost in my exploration. Dr. Popovic was a fabulous advisor: cheery, perceptive, and mindful of the things that truly matter. I am very grateful to my co-supervisor Dr. Judith Hunter. With her enthusiasm, inspiration, and great efforts to explain things clearly and simply, she helped peak my interest in the study of pain. Dr. Jonathan Dostrovsky s guidance and attention to my work consistently led me along the correct path, and he threw enough research questions my way to allow me to consider my research from many angles. I would also like to thank Dr. Carnahan Heather for taking the time to sit on my advisory committee and for providing a fresh perspective on my research. I am indebted to my many student colleagues at REL for providing a stimulating and fun environment in which to learn and grow. I am especially grateful to Helen Zhang and Noel Wu for their research help, insightful advice and time. I am truly grateful to my parents for their endless help, understanding and support through the last two years. Finally, Gaurav Jain for his constant support, enthusiasm and feedback, and without whom this document would not have been possible. iii

4 Table of Contents Glossary... ix Chapter 1:Introduction Motivation Hypothesized cause of CNP Roadmap of the Thesis...3 Chapter 2: Background Central Neuropathic Pain Central Neuropathic Pain and Spinal Cord Injury Psychophysical Testing Thermal Grill Illusion Etiology TGI and Central Neuropathic Pain Research Problem Thermal Grill Devices Research Methodology...14 Chapter 3: Research Objective Objective Hypotheses...18 Chapter 4: Methodology Thermal Grill Apparatus Hardware Design Software Design...24 iv

5 4.2 Subjects Experimental Procedure Pre-Testing Participant Feedback Determination of Thermal Thresholds Uniform thermal stimulus Thermal grill stimulus Evaluation of optimal grill configurations Evaluation of dynamic thermal grill Order of Presentation...34 Chapter 5: Results Subjects Thermal Thresholds Spatial Characteristics Pain Elicited by the TG Static vs. Dynamic thermal testing Intensity ratings Grill Configurations and TG intensity rating Thermal Quality and Characteristics of the TGI Thermal Thresholds and the TGI Variance in Response...44 Chapter 6: Discussion TGI as a Painful Experience TG perception during Static vs. Dynamic Grill testing Spatial Characteristics of the TG Temporal Characteristics of the TG TGI and Thermal Thresholds...50 v

6 6.6 The Stability of the TGI Important methodological issues Using the TG as a Research Tool Limitations of this Study...53 Chapter 7: Conclusions...55 References...56 Appendices...62 A. Screenshots of the User Interface...62 B. Experiment Procedure Forms...63 C. Thermal Grill User Manual...64 D. Study Script...76 vi

7 List of Figures 2.1 Mechanism of the Thermal Grill Illusion Thermal Grill Stimulation Patterns Isometric 3-D view of the Thermal Grill device Mechanical Drawing of the thermal grill device Disturbance rejection ratio of device Body site tested using the TG device Spatial configurations of the Peltier elements Static and Dynamic testing procedure Thermal thresholds on the forearm Graphs of the continuous unpleasantness rating in response to the five thermal stimuli applied in (a) dynamic and (b) static mode Percentage of Burning descriptors used between uniform and TG configurations Box plots indicating VAS ratings between different configurations Progression of the perceived thermal quality of the TGS Scatter plot of CPT vs. maximum VAS score of the TGS...44 A.1 Screenshots of User Interface...62 B.1 Participant feedback form...63 vii

8 List of Tables 2.1 Comparative chart showing previous thermal grill devices used in research Accuracy of ramp rates Order of presentation of stimuli Descriptors chosen to describe the three thermal grill stimuli...41 viii

9 Glossary List of Abbreviations CDT CNP CNS CPT HPC HPT NRS PT SCI SD TG TGI TGS VAS WDT Cold Detection Threshold Central Neuropathic Pain Central Nervous System Cold Pain Threshold Heat Pinch Cold cells Heat Pain Threshold Numerical Rating Scale Pain Threshold Spinal Cord Injury Standard Deviation Thermal Grill Thermal Grill Illusion Thermal Grill Stimulus Visual Analog Scale Warm Detection Threshold ix

10 List of Parameters k thermal conductivity ( Watt/(mK) ) F p variance of the group means / mean of the within group variances probability of obtaining a test statistic at least as extreme as the one that was observed 2 discrepancy between the expected and observed number of times each outcome occurs x

11 Chapter 1 Introduction despite the severity of chronic pain, often you have almost nothing to show for it physically. And that makes treating pain really subjective. - Melanie Thernstrom The Pain Chronicles, August Motivation The capacity to experience pain has a protective role. By contrast persistent pain syndromes, as is often seen in spinal cord injury (SCI) patients offers no biological advantage and often produces drastic impairments in the daily routine and quality of life of these individuals [1]. This pain is frequently more debilitating than major motor impairments, such as the inability to stand, walk, sit and grasp. It often leads to depression, which in severe cases results in suicide [2]. The chronic pain syndromes develop within months following the SCI. As the pain occurs due to the injury to the central nervous system this type of pain is referred to as central neuropathic pain (CNP). On average, close to 30% of individuals with SCI develop CNP following the injury. Typical clinical manifestations of CNP are sensory loss and spontaneous pain such as burning, spontaneous and stimulus-evoked pain [3]. The functional impact of CNP following SCI is profound and is demonstrated by a study which reported that 37% of the individuals with SCI who suffer from CNP would trade pain relief for any chance of regaining motor function [4]. 1

12 Currently, there is no treatment to prevent the development of neuropathic pain, nor to adequately, predictably and specifically control established neuropathic pain. The aim of treatment, thus far, is often just to help the patient cope by means of psychological or occupational therapy, rather than eliminate the pain. Medications include opioids, anticonvulsants, and adjuvants targeted at the CNS. However, the success of these treatments is greatly limited by side effects, such as dizziness, sedation, coordination problems, and dose dependence. Furthermore, opioids commonly result in only a 20-30% reduction in pain intensity [5]. The development and validation of diagnostic clinical tools in the form of questionnaires has undoubtedly been one of the most active and productive aspects of clinical research on CNP in the last decade. However, these questionnaires fail to identify about 10 20% of patients with clinically diagnosed neuropathic pain [6]. More importantly, these tools provide little information about the causal lesion or disease and offer no framework for the clinical management of pain and the assessment of the effects of various treatment options [7, 8]. Etiology alone or the distribution and nature of the pain symptoms provide minimal information on the mechanisms responsible for CNP [9]. Animal studies have identified a number of nervous system abnormalities that produce symptoms similar to CNP in humans. Unfortunately, it is difficult to translate the findings from animal studies into simple tests that can be used in humans to identify the specific mechanism(s) that produce each individual's CNP [10]. Hence, progress in management of CNP is contingent on targeting underlying mechanism(s) of CNP in each individual, i.e., mechanism-based diagnosis and treatment. 2

13 1.2 Hypothesised cause of CNP Research into the mechanism of neuropathic pain showed a distinct loss of thermal sensibility in regions of neuropathic pain but failed to explain the reason behind this. Craig [11] using non-invasive methods of psychophysical analysis, proposed that the thermal sensation in regions of central neuropathic pain (CNP) may reflect similar central nervous system (CNS) interaction between warm and cold sensory inputs that underlie Thermal Grill Illusion (TGI). The TGI is a perception of burning pain in response to a thermal stimulus in which innocuous cool (20 C) and innocuous warm (40 C) stimuli are presented simultaneously, in an interlaced pattern. Craig hypothesized that the burning pain felt by central pain patients is caused by the loss of cool inputs, which consequently releases (or disinhibits) integrated polymodal nociceptive activity in the lamina I pathways [12]. He further used evidence from neuro-imaging and animal studies to support this thermosensory disinhibition hypothesis. Additionally, it was shown that the mechanisms underlying the TGI were pharmacologically distinguishable from those underlying noxious thermal pain [13]. Based on the validity of his hypothesis, Craig proposed the use of the Thermal Grill (TG) as an investigative tool to study the mechanisms of central neuropathic pain and theorized that any agent that could be used to block the TGI can in turn be used for alleviating neuropathic pain and that the absence of the TGI would act as a diagnostic for CNP [14]. However, hitherto there is no standardized TG device or testing protocol to study CNP. Thus, the purpose of this thesis is to aid in the development of a standardized TG and to investigate the effects of different spatial and temporal configurations of the TG on the perception of the TGI. 1.3 Roadmap of the Thesis This document consists of seven chapters. Chapter 1 provides an overview of the motivation and hypothesis behind the study. Chapter 2 contains relevant background 3

14 information for the study: aetiology of central neuropathic pain and the thermal grill illusions as well as prior art. Chapter 3 describes the main objective of this research study. Chapter 4 provides a detailed description of the study s methodology. It details the apparatus design, involved design decisions, subjects and experimental design. Chapter 5 summarizes the experimental results and Chapter 6 discusses these results. Finally, Chapter 7 concludes this study while highlighting the key findings. 4

15 Chapter 2 Background 2.1 Central Neuropathic Pain According to the International Association for the Study of Pain, central neuropathic pain (CNP) is defined as pain caused by a lesion or disease of the central somatosensory nervous system [15]. This includes all pain due to any lesion along the neuraxis including: the dorsal horn, the ascending pathways throughout the spinal cord and brain stem, the thalamus, the subcortical white matter, and the cerebral cortex. The CNP symptoms can be divided into two broad categories based upon their dependency on peripheral stimuli: 1) spontaneous pain - which occurs independently of peripheral stimuli, may be persistent, and may be described as numbing, burning, cutting, piercing or electric-like pain [16] and; 2) peripherally evoked pain - which occurs in response to either normally non-noxious or noxious stimuli. Hyperalgesia, a stimulusdependent (evoked) pain, is an exaggerated response to a painful stimulus; allodynia, is defined as pain evoked by a stimulus that is normally not considered painful [16]. An example of hyperalgesia is when a small pinprick results in a sharp, stabbing pain. An example of allodynia is when something as innocuous as the light touch of clothing is painful and unbearable. Identifying and diagnosing the specifics of someone's neuropathic pain requires a thorough examination, including a history, physical and neurological evaluations [17]. A history allows the physician to begin to pinpoint which parts of the body are affected and what parts of the nervous system may be involved. In a neurological exam, the investigator observes the response to various types of stimuli such as: light touch, cold, 5

16 heat, pressure and pin pricks. The response to stimulation of various body locations is mapped out to determine the nature of the neurological deficits. Currently neuropathic pain is treated mainly with medications. Anticonvulsants (seizure medicines), antidepressants and anti-arrhythmics are categories of drugs commonly used to combat neuropathic pain [18]. A completely different class of drugs, namely opioids (or narcotics), are sometimes prescribed for CNP. Because of side effects as well as perceived possible addiction issues, their use is still somewhat controversial. Patients also often go through an intensive psychotherapy program to address issues of despondency, depression and despair that may arise secondary to the long-lasting impact of CNP [18]. 2.2 Central Neuropathic Pain and Spinal Cord Injury Among various medical diagnostic groups, the greatest prevalence of CNP is in those with SCI [5]. Siddall et. al.[3] classified the types of pain seen after SCI. Within the neuropathic group he classified the clinical presentation into three categories based on location of the symptoms as follows; 1) above-level pain, which occurs at regions cranial to the injury site; 2) at-level pain, which occurs in regions near the SCI, where pain is often characterized as stabbing or is stimulus-independent; and 3) below-level pain, which is localized to regions distal to the injury site and is often classified as a stimulus independent, continuous burning pain [5]. CNP is either at-level or below-level neuropathic pain. Classification of these pains can be further refined according to the structure or pathology. Historically, CNP has been classified only descriptively by the above mentioned symptoms and CNS injury site/pathology, without a clear understanding of the specific mechanisms underlying each person's pain [19]. However, animal studies have revealed that multiple molecular and cellular nervous system mechanisms underlie each pain symptom and many different mechanisms can produce the same pain symptom. A 6

17 criticism of animal models however, is the lack of a direct measure of pain; the tests available are based solely on the observation of behavioural changes and adverse reactions to a given stimulus [20]. Thus, animal studies alone cannot establish the precise relationship between painful symptoms and mechanisms, and in this respect human studies are needed. In order to validate and test these hypotheses and bridge the gap between our knowledge of neurophysiological mechanisms and the clinical diagnosis and treatment of neuropathic pain, researchers are looking to better understand the somatosensory phenotype of patients [22]. Various authors have recently proposed that the careful analysis of the psychophysical measures of somatosensory function in individuals with CNP can help identify subgroups of patients based on somatosensory patterns and correlate the specific individual patterns with the likely underlying mechanisms of CNP [21, 22, 23]. 2.3 Psychophysical Testing The first step towards mechanism-based treatment is hence, to characterize the somatosensory profile of patients as precisely as possible. Psychophysical methods specifically quantitative sensory testing (QST), non-invasively evaluate somatosensory function. QST measures the relationship between the characteristics of a physical stimulus (modality, location, intensity and timing) and an individual s perception of that stimulus [24]. QST was developed to overcome some of the limitations of qualitative traditional bedside examinations, by allowing a more precise assessment of the magnitude of sensory deficits and a quantification of thermal allodynia and hyperalgesia [65]. QST systems are separable into devices that generate specific physical stimuli and those that deliver electrical impulses at specific frequencies [25]. Devices that generate highly controllable, ramping thermal stimuli utilize the Peltier principle, in which the intensity and direction of current flow controls the surface temperature of a test electrode (thermode). The thermode contacts the skin and a subject is asked to report the sensation 7

18 of temperature change or heat/cold pain. A technical challenge for QST is to deliver a sensory stimulus and determine accurate and reproducible sensory thresholds in a reasonable amount of time [24]. Tests for pain sensation have the additional challenge of minimizing the number and duration of stimuli that are unpleasant to the patient. Rolke et al. (2006) established a standardized protocol and age- and gender-matched absolute and relative QST reference values from healthy subjects, across different body parts. Recently, Backonja et al. (2009) using thermal QST tools, proposed a new standardized protocol for the psychophysical testing of patients with NP. This protocol, although an important first step towards the individualized characterization of somatosensory profiles, is limited to the testing of sensory thresholds to a single type of stimulus (for example warm, cold, or touch). Threshold testing of patients with SCI revealed that CNP was only present in areas with impaired or absent heat pain sensibility [26, 27], and was confined to areas of maximal thermal deficit [28]. Although Rolke s protocol identified that the loss of thermosensation was a significant correlate of CNP, it did not adequately characterize the relationship between the observed thermosensory deficits and CNP. Craig [14] used the Thermal Grill Illusion (TGI) as a psychophysical method to understand the interaction between innocuous cold and warm cutaneous sensory inputs. The TGI is an illusion of heat pain, that is often burning in nature, when a person s skin is in contact with interlaced innocuous cool (20 C) and innocuous warm (40 C) stimuli [29]. Craig proposed that the loss of thermal sensation in regions of CNP may reflect similar CNS interaction between warm and cold sensory inputs that underlie the TGI.. The following section shall provide an in depth look at the hypothesized mechanism of the TGI. 8

19 2.4 Thermal Grill Illusion As described by Defrin [26], several hypotheses have been developed in an attempt to explain the neural mechanisms that define different pain qualities. An early theory, namely the pattern theory of pain, states that pain is signalled via non-specific channels concerned with the conduction of both nociceptive and non-nociceptive events, and is dependent on the degree of excitation of these channels [30, 31]. However, the identification of specific receptor organs for detecting noxious stimuli in 1968 [32], led scientists to discard this theory. A contradictory view, which was introduced by Muller, and is better known as the labelled-line code, maintains that pain is processed via dedicated pathways and that the excitation of a specific sensory receptor elicits the same amount of pain regardless of the stimulus energy [33]. However, this view was contradicted by the observation that neither damage nor stimulation of somatosensory cortices affects pain, and that clinical stimulation of somatosensory thalamus can alleviate chronic pain. A third view, proposed by Wall and McMahon (1986), states that the perception of pain is due to the central integration of sensory information, including information derived from the response of nociceptors. Work carried out by Defrin et al. (2002), further supported this latter theory by showing that the quality of thermal pain is determined by integration of information conveyed simultaneously by both dedicated pain pathways and a non-nociceptive thermal pathway. In this perspective, an imbalance or lesion in the thermosensory systems may contribute to CNP after SCI. Craig further proposed that pain could be considered a homeostatic emotion and an aspect of interoception or the physiological condition of the body [35]. The ascending neural activity that represents all physiological conditions of the body is conveyed by the lamina-i spinothalamocortical pathway. Lamina-I, the most superficial layer of the spinal dorsal horn, is the only neural region that receives monosynaptic input from small-diameter (Aδ and C) primary afferent fibres [35], which innervate essentially all tissues of the body. The Aδ- and C-type primary afferent fibers that are relayed by lamina-i, transmit homeostatic information specifically pain and temperature sensations from all tissues. 9

20 There are two classes of neurons that signal sharp pain and burning pain, that selectively receive inputs from Aδ-nociceptors and polymodal C-nociceptors (HPC), respectively. In addition, there are two types of thermoreceptive lamina-i cell that respond selectively to cooling or warming [36, 37]. Research indicates that the summated activation of lamina 1 HPC cells (noxious heat, pinch and cold) causes a conscious perception of pain in humans and signal burning pain at low temperatures (<15 ºC). The lamina-i (COOL) cells that are sensitive to cooling respond predominantly to Aδ-fibre input and have ongoing discharge at normal skin temperature that is inhibited by warming. They display a linearly increasing response at temperatures below a neutral skin temperature (~34ºC) and reach a plateau at cold temperatures in the noxious range (<15 ºC) [38]. Craig (2002) proposed that the illusion of thermal grill-induced burning pain, could be explained by the relative activity between the spinothalamic thermal and nociceptive channels (refer to Figure 2.1). The burning sensation caused by polymodal C-nociceptor activation of HPC cells, is normally masked centrally by the cold sensitive Aδ-fibre activation of COOL cells. When the activity of cooling receptors is reduced due to the presence of interlaced warm stimuli in receptive field (as is the case in the TG stimulus), the HPC activity that is evoked by cooling is disinhibited centrally and causes a burning sensation at these temperatures that is normally felt only at noxious cold temperatures [39]. The effect of the thermal grill stimulus is a relative balance of HPC and COOL cell activity that is similar to the relative activation seen in response to a noxious cold stimulus of ~10ºC; the equivalence of which has been verified psychophysically [12, 40]. 10

21 Figure 2.1 Mechanism of the Thermal Grill Illusion. The burning pain sensation caused by polymodal C-nociceptors (HPC), which are sensitive to noxious heat as well as to noxious cold, is normally masked centrally by the activity of A -fibre thermoreceptors that are responsible for cooling. When the activity of cooling receptors is reduced due to the presence of interlaced warm stimuli, the HPC is disinhibited centrally and causes a burning sensation or the TGI (Figure adapted from [14]). 2.5 TGI and Central Neuropathic Pain Craig and Bushnell (1994) were the first to investigate the TGI in the context of the study of pain, particularly CNP [14]. Craig speculated that the unmasking mechanism underlying the TGI mirrors the patho-physiology of some neuropathic pain patients. A majority of patients suffering from neuropathic pain due to SCI have dysfunctional thermal sensibilities in which a dramatic loss of warm/cool temperature sensation is seen in regions of ongoing pain [12]. Craig observed that this characteristic closely mimicked the TGI, in which reduced warm/cool sensations are reported. Based on electro-physiological recordings of spinal dorsal horn neurons in animals and neuro-imaging (fmri) studies in humans, Craig proposed the "thermosensory disinhibition" hypothesis to explain the TGI and the burning pain. Namely, Craig 11

22 suggested that: 1) the paradoxical burning induced by the TG was due to the reduction of the inhibition normally exerted by cold afferents on the nociceptive pathways in the central nervous system; 2) in certain individuals, CNP may similarly reflect imbalanced integration of pain and temperature; and 3) the TGI can be used to evaluate the presence/absence of the central nervous system mechanism for cold-inhibition of pain. A preliminary study of subjects with CNP, as a consequence of multiple sclerosis, further supported Craig s hypothesis [41]. The patient in this study reported less pain in response to the TGS than to the cool component (20 C) itself. Furthermore, a study carried out on a patient with complex regional pain syndrome-i (CRPS I) reported that the patient experienced an intolerable burning sensation on her affected hand when it was placed on the TG [42]. A study carried out by Kern et al. (2008) provided evidence that the central mechanism underlying the TGI is pharmacologically distinguishable from the neural mechanisms underlying both innocuous thermal sensations and noxious thermal sensations. Kern found that the administration of morphine (known to suppress the activity of lamina-i nociceptive neurons) produced correlated reductions in the pain intensity reported in response to the TGS. If the hypothesis that the fundamental dysfunction in CNP is the same mechanism that underlies the TGI holds true, then any agent that blocks the TGI could be efficacious for alleviating CNP, and the absence of the TGI effect would be diagnostic for CNP. Craig further proposed the use of the TG as an investigative tool to examine the mechanisms of pain. The TG has potential for further studying and understanding the interactions between the thermal and nociceptive pathways. In particular, the TGI imitates symptoms of CNP in healthy volunteers. Kern et al. (2008) similarly discussed the potential of using the TG as a tool to uncover the physiological mechanisms and impacts of analgesics on CNP. Despite its potential value for studying pain mechanisms in humans, there are only few studies that evaluated the psychophysical properties of the TGI or its application as an investigative tool for patients with CNP [12, 43, 44, 45]. Furthermore, based on the above evidence, it can be concluded that a standardised TG device is needed to advance 12

23 research in this area. The lack of research on the TGI may be attributed to the fact that there is no commercially available or standardized TG device or standardized research methodology [14]. 2.6 Research Problem Thermal Grill Devices Existing TGs were created purely on an ad hoc basis for research purposes on healthy subjects and vary in terms of design, size of thermal actuators, rates of temperature change, range of temperatures and materials that couples skin and the thermal actuator, as depicted in Table 2.1 [19, 43, 44, 45, 46, 47]. The existing diversity makes it difficult to compare data obtained from different researchers and can negatively affect the results and conclusions drawn from the studies. Researcher Number of Actuators Actuator size Surface Material Sensation produced Manufacturer Green [43] 4 x cm 2 Copper plate Non-painful heat Pierce Laboratory at mild temp Bouhassira [45] 1 x 6 (bars) 1.2 x 16 cm (3 per bar) Copper plate Painful sensation Seicer (France) Defrin [26] 1 x 6 (pair 3 x 3 cm Aluminum Painful sensation TSA 2001 of) plate Medoc Fruhstorfer 1 x 6 35 x 8 x 0.8mm Bronze plate Non-painful heat In-house design [46] Leung [44] 1 x x 10 cm Copper tubes Painful sensation In-house design Alston [47] 2 cylinders 7.5 x 12 cm Brass Non-painful heat In-house design 0.5 mm (diam) cylinders Craig [19] 1 x 15 (bars) 20 x 14 cm Silver plate Painful sensation In-house design Table 2.1 Comparative chart showing some of the previous thermal grill devices used in research. A high degree of variation is seen in both the grill layout and actuator size. 13

24 2.6.2 Research Methodology Leung et al. (2005) tested various combinations of innocuous temperatures (18/42 C, 20/40 C, 22/38 C, 24/36 C) in order to evaluate the potential of using the TG as a research tool. They found that the subjects reported the most painful sensation for the 20/40 C and 18/42 C combinations. Bouhassira et al. (2005) showed that the frequency and intensity of the painful sensation produced by the TG was directly related to the magnitude of the difference in temperatures between the warm and cool bars. The combination of increasingly colder temperature to a given warm temperature was shown to induce similar effects as combining increasingly warmer temperature to a given cold temperature. These results suggested that pain can be the result of a simple addition of non-noxious warm and cold signals. Studies conducted by Li et al. (2009) using a 6x1 array TG, demonstrated that the occurrence of the TGI did not display a significant dependence on gender. Research conducted by Dranga et al. (2008) in our laboratory, investigated the effect of stimulus duration on the perception of the TGI. Dranga found that at the 5 sec time point, the continuous pain ratings in response to the TGS were significantly higher than those in response to the warm and cool stimuli alone [49]. Also, at the 60 sec mark, the pain reported in response to the TGS was significantly higher than that reported in response to the uniform stimuli. To date, research on the TGI with relation to CNP has shown little consistency in terms of methodology. Prior psychophysical testing of the TGI was limited to the distal upper extremity, i.e., the palm and/or forearm. However, CNP can occur in any area of the body, thus necessitating that the TG be adaptable for applications to any surface of the body [21]. Li et al. (2009) using a thermal stimulation apparatus composed of six hollow brass bars perfused with warm or cold water, tested twenty-one different stimuli applied to a group of 19 healthy subjects on the glabrous skin of the palm and fingers. By using various combinations of warm and cold bars and by alternating the number of bars in contact with the skin, they showed that neither the distance between adjacent warm (40±1 C) 14

25 and cold (20±1 C) bars, nor the number of the stimulation bars (2 6) notably affected the occurrence of the TGI. Previous studies have also shown a huge variation in the method of application of the TG stimulus. The original animal studies conducted by Craig (1994) used a dynamic protocol; the temperature of the grill was varied to a set-point temperature while the participant made contact with the grill. However, subsequent studies in humans have each used different skin contact times and methods of application of TG such as: a) 3sec (dynamic The subject places his/her hand on the TG, at which point the grill was held at an adaptation temperature for a period of 5min before being warmed/cooled at a rate of ±2.0º/s to a target temperature. After the target temperatures were reached in all actuators, the desired temperatures were held for 3sec. The subject s skin was in continuous contact with the thermal actuators) [43], b) 10sec (static The subject s skin contacted the actuators after they had been heated or cooled to the target temperature. The fingers remained in contact with the grill for the entire duration of the 10sec long experiment) [44] and c) 30 sec (static - The subject s skin contacted the actuators after they had been heated or cooled to the target temperature, and stayed in contact with the grill for the entire duration of the 30sec) [45]. Green and Pope (2003) reported that the TGI is optimally perceived when thermal ramping and stimulation occur as the actuators rest against the skin for the entire stimulation period (dynamic condition), i.e. no simultaneous tactile contact, and TGI is infact greatly reduced by simultaneous cutaneous tactile inputs i.e. contact suppression occurring when the subject places their hand on the grill simultaneously as they first experience the TG stimulus (static condition). Additionally, both Leung and Bouhassira (2005) noted that while using static testing conditions, the quality and intensity of the sensation could change during the TG stimulus and infact decreased with time. As the TGI illusion can be simply produced by the simultaneous application of warm and cool stimuli, a number of different patterns of these warm and cool stimuli can be imagined, that can invoke the TGI. Figure 2.2 demonstrates this fact with the case of the 3x2 array TG used in this thesis. 15

26 Figure 2.2 Thermal Grill stimulation patterns. Six possible temperature configurations that can be produced using a 3x2 TG array. No research has been carried out to date, that examined the effect of different temperature patterns on the TGI. Preliminary research carried out in our laboratory has shown that the spatial distribution of warm and cool stimuli can significantly affect the perceived intensity of the TGI [50]. 16

27 Chapter 3 Research Objective 3.1 Objective The goal of this thesis was to design the user interface and data acquisition system of a prototype thermal grill device and to use it to further describe the TGI amongst healthy subjects, while investigating the physiological factors which underlie this phenomenon. In light of this goal, the following paragraphs outline the research objectives. An important feature of the TG device was the ability to control the individual stimulus elements and hence produce various thermal stimulus patterns. An aim of this thesis was to explore this feature and help determine the best thermal element pattern and spacing that could be used to elicit the TGI. To evaluate the ramping functionality of the TG, a pilot study was designed to study the effect of static vs. dynamic grill testing (i.e. w/o and w/ ramping) on the TGI. This thesis also aimed to compare an individual s thermal thresholds using one vs. six thermal actuators and hence investigate the relation between thermal thresholds and stimulation area. A further objective was to design a pilot study to explore the relation between the measured thermal thresholds and a subject s TG intensity ratings, using the same stimulation area. An objective of this thesis was to minimize any subject bias towards reporting the TGI as painful, hence the study had to be designed such that subjects were, at no point instructed that the sensation they would experience would be painful. Rather subjects were simply told to expect a unique sensation to the TG configurations and to rate the level of 17

28 unpleasantness. This is in contrast with prior research [11, 12, 27, 43, 62] that asked subjects to specifically report and rate their sensations of pain. 3.2 Hypotheses This thesis investigated the following three research hypotheses: (1) The Thermal Grill (TG) device can be used to generate a painful sensation in healthy individuals. This hypothesis originates from the prior findings that the simultaneous application of warm and cool stimuli can produce a burning sensation, known as the TGI [39, 43, 44, 48]. (2) The Thermal Grill Illusion (TGI) can be evoked in each able-bodied individual. This hypothesis is based on Craig s thermosensory disinhibition theory [12] that states the central mechanism underlying the TGI is the same as that underlying CNP and hence the TGI should be present in all ablebodied individuals. According to that theory, the absence of the TGI would hence act as a disgnostic for CNP. (3) The intensity of the TGI is dependent on the distribution pattern of the warm and cool actuators in the TG stimulus. This hypothesis is based on preliminary research carried out demonstrating that the spatial distribution of warm and cool stimuli can significantly affect the perceived intensity of the TGI [50]. 18

29 Chapter 4 Methodology This section will begin with a detailed overview of the Rehabilitation Engineering Laboratory TG prototype, followed by a description of the experimentation protocol to be used in order to meet each of the project objectives. 4.1 Thermal Grill Apparatus To address the need for a standardized thermal grill, a custom designed prototype was created by an external contractor (Oven Industries; Mechanicsburg, Philadelphia) in affiliation with the Rehabilitation Engineering Laboratory (REL), to further study the effects of the TGI. Oven Industries was primarily in charge of the mechanical design and construction of the device, as well as the preliminary design of the control system for the grill. The major contributions made in the thesis towards the design of the TG device are highlighted below: (1) Creation of the requirements for the hardware design of the TG and the subsequent testing of the device prototype to ensure that requirements were met. (2) Design of the user interface to facilitate easy use for users with little to no technical background. (3) Partial design of the control system to ensure reliable temperature control, data acquisition, and recording of the subject s response. 19

30 4.1.1 Hardware Design Requirements: The grill must contain a minimum of 6 individual square contactthermodes arranged in a 3x2 matrix to allow for testing of different temperature patterns/configurations. Each element must be individually controlled to allow for a range of stimuli between 0 to 50 C and must be capable of achieving a ramp rate of at least 1 C/s. Contact thermodes which will be in touch with the skin, should be composed of a material that allows for maximal heat transfer and should not exceed 60mm x 60mm. The spacing between the thermodes should be such so as to allow for no temperature leakage. Each thermal element must be monitored by a thermistor for continuous temperature feedback of the thermode-skin interface (resolution 0.6 C). Methodology: Research shows that thermal detection thresholds and thermal pain thresholds vary inversely with the amplitude and the duration of the stimulus, hence making it important to maintain a constant thermode size in any comparative studies of thermal thresholds [36]. Additionally, the ramp rate achievable by the peltier element is dependent on the power rating and therefore the size of the element. Hence, a trade off had to be made between the size and achievable ramp rates in order to meet the desired specifications. Recent studies conducted by Pavlakovic et al. also revealed that the choice of the material that couples the skin and the thermal actuator, and hence the heat transfer capacity of the coupling material, can highly influence a person s thermal sensory detection and thermal pain detection thresholds [51]. Materials with high thermal conductivities (such as aluminum: k Al = 250, copper: k Cu = 401, and silver: k Ag = 429) tend to transfer heat/cold throughout their surface more evenly and more rapidly [52]. Table 2.1 displays the coupling materials used for TG devices to date. Auditory noise produced by the thermal stimulation device has also been shown to significantly raise the heat pain and cold pain thresholds of the subject [53]. Hence, a water circulating cooling unit, as opposed to a fan cooled unit, was chosen for the device to minimize auditory noise. 20

31 Implementation: The TG device consists of a matrix of six thermal actuators or thermoelectric modules (TEM), each measuring 50mm x 50mm (Figure 4.1). The direction of current flow between the two surfaces of the TEM dictates its action as a heat generator or a heat sink. Each TEM is individually capped by an aluminum tile measuring 50.8mm x 50.8mm x 5mm. Figure 4.1 Isometric 3-D view of the Thermal Grill Device used in this study (a) top view and (b) bottom view The thermal tiles are arranged in a 3x2 grid, thermally isolated from each other with an inter-tile gap of 1.02mm, allowing for a 61cm 2 flat testing platform (Figure 4.2). The tiles are placed atop of a water-circulating heat sink to ensure rapid temperature shifts, thus allowing an operating surface temperature between 0 to 50 C. Figure 4.2 Mechanical drawing of the Thermal Grill device developed by Oven Industries in collaboration with REL.A1, A2, B1, B2, C1 and C2 represent the array tiles. 21

32 Each array tile is individually monitored by a class T, 15 kω thermistor (TS-67, Oven Industries, USA) embedded in the aluminum cap, 1.9cm below the surface of the grill, for continuous temperature feedback of the tile-skin interface (resolution ±0.5 C). This temperature measurement is then used by a closed-loop proportional-derivative-integral (PID) controller to regulate tile temperature in real-time [54]. The tiles have dedicated controllers enabling the experimenter to define a programmable temperature profile for ramping or a steady-state temperature for each tile individually. The box housing the array tiles has connectors allowing for easy connect/disconnect from the cooling unit and control modules. Evaluation: The device was evaluated in terms of its: a) accuracy of thermistor readings; b) disturbance rejection to touch, i.e., heat perturbation; and c) accuracy of ramp rates. To assess the accuracy of the thermistor readings, the individual tiles were set to a range of temperatures from 0-50 C and the thermistor readings of the individual tiles were compared to those obtained using an external thermocouple monitoring device (Omega HH21A monitor with Thermocouple MQSS series exposed probe mm diameter, Omega Technologies, Stanford, USA). The temperature was measured on the surface of the tile both at the centre of the tile and on the perimeter. The accuracy of the TG s thermistor readings at both locations (tile centre and perimeter) were found to be within the range of ±0.2 C; well within the specified limits. The disturbance rejection of the system is a measure of how well the system overcomes perturbation caused by skin contact with the thermal tiles. A tile temperature of 0 C would ensure the maximum temperature differential between the tile surface and the user s skin (32-36 C), and is thus used to measure the worst case disturbance rejection behaviour of the system. Figure 4.3 demonstrates that at a set-point temperature of 0 C, contact of the subject s forearm with the tile surface causes a 0.4 C spike in temperature for a period of 10 sec before returning to steady state temperature. This falls well within 22

33 the requirements for the TG to control temperature within ±1 C (i.e., (40±1 C) and (20±1 C)). Figure 4.3 Disturbance rejection of the device at 0 C. At a set-point temperature of 0 C, tactile contact with the tile surface causes a 0.4 C spike in temperature for a period of 10 sec. Red arrow indicates the time when the contact with the tile occured. The accuracy of ramp rate was verified by measuring the time taken by the tiles to reach and stabilise at the set temperature using a given ramp rate. The device was found to function well under ramp rates of 0.5 to 4 C/s. At higher ramp rates (approximately 5-15 C/s), an overshoot in reaching the desired temperature was seen as the PID controller had to increase the current flow to the peltiers. For the purpose of this thesis, only ramp rates of 0.5 and 1.0 C/s were used. Table 4.1 demonstrates the measured accuracy of these ramp rates. 23

34 Start Temp ( C) End Temp ( C) Temp diff ( C) Ramp Rate ( C/s) Time to reach set point w/o forearm (s) Time to reach set point w/ forearm (s) Table 4.1 Accuracy of ramp rates. Time taken to reach set temperature using a given ramp rate measured using an external stop watch. All readings are averaged values, obtained from three trials done (w/o) with no physical contact with the grill; and (w) with hand placed on the grill Software Design Requirements: The user interface had to be designed for clinicians and researchers with minimal technical background, and must allow for reliable temperature control, data acquisition, and recording of the subject s response. The primary response measure was a computerized Visual Analog Scale (VAS) [55] rating of unpleasantness. The representation of the VAS was a graphic that consisted of a slider on a horizontal line with the anchors labelled by work descriptors (see section below).the subject used a mouse to move an onscreen indicator along the line to the point that they felt represents their current perceived stimulus-induced unpleasantness level. Software was developed to record and display the VAS response as a function of time. Any left-right movement of the mouse was translated into a corresponding value on the VAS. The software controller automatically recorded data input by the test subject as well as the tile temperatures sampled at every 0.1 seconds and stored it in an excel file. 24

35 Additionally checks were required to be placed within the software to ensure the safety of the subject being tested and to prevent any overshoot in temperature beyond threshold limits. A further requirement of the interface design was that the subject should have no prior knowledge of the grill configuration that he/she is being tested with, in order to remove any form of bias from the feedback. Methodology: The user interface was designed by taking the following facets of user interaction into account [56]: Functionality Design The functionality as far as relevant to the user, including actions and objects required by the system to accomplish the goals of the project and satisfy the potential needs of the users. Dialog Design Structure of the interface without any reference to presentational aspects i.e. the navigational structure and dynamic behaviour of the interface. Dialog design aspects such as suitability of design for the specified task, self-descriptiveness, conformity with user expectations, etc. Presentation Design The actual representation of the user interface including details such as layout, colors, sizes, and typefaces. To increase usability, the functionality and hence design requirements of the system needed to be well defined in order to support the TG experiment methodology tasks in the most optimal manner. Checks had to be put in, to ensure patient safety where appropriate. Besides defining the major components of the user interface in terms of functionality, the dynamics of the user interface (i.e. user interaction with the system) needed to be specified as well. For example, clicking on the screen to indicate a pain threshold had to stop the temperature ramping of the thermode and bring the thermode back to adaptation temperature. The design had to take into consideration all aspects of the user s interaction with the system including the amount of mental strain that the design has on the user. Pre-set 25

36 configurations and choices pertaining to the task at hand were included in the interface to reduce the amount of mental load on the user [56]. Implementation: The user interface and data acquisition system of the device were designed using LabView software (National Instruments, v 9.0 (2009), Texas, USA). The display was split so that the subject was only allowed to see his VAS rating while the research coordinator had display of the temperature control, data acquisition, real time temperature and the subject s feedback. Additionally the grill configurations were tested in a randomised order. This ensured that the user had no prior knowledge of the grill configuration being chosen by the research coordinator for testing. The user interface was divided into three modes of testing: Static, Dynamic and Threshold Testing, that mimicked the modes of testing commonly used by clinicians and researchers for TGI studies. The Method of Limits methodology [57] was used for sensory threshold testing. The temperature of the TG tiles was simultaneously increased/decreased at a constant, researcher defined, ramp rate. The subject was instructed to terminate the ramp by clicking down at any point of the screen, at the moment the requested sensation was perceived. This simple push-button response by the subject was also recorded by the computer and completed each cycle of the examination. For TG testing, i.e. static and dynamic grill modes, pre-set grill configurations were delivered, upon the researcher s choice. Both the ramp rate and the trial duration were also defined by the researcher. There were two modes of application, termed static and dynamic. For the current study static mode was defined as follows: the thermal actuators were set to a predetermined temperature configuration before stimulus application. While the actuator was in contact with the subject, temperatures remained constant. In contrast, the dynamic mode was defined as follows: the thermal actuators set to the reference adaptation temperature (30 C), and then applied to the subject. Temperature change from adaption temperature to target temperature was initiated after 26

37 contact with the skin. Temperatures then remained constant after the target temperature was achieved. A LED indicator was turned on to indicate when the subject should place his/her forearm on the TG when testing in the dynamic or threshold testing mode. The TG thermodes could be selectively powered on/off thus providing the option to use the grill in different configurations, for example as a 2 x 3 array or a 2 x 2 array. A computerised VAS scale displayed on the subject s screen, allowed for real-time capture of the subject s response to the TG stimulus. The subject s response was also simultaneously displayed on the researcher coordinator s screen. Time stamped data was automatically stored in a user defined excel file every 0.1 seconds. The user interface (UI) was programmed to have the VAS scale automatically zeroed at the start of the experiment. This helped eliminate the initial spike in VAS recording that may arise if the mouse was not properly zeroed (i.e., far left of the screen). Continuous graphical and numerical feedback of the thermodes temperatures was displayed to the research coordinator in real time to allow proper monitoring of the device (refer to Appendix A). An adaptation temperature of 30 C was pre-programmed into the grill. Before each trial, the grill automatically defaulted to this adaptation temperature for a period of 10 sec, thus ensuring that the subject s skin was kept at the same temperature before each thermal stimulus. Evaluation: The device was evaluated in terms of: a) the time lag between user response and data acquisition; and b) the response time to subject feedback. The lag in the data acquisition system was defined as the delay from the point at which the user clicks the mouse to the capturing of data (tile temperature values) by the data acquisition system. Since the mouse used was a USB connected device, this lag was the summation of the Windows USB polling lag (8ms) and the Data Acquisition system 27

38 sampling rate (100msec) [58]. This lag could be considered negligible for the purpose of this study as it was significantly below the average user response time (2.0 ± 0.5 sec) [48]. To ensure that the grill temperature did not exceed the subject s pain threshold during testing, the response time of the software to subject s feedback during thermal testing was monitored by an external timer. This was measured as the time between the subject clicking down on the mouse to indicate a threshold and the instant temperature ramping stopped and the tiles returned to adaptation temperature. This interval was calculated to be ±0.1 s and the maximal temperature increase/decrease after the threshold indication, was measured to be 0.2 C. Please refer to Appendix C, Thermal Grill User Manual, for a detailed overview of the device operation and user interface. 4.2 Subjects Eighteen participants were recruited through advertisements posted throughout the St. George campus of the University of Toronto. Candidates were screened by telephone to assess eligibility. Individuals were included if they were male, between years of age, generally healthy, and fluent English-speakers. Participants were asked to refrain from consuming caffeinated products for 3 hours before testing. Exclusion criteria included individuals suffering from or having previously suffered from any of the following diseases or symptoms: Systemic or neurological disease Psychiatric disorders History of diabetes or any other disease that can affect the peripheral nerve function History of chronic pain Any skin disease, hypersensitivity or contact allergies Experiencing any pain prior to the experiment. 28

39 4.3 Experimental Procedure To maintain consistency between subjects and between multiple experimental runs, testing was performed in a quiet room with the temperature maintained at 23 ± 1 C. Further, to limit inter-subject variability in data, only the forearm of the non-dominant side of the subject was used for testing, as demonstrated in Figure 4.4. Dominance was determined by the Edinburgh Laterality Quotient score [67] a measurement scale used to assess the dominance of a person's right or left hand in everyday activities. The choice of non-dominant side for testing was dictated by the fact that this allowed the subjects to use their dominant hand to indicate their response to testing. The participants were instructed to place their anterior forearm in contact with the TG. Figure 4.4 Body site tested using the TG device. The non-dominant anterior forearm, was used for testing. During all experiments, the participant was asked to apply only enough pressure to ensure full contact with the TG tiles. Before each stimulus, the tile was set back to the adaptation temperature (30 C). Participation entailed a single testing session, which lasted approximately two hours with twenty 30sec test conditions as follows: a warm stimulus (all tiles set to 40 C - Figure 4.5.a); a cool stimulus (all tiles set to 20 C Figure 4.5.b); and the thermal grill configurations (patterns of tiles set to interlaced temperatures of 40 and 20 C Figures 4.5.c, 4.5.d and 4.5.e). The order of presentation of the test conditions was randomly assigned based on a computer generated sequence. 29

40 The duration of stimulation was chosen based on pilot experiments conducted by Bouhassira et al. (2005) which indicated that for forearm stimulation a duration of upto seconds (depending on the combinations of temperatures), was necessary for stabilization of the sensation. The choice of temperatures was based on the results from past studies, which indicated that the combination of 20 and 40 C effectively elicited a painful TGI amongst most of the participants [12, 44, 45, 59]. Additionally, these temperatures are outside the range of nociceptor activation and were thus appropriate for TG testing Pre-Testing Prior to the experiment, each participant was asked to read, understand, and sign a consent form. Participants were informed that the purpose of the study was to evaluate the range of responses to the TGI amongst a group of healthy individuals. Participants were not informed about the quality of the sensation that they would experience ensuring no pre-disposition to reporting a painful sensation. The research coordinator then explained the procedure of the experiment and the different testing conditions that would be used. Please refer to Appendix D for the detailed study script Participant Feedback A computer-driven visual analog scale (VAS) (see section 4.1.2) was used to continuously sample the participant s current perceived unpleasantness of the TG thermal stimulus. Participants were requested to move a linear, mouse-driven scale, displayed on the monitor, to register their unpleasantness rating; with the leftmost point being described as not unpleasant (VAS value of 0) and the rightmost point described as most unpleasant (VAS value of 10). To ensure the validity of the VAS across 30

41 individuals, subjects were asked to relate the anchor points to the least unpleasant sensation imaginable and the most unpleasant imaginable. During stimulus application, the participants were asked to verbally report on the primary sensation felt at 10sec and 30 sec intervals (Figure 4.6) from the instant that the stimulus was initiated. At the end of a trial for each test condition, participants were asked to pick a word(s) out of a list of descriptors (refer to Appendix B) that best described the overall sensation evoked by the grill Determination of Thermal Thresholds Uniform thermal stimulus Thermal threshold testing was conducted on the subject s forearm in the following order: cold detection threshold (CDT), warm detection threshold (WDT), cold pain threshold (CPT), and heat pain threshold (HPT). The method of limits protocol described by Yarnitsky et al (1995) was used to determine thermal thresholds. Two sizes of stimulus applications were used; one tile, or all six tiles. In this procedure, the temperature of one or all six TG tiles were first maintained at adaptation temperature (30 C) and were then decreased/increased at a rate of 1 C/s for cold and heat pain thresholds (CPT and HPT) respectively, and by 0.5 C/s for cold and warm detection threshold (CDT and WDT). The participant was asked to signal the reach of a threshold by clicking on a computer mouse, at which point the temperature on the tiles stopped ramping, reversed the direction of temperature change, and returned to the pre-configured adaptation temperature. Three trials were run to measure each of the thresholds, with a minimum inter-trial interval of 30sec between the determination of detection thresholds and 60sec between the determination of pain thresholds (PTs). 31

42 Thermal grill stimulus The threshold testing protocol when all six tiles were active in grill mode (i.e. interlaced warm and cool configurations) required the participant to click on three separate buttons on the screen to indicate their CDT, WDT and PTs. Three consecutive trials were run for each of the three grill stimulus configurations. The results from the consecutive runs for each configuration were averaged together to determine the thresholds for that configuration Evaluation of optimal grill configurations In order to identify the optimal stimulation pattern of the TG, individual tiles were set to warm or cool temperatures in various patterns. Figure 4.5 Spatial configurations of the peltier elements to be tested. Red indicates the peltier is set to a warm temperature and Blue indicates that the peltier is set to a cool temp. In static grill condition, the TG was set to one of the five configurations in Figure 4.5 in a randomised order. Once the tile temperatures had reached steady state, the participant was asked to place his forearm on the TG for 30sec. The configurations included both thermal grill patterns as well as uniform stimuli. Based on prior research conducted in the laboratory [48], three TG patterns, as illustrated in Figures 4.5(c), 4.5(d) and 4.5(e), were 32

43 chosen to be tested in order to determine the best thermal element pattern that can be used to elicit the TGI. Each of the above thermal configurations was run twice. During the first run, the participant was asked to provide his verbal feedback on the thermal grill sensation. During the second run, the participant was asked to use the online VAS to continuously rate the intensity of unpleasantness he was experiencing in response to the stimulus. This breakup of the experimentation methodology in two separate runs allowed the participant to devote his complete attention to the continuous VAS rating by eliminating the simultaneous need for verbal descriptors. At the end of each VAS run, the participant was asked to pick his overall sensation from a list of descriptors. Figure 4.6 represents the order of presentation of stimuli during static and dynamic testing trials. Figure 4.6 Static and Dynamic testing procedure. Each TG configuration was tested twice. In the first run the subject responded using a questionnaire and the online VAS. In the second run, the subject verbally described his sensation at the 10 and 30sec mark Evaluation of dynamic thermal grill In the dynamic grill condition, the participant was asked to place his forearm on the grill and the grill was maintained at an adaptation temperature of 30 C for a duration of 60sec, 33

44 after which the tiles began ramping (1 C/sec) until they reached the set-point temperature. This temperature was held for a duration of 30sec with the participant s forearm being in contact with the grill throughout the process. The thermal configurations chosen for thermal testing were the same as shown in Figure 4.5, and were administered in a randomised order. There were two runs for each thermal configuration. During the first run, the participants used the online VAS to dynamically rate the level of unpleasantness felt during the 30sec testing period (Figure 4.6). In the second run, participants were asked to provide verbal descriptors of the primary sensation of the stimulus Order of Presentation Table 4.2 depicts the order of execution of the study. The order in which the five thermal grill patterns were tested was randomized. A minimum 1 minute rest period was given between each TG stimulus for static and dynamic testing. Threshold Testing (Single Tile) Threshold Testing (Six Tiles) Static Grill Testing Dynamic Grill Testing C D T W D T C P T H P T PT + DT VAS Descrip. VAS Descrip. Pattern Table 4.2 Order of presentation of stimuli. Patterns 1,2,3,4,5 represent the grill configurations shown in Figure 4.5 that were used for testing. The order of the configurations will be randomly assigned based on a computer generated randomised sequence. 34

45 Chapter 5 Results 5.1 Subjects Eighteen young men (mean age of participants was 25 years (SD = 2)) participated in the study. The majority of participants were right-handed (n = 16). 5.2 Thermal Thresholds Spatial Characteristics The CDT, WDT, CPT and HPT were measured on the forearm on the subjects with one thermode and with all six thermodes, to study the spatial properties of temperature thresholds. The temperature of the tiles was ramped up/down from a baseline temperature of 30 C until the subject indicated a threshold was reached. Both pain thresholds and detection thresholds measured with a single thermode were significantly higher than those measured with six adjacent thermodes (One-way ANOVA; p 0.05, in all four cases i.e. CPT (p = 0.05), CDT (p < 0.001), HPT (p = 0.011) and WDT (p < 0.001). The decrease in thresholds with the increase in stimulation area indicates the presence of spatial summation of thermal stimuli. Figure 5.1 presents the group pain thresholds and detection thresholds measured with both one and all six thermodes. 35

46 TEMPERATURE Evaluation and Characterisation of the Thermal Grill apparatus for Spinal Cord Injury patients 2011 Figure 5.1 Thermal thresholds of the forearm. Box-plots of the Cold Detection threshold (CDT), Cold Pain threshold (CPT), Warm Detection threshold (WDT), and Heat Pain threshold (HPT) are depicted for both one (_1) and six (_6) tiles. The bottom, middle, and top lines of the box represent the 25 th, 50 th, and 75 th percentile value, respectively. The whiskers represent the minimum and maximum values. 5.3 Pain Elicited by the TG The thermal grill Pain Threshold was measured in subjects as the temperature differential of the thermodes in each of the TG configurations (starting from a baseline temperature) that induced the sensation of pain (using a ramp rate of 1 C/s). Only 4 subjects (22.2%) reported pain thresholds to the TGS before the TG boundary temperatures i.e. 20 C for the cool stimuli and 40 C for the warm stimuli, were reached. The average temperature differential of the TGS required to elicit pain in these four subjects was found to be C (SD = 1.05). In 5 out of the remaining 16 subjects who did not indicate pain to the 20/40 TGS, the thermal grill Pain Threshold was measured by allowing the temperature of the tiles to exceed the 20 C and 40 C boundary temperatures. In this case tiles were ramped from a baseline temperature upto a cool stimulus temperature of 0 C and a warm stimulus 36

47 temperature of 50 C, or until a subject indicated their pain threshold had been reached. The average temperature differential of the TGS required to elicit pain in the five subjects was found to be C (SD = 3.98). The inter-configuration difference in thermal grill pain thresholds as measured above was not found to be significant. The thermal grill pain thresholds were further examined in relation to the subject s thermal pain thresholds (i.e. the HPT and CPT). A significant correlation (Spearman s correlation: = 1.00, p < 0.001) was found between the subjects thermal grill pain thresholds (averaged between the three thermal configurations tested for each subject) and the differential between their thermal pain thresholds (HPT CPT) i.e. subjects with a low HPT and low CPT were found to have a lower threshold to the TG stimulus, and vice versa. 5.4 Static vs. Dynamic thermal testing Intensity Ratings The maximum pain intensity ratings recorded using the visual analog scale were analysed by performing a Paired t-test (within-subject factor: stimulus type). The effect of static TG condition was found to be significant when measured at the 5sec mark (Figure 5.2). The maximum reported pain ratings were significantly higher in the dynamic testing condition than in the static testing condition at the time point (Config_1: F= 17.0, p =.003, Config_2: F = 17.0, p =.001, Config_3: F = 17.0, p =.005, Config_4: F = 17.0, p<.001, Config_5: F = 17.0, p =.031). However, at 30sec, the difference between the unpleasantness ratings for static and dynamic grill condition were not found to be significant (p > 0.05). Figure 5.2 compares average pain intensity ratings recorded using the VAS under conditions of static versus dynamic grill contact. The time variation of the VAS ratings was also examined in relation to the TG configurations. 37

48 Figure 5.2 Graphs of the continuous unpleasantness ratings in response to the five thermal stimuli applied in (a) dynamic and (b) static mode. Using an on-line VAS (0-10), a rating was obtained every 100ms.The line graphs depict the continuous rating of pain over 30 s, averaged across the 18 participants. By the 5s mark, the unpleasantness intensity ratings in response to the dynamic stimulus were significantly higher than the static condition in all five configurations (p< 0.05). At 30 s, the difference between the unpleasantness ratings for static and dynamic grill condition were not found to be significant (p> 0.05). The frequency of painful or burning reports for the dynamic TGS was significantly more than those for the static stimuli (p < 0.001). Additionally, when comparing the static and dynamic testing conditions, the percentage of participants reporting nociceptive sensations to the grill configurations was found to decrease to a greater extent for the uniform thermal configurations than the TG configurations (p < 0.05), as shown in Figure Grill Configurations and TG intensity rating Of the 18 subjects, 15 reported pain and/or unpleasantness (when asked to orally describe the sensation) in response to the TGS (83.3%). Subjects were significantly more likely to report pain in response to the thermal grill configurations than the uniform warm and cool stimuli (Wilcoxon test; Z = , p = for warm vs. TGS and Z = -2.00, p = for cool vs. TGS) as demonstrated in Figure 5.3. However, no statistically significant difference was seen in the average or maximum unpleasantness intensity VAS ratings 38

49 Percentage of participants reporting the sensation as 'Burning' Percentage of participants reporting the sensation as 'Burning' Evaluation and Characterisation of the Thermal Grill apparatus for Spinal Cord Injury patients 2011 reported by subjects between different grill configurations (One-way ANOVA; F = 0.380, p = for dynamic condition and F = 0.909, p = for static condition) and between the TGS and uniform stimuli (warm vs. TGS; F = 1.576, p = and cool vs. TGS; F = 0.001, p = 0.980). Figure 5.4 graphs the average and maximum VAS scores for each configuration in static and dynamic conditions STATIC DYNAMIC All Warm All Cool TGS 0 All Warm All Cool TGS Figure 5.3 Percentage of burning descriptors used between uniform and TG configurations. Subjects were significantly more likely to report burning sensation or pain in response to the thermal grill configurations than the uniform warm and cool stimuli in both static and dynamic testing conditions. 39

50 Figure 5.4 Box plots indicating VAS ratings between different configurations.no significant difference was seen in (a) average VAS ratings and (b) maximum VAS ratings obtained across subjects over 60s stimulus duration. The time variation of the VAS ratings was also examined in relation to the TG configurations. At the 5sec time point, the continuous unpleasantness ratings in response to the TGS were significantly higher than those recorded at the thirty second time point (Config_3: 2=18.669, p < 0.001; Config_4: 2=20.086, p < 0.001; Config_5: 2=26.525, p < 0.001). 40

51 5.6 Thermal Quality and Characteristics of the TGI In 49.07% of the TG runs, subjects characterised the sensation as being burning or painful in nature. The use of these nociceptive descriptors (such as burning or painful ) were significantly more in the case of TGS than for uniform stimuli (Binomial test: Z = 0.50, p =.002). Subjects who reported pain and/or unpleasantness to one or more of the TGS were termed responders. Conversely, approximately 17% of this study s sample reported feeling neither pain nor unpleasantness in response to the TGS (n = 3) and were termed as non-responders for the purposes of this study. Table 5.1 shows the variation in response between responders and non-responders for various grill configurations. This data is extracted from the questionnaires that subjects were required to fill in after each 30sec VAS trial. Condition All participants Descriptors (%) TGS responders only Descriptors (%) Static Warm (88.9) Neutral (11.1) Warm (93.3) Neutral (6.7) Dynamic Warm (77.8) Burning (5.6) Warm(93.3) Burning (6.7) Static Cold (77.8) Burning (10.1) Cold (73.3) Burning (13.3) Dynamic Cold (66.7) Burning (22.2) Cold (100.0) Burning (20.0) Static Mixed (40.0) Burning (11.1) Mixed (31.3) Burning (13.3) Dynamic Mixed (35.0) Burning (27.9) Mixed (25.0) Burning (25.0) Static Mixed (57.8) Burning (15.8) Mixed (43.7) Burning (18.8) Dynamic Mixed (33.3) Burning (47.6) Mixed (25.0) Burning (50.0) Static Mixed (30.0) Burning (20.0) Mixed (25.0) Burning (25.0) Dynamic Mixed (42.8) Burning (28.6) Mixed (37.5) Burning (37.5) Table 5.1 Descriptors chosen to describe the three thermal grill stimuli. Descriptors were chosen from a list provided to subjects as well the subject s own interpretation of the sensation. The frequency reported in brackets indicates the percentage of participants that used a particular descriptor. TGS responders refers to participants that reported pain and/or unpleasantness in response to the application of atleast one of the TGS. Participants were free to use as few or as many words as they thought appropriate. 41

52 When asked to identify the main underlying quality felt, subjects correctly identified the thermal quality of the cool stimulus (config_2) in 78% of runs for static conditions and 67% of the runs for dynamic condition (describing it as cool or cold ). 90% of participants correctly identified the thermal quality of the warm stimulus (config_1)in static grill condition while 78% of participants described the stimulus correctly in dynamic condition (describing it as warm or hot ). 60.2% of the TG runs were correctly identified as being mixed (i.e. warm and cool) in nature. However, when subjects were asked to identify a single predominant thermal quality, the TGS were more frequently described according to the warm component, i.e., as either warm or hot (count of warm or hot vs. cool or cold : Binomial tests; p = 0.02). The use of painful descriptors for the different TG configurations was analysed. Configurations involving a greater percentage of cool (i.e., cool columns surrounding a warm column) was found to be significantly more painful and unpleasant than equal area configurations having a larger region of warm stimuli (i.e. warm columns surrounding a cool column) (χ 2 = 3.846, p = 0.04). Figure 5.5 graphs the subject reported descriptors on a thermal scale progressing from extremely cold to extremely hot sensations. 42

53 Figure 5.5 Progression of the perceived thermal quality of the TGS for (a) Static Condition and (b) Dynamic Condition. Participants were asked to describe the predominant thermal quality of the TGS at 10, and 30s. The temporal progression of the thermal quality of the stimulus was coded as fixed combinations (e.g., when the participant initially indicated mixed sensations that progressed to a predominantly hot sensation, this was coded as mix hot ). Combinations where the participants indicated pain and/or unpleasantness are located at the extreme ends of the graphs. Cold sensations are located on the left-hand of the graph. This is followed by combinations of cold and mixed sensations; mixed sensations; hot and mixed sensations; finally, combinations indicating predominantly hot sensations are found on the righthand side of the graph. 43

54 max VAS score max VAS score Evaluation and Characterisation of the Thermal Grill apparatus for Spinal Cord Injury patients Thermal Thresholds and the TGI A Spearman s correlation was calculated for the four different thresholds and the unpleasantness intensity ratings (NRS) elicited by the TG. The only threshold that was consistently significantly correlated with these ratings was the CPT (ρ =0.550, p = for static condition; and ρ =0.535, p = for dynamic condition) as demonstrated in Figure 5.6. STATIC DYNAMIC CPT ( C) CPT ( C) Figure 5.6 Scatter plot of CPT vs. maximum VAS score of the TGS. The CPT was found to be significantly correlated to the TGS VAS score (averaged across the three TGS conditions) in both static and dynamic grill conditions. 5.8 Variance in Response Although the TGI was successfully elicited in a majority of subjects, the response to the TGS between individuals was varied: pain intensity ratings ranged from zero (i.e., no pain ) to scores of ten out of 10 points (10 = worst pain imaginable ). Subject reported descriptors to the stimuli further reflect this variability. Non-responders perceived the TGS to be warm or hot. While a few non-responders described the TG stimulus to be neutral and not unpleasant or pleasant, just two participants characterized the TGS as pleasant and comforting. However, in the case of these two participants, only a single configuration was characterised as being pleasant, while the other two TG configurations were characterized as unpleasant. Responders described their experience with the TGS as 44

55 uncomfortable, unpleasant, painful and a sensation they didn t like/disliked. One responder reacted strongly to the TGS and could only maintain contact with the grill for a maximum of 5 sec before withdrawing his hand. 45

56 Chapter 6 Discussion The present results indicate that the simultaneous application of adjacent cutaneous warm and cold stimuli, at stimulus temperatures below the heat and cold pain thresholds, is capable of producing a paradoxical sensation with a burning quality in a large majority of subjects (83.3% of subjects reported pain and/or unpleasantness to one/more of the TGS). 6.1 TGI as a Painful Experience In this study, the burning sensation attributed to the TGS was coupled with reports of pain and unpleasantness. The nature of the TGI has not been clearly defined and has been a topic of debate [11, 39, 44, 45, 46]. Although a majority of the authors reported that the TG sensation could be painful, its relationships with normal thermal sensitivities (under the same spatial conditions) had not been specifically investigated. In this respect, the present results (refer to Figure 5.3 and Table 5.1) clearly demonstrate, in a large number of naïve subjects, that the paradoxical sensation induced by a thermal grill can be described as painful and/or unpleasant and hence confirms the hypothesis that the TG device can be used to elicit a painful sensation in healthy individuals. This study investigated the characteristics of the TGI by employing warm (40 ± 1 C) and cold (20 ± 1 C) stimuli of various configurations. Craig reported that the uniform 20 C and 40 C stimuli were rarely rated as non-painful by their 11 participants [10]. None of the 13 individuals that participated in Leung et al. s (2005) study commented on feeling pain in response to the presentation of thermodes set to 18 C, 20 C, 24 C, 36 C, 40 C, or 42 C. In this study s protocol, participants were required to report on feelings of unpleasantness in response to the thermal grill stimuli and were not given any indication 46

57 if the stimuli were to be painful or not. Compared to the warm and cool temperatures alone, pain in response to the TGS was elicited more frequently and was often described to be burning in nature as demonstrated in Figure TG perception during Static vs. Dynamic Grill testing This study was the first to compare the effects of dynamic and static grill conditions of the TGS within the same group of subjects. Results show that the paradoxical sensations can be perceived during synchronized dynamic cooling/warming of the forearm to innocuous temperatures, but this response was not apparent in the static testing conditions. Thermal receptors are most active during a change of temperature [63, 64]. In the case of static testing, a sudden temperature change is seen as the forearm is placed in contact with the preconfigured TGS. In contrast, testing with the dynamic grill requires that the forearm is resting on the grill (which is at skin temperature) before temperature change begins. Intuitively one would expect to see a larger initial VAS response in the static condition, since the temperature change is immediate and should cause the thermal receptors to fire rapidly at the time of initial stimulation. However, the initial VAS response was markedly higher in the static dynamic condition. Interestingly, this was observed in response to both the uniform and the TG stimuli and was short lasting (given the time frame). By the 30sec point there was no significant difference seen in the effect of static vs. dynamic condition on the VAS ratings. This difference in the initial response may thus reflect the effect placing the forearm on the thermode including; the effect of tactile contact of the thermode with the skin surface, or factors related to the motor act of placing the hand on the grill. Tactile stimulation in the case of static grill testing activates the rapidly adapting mechanoreceptors including Meissner corpuscle, Pacinian corpuscle, and hair follicle receptors. Since they are rapidly adapting or phasic, the action potentials generated quickly decrease and eventually cease. In the dynamic grill testing condition, tactile receptors fire minimally due to adaptation to the stimulus [60]. Green (2009) reported 47

58 that temperature perception on the hand is attenuated and its quality is changed when thermal stimulation is accompanied by simultaneous tactile stimulation. The spatiotemporal properties of the tactile stimulus dictate the level of contact suppression, and suppression did not occur in significant amounts when a thermode was lightly drawn across the surface of the skin as opposed to being touched to its surface [61]. His results strongly implied that contact suppression results primarily from stimulation of lowthreshold mechanoreceptors that are more sensitive to vertical impact than to skin deformation and that touch contributes in fundamental ways to normal temperature perception. However, subjects voluntarily placed their forearm on the grill in the static condition only. Voluntary movement could cause descending inhibitory inputs which could cause suppression of nociceptive transmission in the dorsal horn or higher centres [38]. Additionally, placing the hand requires attention which may affect the initial perception of the thermode, or ability to focus on movement of the mouse, and thus the ability to respond accurately in the initial few seconds of stimulation. These possibilities were not evaluated in this study, and require further study. 6.3 Spatial Characteristics of the Thermal Grill Different temperature configurations of the TG were used in this study. Figure 5.2 demonstrates that no statistically significant difference was seen in the unpleasantness VAS intensity ratings reported for each of the configurations during stimulus application. However, in post-stimulation questioning, the TG configuration with a greater cool stimulation area was described to be significantly more painful than configurations with a larger warm stimulation area, as reported in Figure 5.3. Throughout the experiment, participants were simply told to indicate the level of unpleasantness of the TG stimulus. This protocol was designed to minimize any suggestions that the grill may be painful and so were not asked to rate pain during the stimulus application. Instead, participants were given a questionnaire with a list of 48

59 descriptors to choose from and were additionally asked to describe the sensation in their own words. A TG stimulus may have been perceived as qualitatively unique to uniform warm/cool stimulus but equally as unpleasant. This may account for the higher percentage of burning or painful descriptors used for the TGS when subjects were asked to describe the sensation in their own words, even though the VAS ratings for the TGS and uniform stimuli were similar. Overall, it can be shown that although there was no significant variance in the unpleasantness ratings between the different TG configurations, a significant difference was seen in the descriptors used for these configurations. Specifically, TGS configurations with a larger cool stimulation area were described to be more painful. This contradicts previous finding that show that a cool bar interposed in a field of warm was much more effective at evoking the TGI [50]. In all, these results confirm the hypothesis that the perceived intensity of the TGI is dependent on the distribution pattern of the warm and cool bars in the thermal grill stimulus. 6.4 Temporal Characteristics of the Thermal Grill Descriptor analysis showed that the perceptions varied with time in no observable pattern. Similarly, Alston [48] reported that participants experienced a fluctuation between detecting both warm and cool, and feeling heat. Craig (2002) and Green (2009) also reported that the ability to detect the thermal quality of cold diminished during the simultaneous presentation of both warm and cool temperatures (i.e., TGS). Leung et al (2005) comparing the perception elicited by the TGS after 3sec of stimulation to that produced by a uniform stimulus, found that participants matched the TGI to painfully hot stimuli that surpassed the temperature of the warm component. He found that following 10sec of stimulation, the sensation evoked by the TGS still resembled hot (and not cold) stimuli; however, the temperatures of these stimuli were not significantly higher than the warm component of the TGS. These authors suggested that the diminished noxious nature of the TGS may reflect adaptation of the 49

60 central process underlying the TGI. Bouhassira et al. (2005) reported that their participants described mixed sensations in response to the TGS over the 30sec of application. The current data supports the observation that the perceived thermal quality of the TG evoked response fluctuates during stimulus application. Further study is needed to evaluate whether this reflects participant s attending to aspects of the stimulus or the effect of neuronal responses at lower levels of the nervous system. 6.5 TGI and thermal thresholds The intensity of the painful response to the TGS was significantly correlated to the CPT (Section 5.7). This finding suggests that the CPT and TGI share a common physiological mechanism. Prior researchers hypothesized that cold thermoreceptive channels (ascending lamina-i Cold) modulate the effect of nociceptive (lamina-i HPC) pathways [12]. Both the CPT and TGI would be affected by this integration. Preceding research has shown various lines of evidence suggesting a relationship between cold pain, cold thermoreception, and the TGI. Following the administration of morphine, there is a significant correlation between the reductions in the CPT and the lower pain intensity felt in response to the TGS [43].Craig and Bushnell (1994) theorized that the disinhibition of pain seen in the TGI was linked to the cold allodynia experienced during myelinated nerve blocks. Additionally, in post SCI patients experiencing central neuropathic pain, the painful areas were found to co-localize with areas of maximal thermo-sensory deficits [27, 62]. Collectively, these results suggest a modulatory role for innocuous thermo-receptive input in the perception of pain. 50

61 6.6 The between-subject variability of the TGI Despite between-subjects variation in pain and detection thresholds, the thermal grill pain threshold was found to be significantly correlated to the temperature differential between the heat and cold thermal threshold (i.e. HPT - CPT). The results from this study also indicate that the perception and intensity of the TGI is a highly variable phenomenon between individuals. Three participants (representing 16.6% of the sample) did not report either pain or unpleasantness from the TGS. Previous researchers identified within their samples a similar proportion of non-responders [26, 27, 28, 43, 62]. This shows that the TGI can be evoked in a majority of able-bodied subjects using the temperature combination of 20 C and 40 C, within the limitations of our study. Of the four thermal thresholds, CPT is the most variable between subjects [22, 57]. Therefore, the relation between the subject s CPT and perception of the thermal grill illusion may hold some insight into explaining the consistent proportion of nonresponders across the different studies. Further research needs to be carried out in order to examine the role (played by) cold pain thresholds on the perception of the TGI. 6.7 Important methodological issues A crucial methodological difference between the present experiment, and previous research [11, 12, 27, 43, 62] lies in the instructions to participants. In the present experiment the subjects were instructed to describe the evoked perception for warm, cold, and simultaneous warm and cold stimulation by choosing descriptors from a list (cold, cool, warm, hot, neutral, burning cold, other, burning heat), and spontaneously describe the perception verbally. Additionally at no point in the pre- or intra-experimental sessions, were subjects told that the sensation could be painful. Subjects were simply told to expect a unique sensation to the TG configurations and to rate the level of unpleasantness on a scale of However, the participants still 51

62 volunteered comments indicative of the perception of pain and stinging, which are characteristic of the thermal grill illusion. In contrast, in the experiment by Craig and Bushnell (1994) participants were given a list of 15 words from the McGill Pain Questionnaire [66], and a common definition of pain as any uncomfortable sensation, such as pricking, stinging, or burning, even if the stimulus is tolerable. The replicability of the painful grill illusion in subjects without prior bias shows that the perception of the thermal grill illusion is a very robust phenomenon. Whereas previous research measures thermal thresholds using a single thermode, this study used the same stimulation area to measure both the thermal thresholds and thermal grill intensity ratings [63, 65]. This allowed us to better understand the relation between the thermal grill illusion and thermal thresholds. Using the same component temperatures for the TGS across all individuals meant that, for some trials, the cold temperature or the warm temperature fell either below or above pain thresholds, respectively. To offset this possibility, some researchers have defined the cool and warm temperature with respect to the CPT and HPT, respectively (e.g., CPT +2 C/HPT -2 C) [28, 43, 45, 61]. The use of fixed temperatures was based on prior research [12, 44, 45] indicating that the 20 C and 40 C combination produced the TGI in a high number of individuals. 6.8 Using the TG as a Research Tool It was proposed that the TGS can be used to mimic the burning pain experienced by neuropathic pain patients, as well as to evaluate the sensory effects of analgesic agents [11, 45]. The device developed for this study allows for full control over stimulus variables, i.e. thermode temperatures, spatial configuration of warm and cool thermodes, number of thermodes used and temperature ramp rates. Additionally, the safety checks are in place to ensure that the temperatures reached by the grill do not present a physical harm to the participant, hence making it ideal for prolonged testing paradigms. Most 52

63 importantly, the grill is mobile and can hence be used for testing in any region of the body where neuropathic pain may occur. In this study, we were able to successfully elicit the TGI in a majority of the able-bodied subjects. To use the TG effectively as a clinical research tool, further research must be carried out to understand of the mechanisms that cause the TGI and hence reproduce it consistently in a large sample of healthy individuals. 6.9 Limitations of this Study In the present experiments, the thermal grill illusion was elicited through six thermodes arranged in a 3 x 2 array with a total surface area of 61cm 2. However, throughout the history of research on the TGI various stimulation areas have been used to produce the stimulations. The large actuator size used in this experiment may account for the difference in pain ratings seen from prior research. This study was not specifically designed to analyze the effect of tactile stimulation on the TGI; but rather was designed to study the effect of the TG ramping functionality on the TGI. Hence, the lack of control over the various variables involved in understanding the difference between static and dynamic grill testing, presents a limitation in interpreting the results. The VAS is a well-studied method for measuring both acute and chronic pain, and its usefulness has been validated by several investigators. Since pain is a very subjective sensation, subjects often claimed it difficult to judge and mark their level on unpleasantness on the linear length of the VAS scale. This may account for the discrepancy seen between the verbal descriptors used by subjects and their corresponding VAS ratings. 53

64 The room temperature, humidity level and ambient noise were controlled to the best of our abilities. However, normal day to day variations do occur which have been shown to have an impact on a person s perception of thermal stimuli [51, 53]. 54

65 Chapter 7 Conclusion There has been considerable interest in the use of the Thermal Grill Illusion (TGI) for the study of central neuropathic pain. To this end, the present study developed a portable and reliable device that could successfully elicit the TGI in a majority of the able bodied subjects. The present study was also the first to compare the effects of dynamic and static contact of the TG within the same group of subjects. Results show that static testing conditions resulted in significantly suppressed initial responses to thermal stimulation. The source of this difference requires further investigation. A high correlation was also seen in the subject s TG intensity scores and their cold pain threshold. However, the spatial arrangement of the warm and cool stimuli was shown to have a significant effect on the quality perception of the stimulus but not on the intensity ratings of those same stimuli. Future studies should attempt to manipulate the TGS to further illicit the TGI in all healthy subjects in an attempt to further elucidate the mechanisms of the paradoxical pain response elicited by this mixed stimulus. 55

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72 Appendix A Preset Grill Temperature feedback Preset Patterns Waveform display Set Dynamic Testing parameters Temperature feedback Figure A.1. Screenshots of User Interface (a) Static Testing screen (b) Dynamic Testing screen 62

73 Appendix B Figure B.1. Participant feedback form 63

74 Appendix C THERMAL GRILL USER MANUAL The Thermal Grill is a computerized device designed to enable the determination of a psychophysical measure called the thermal grill illusion (TGI); an illusion of pain that occurs in individuals when interlaced comfortable warm (40 C) and cool (20 C) bars are applied to the skin. 1.1 Principle of operation: The TG consists of 6 peltier elements, called Thermodes, arranged in a 3x2 matrix which act as the contact surface with the subject s skin. The device is capable of heating or cooling the skin, as needed. An adaptation temperature of 30 C is pre-programmed into the grill to be used prior to each thermal experiment. For threshold measurement, a quantified measurable thermal stimulus is induced by the device. A simple push-button response by the patient, recorded by the computer, completes each cycle of the examination. For thermal grill testing, preset grill configuration are included, which upon the user s choice induce a thermal stimulus by the device. A mouse driven visual analog scale, recorded by the computer, allows for patient feedback. 64

75 1.1 Overview of Testing Methods Threshold Testing Detection of sensory thresholds depends on subjective data input. The Method of Limits methodology is used by the device for sensory threshold testing. Testing consists of stimuli of continuously changing intensity, which is halted by the subject at the moment the requested sensation is perceived. Static Testing In Static Mode, the thermal tiles are set to a predetermined temperature configuration and the thermodes will be held at that temperature till the experiment end. Dynamic Testing In Dynamic Mode, the tiles will be ramped up/down to a user defined temperature configuration and be held at that temperature for the duration of the experiment at which point the tiles will be ramped back to a reference adaptation temperature. Both the ramp rate and the experiment duration are defined by the user. 1.2 Installation and Setup 1. Make sure that the TG controller modules are turned off. 2. Connect the ULinx Serial Connector to the USB port on the computer. 3. Check the water level within the cooling unit and ensure that no bubbles are present within the tubing. 4. Plug the cooling unit into the power outlet and check to ensure that water is circulating within the unit. 5. Connect the controller modules to a power outlet. 65

76 6. Turn on all three of the controller modules (switch is located at the back of each controller box) 1.3 Operation The user interface is designed such that at all times, the experimenter and the subject have different displays. This allows the experimenter to collect feedback data from the subject without biasing the results. In the following pages, unless specified, the user interface displays will refer to those seen by the experimenter. In majority of the test cases, the subject is shown a blank screen alone. The TG Main Screen that is illustrated below is displayed each time you enter the Labview program. 1. Navigate to folder labeled Thermal Grill Code located on the desktop and open Grill-Final Version.vi to start the Labview program. 2. A Front Panel Labview screen displaying the TG User Interface pops up. To access the back panel or System Block Diagram press Ctrl+e. This shortcut allows you to easily switch between the front panel and block diagram screens. 3. Click on the arrow on the top right hand corner of the Labview menu (as indicated below) to start Labview. 4. Click the Start Program button to activate the Thermal Grill program. 66

77 5. The green light besides COMM PORT should light up to indicate that there is no communication failure between the TG and the computer. WARNING: If the light is does not turn on, stop the program by clicking on the red stop sign in the Labview menu (as indicated below). Unplug the USB series connector and replug it. Repeat step 6. This would automatically restore the connection with the Labview Program. 6. Peltier Status indicates which tiles are being actively controlled by the grill. To deactivate a tile, press down on its corresponding switch on the screen. 67

78 1.4 Running an Experiment Static Testing Mode Click on the Static Testing button on the main screen of the user interface to enter this mode. The following screen will become visible to the experimenter. Actual Temperature indicates the current temperature of each of the grill tiles as recorded via the tile s embedded thermistor. Real time graphical feedback of the tile temperature is also displayed on the screen Set Temperature indicates the set point temperature of each tile as defined by the experimenter. Preset Patterns easy access grill set point patterns that the experimenter can define by clicking down on their corresponding switches. The experimenter is also given the option to enter in his own Customized Pattern for the grill. 68

79 In static mode testing is done via two methods (a) Descriptive Response (b) Visual Analog Scale In Descriptive Response mode of feedback, the subject is asked to indicate their overall sensation at the 10sec and 30sec. A stop watch has been built into the user interface display for this purpose. 1. Select the Preset Pattern or a Customized Pattern for the grill by click down on its corresponding switch. Once you do so the values of Set Temperature should change to indicate your selection and the tiles will start ramping to reach this defined temperature. The tile temperatures can be read numerically form the Actual Temperature box or graphically on the screen display. 2. Once the tiles have reached their preset temperature configuration, ask the subject to place his/her hand on the grill. 3. Click down on the Start button in the stop watch window to begin the counting. The Elapsed Time indicates the number of seconds that have elapsed since the stop watch was started. To stop the stopwatch, click down on the Start button again. 4. To restart the stop watch simply click down on the Start button to reset and restart the timer. In Visual Analog Scale mode of feedback, the subject is requested to move a linear, mouse-driven scale, displayed on the monitor, to register their unpleasantness rating. Any left-right movement of the mouse is translated into a corresponding value on the VAS. 1. Select the Preset Pattern or a Customized Pattern for the grill by click down on its corresponding switch. Once you do so the values of Set Temperature should change to indicate your selection and the tiles will start ramping to reach this defined temperature. The tile temperatures can be read numerically form the Actual Temperature box or graphically on the screen display. 2. Click on the Patient Feedback VAS button. The following screen will pop up allowing the experimenter to specify the file name to which the subject feedback 69

80 data will be stored. Enter the necessary file name in the box labeled Patient Feedback Static and click on the button to enter testing mode. 3. The following screen will be seen by the experimenter which displays numerically and graphically the current tile temperature as well as the Pain/Unpleasantness rating as indicated by the subject. 4. The stop watch inbuilt on the screen allows the experimenter to time the experiment duration. 70

81 5. Simultaneously the following screen will be visible to the subject. The subject can provide feedback by simply click on the screen to move the pointer along the scale. All feedback will be automatically recorded and stored in the excel file defined by the experimenter in Step At the end of the experiment duration, the experimenter must simple click on Return to Static Testing to continue with the experimental protocol. 71

82 Dynamic Testing Click on the Dynamic Testing button on the interface main screen to enter this mode. The following screen will appear on the experimenter s screen Experiment Duration Ramp Rates Preset Patterns indicates the length of time that the tiles will be held at the experimenter defined grill configuration before ramping back to the adaptation temperature indicates the rate at which the tiles will ramp from the adaptation temperature of 30 C to the experimenter defined set point temperatures. All ramp rates are in C/s. easy access grill set point patterns that the experimenter can define by clicking down on their corresponding switches. The experimenter is also given the option to enter in his own Customized Pattern for the grill. In dynamic mode, testing is done via two methods (a) Descriptive Response (b) Visual Analog Scale 72

83 In Descriptive Response mode of feedback, the subject is asked to indicate their overall sensation at the 10sec and 30sec. A stop watch has been built into the user interface display for this purpose. 1. Select the Preset Pattern or a Customized Pattern for the grill by click down on its corresponding switch. Select the Experiment Duration and Ramp Rates to create a ramping profile for the grill. 2. Click the Testing button to begin the testing protocol. The following screen will pop up allowing the experimenter to specify the file name to which the subject feedback data will be stored. Enter the necessary file name in the box labeled Patient Feedback Dynamic and click on the button to enter testing mode. 3. The following screen will be seen by the experimenter which displays numerically and graphically the current tile temperature. The stop watch inbuilt on the screen allows the experimenter to time the experiment duration. The tiles will follow the ramping profile as determined in step At the end of the experiment duration, the experimenter must simple click on Return to Dynamic Testing to continue with the experimental protocol. 73

84 In Visual Analog Scale mode of feedback, the experimenter will follow the same steps as described above. Although in this case the subject will provide feedback via the VAS scale as done in Static Testing VAS mode. Threshold Testing Click on the Dynamic Testing button on the interface main screen to enter this mode. The following screen will appear on the experimenter s screen. In threshold mode, testing is done via two methods (a) Uniform Threshold Testing (b) Thermal Grill Threshold Testing In Uniform Threshold Testing mode, the tiles will be simultaneously ramped up/down to the upper/lower temperature limit of the grill. A simple mouse click by the subject will to indicate threshold limit, will stop ramping and the corresponding temperature will be recorded by the computer. 1. Select the Preset Pattern or a Customized Pattern for the grill by click down on its corresponding switch. Select the Experiment Duration and Ramp Rates to create a ramping profile for the grill. 2. Click the Testing button to begin the testing protocol. The following screen will pop up allowing the experimenter to specify the file name to which the subject feedback data will be stored. Enter the necessary file name in the box labeled Threshold Testing Uniform and click on the button to enter testing mode. 74

85 3. Ask the user to click down on the screen when the threshold limit is reached to stop ramping and return to the Dynamic Testing mode screen. 4. All feedback will be automatically recorded and stored in the excel file defined in Step 2. In Thermal Grill Threshold Testing mode, the tiles will be ramped up/down to an experimenter defined TG configuration pattern. The subject is threshold feedback by clicking on the appropriate buttons on the screen. Ramping stops once the subject clicks to indicate that their pain threshold has been reached. 1. Select the Preset Pattern or a Customized Pattern for the grill by click down on its corresponding switch. Select the Experiment Duration and Ramp Rates to create a ramping profile for the grill. 2. Click the Testing button to begin the testing protocol. The following screen will pop up allowing the experimenter to specify the file name to which the subject feedback data will be stored. Enter the necessary file name in the box labeled Threshold Testing Uniform and click on the button to enter testing mode. 3. The following screen will be visible to the subject to indicate their detection and pain thresholds. All feedback will be automatically recorded and stored in the excel file defined in Step When the subject s pain threshold limit is reached, ramping stops and the display returns to the Dynamic Testing mode. 75