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Default Mode Network Functional Connectivity and Its Relationship with Pain Processing Networks via Lidocaine

Permanent Link: http://ufdc.ufl.edu/UFE0045467/00001

Material Information

Title: Default Mode Network Functional Connectivity and Its Relationship with Pain Processing Networks via Lidocaine
Physical Description: 1 online resource (46 p.)
Language: english
Creator: Letzen, Janelle E
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2013

Subjects

Subjects / Keywords: fmri -- pain
Clinical and Health Psychology -- Dissertations, Academic -- UF
Genre: Psychology thesis, M.S.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: The default mode network (DMN), a group of brain regions implicated in passive thought processes, has been proposed as a potentially informative neural marker to aid in novel treatment development. However, the effect of current analgesics on DMN functional connectivity and its temporal relationship (i.e. functional network connectivity, FNC) with pain-related networks has not been explored, and therefore such research is important to inform whether this network is in fact sensitive to analgesic effects. We examined whether DMN connectivity and FNC with pain-related networks changed under lidocaine in irritable bowel syndrome (IBS) patients. Eleven females with IBS underwent a rectal balloon distension paradigm during fMRI in two conditions (i.e., natural history and lidocaine). Results showed increased DMN connectivity with pain-related regions during natural history and increased within-network connectivity of DMN structures under lidocaine. Further, there was a significantly greater lag time between two networks involved in cognitive and affective processes of pain, comparing lidocaine to natural history. These findings suggest that 1) DMN plasticity is sensitive to analgesic effects and 2) reduced pain ratings via analgesia reflect less DMN functional connectivity with pain-related regions. Findings show potential implications of this network as an approach for understanding clinical pain management techniques.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Janelle E Letzen.
Thesis: Thesis (M.S.)--University of Florida, 2013.
Local: Adviser: Robinson, Mike E.
Local: Co-adviser: Perlstein, William Michael.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2013
System ID: UFE0045467:00001

Permanent Link: http://ufdc.ufl.edu/UFE0045467/00001

Material Information

Title: Default Mode Network Functional Connectivity and Its Relationship with Pain Processing Networks via Lidocaine
Physical Description: 1 online resource (46 p.)
Language: english
Creator: Letzen, Janelle E
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2013

Subjects

Subjects / Keywords: fmri -- pain
Clinical and Health Psychology -- Dissertations, Academic -- UF
Genre: Psychology thesis, M.S.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: The default mode network (DMN), a group of brain regions implicated in passive thought processes, has been proposed as a potentially informative neural marker to aid in novel treatment development. However, the effect of current analgesics on DMN functional connectivity and its temporal relationship (i.e. functional network connectivity, FNC) with pain-related networks has not been explored, and therefore such research is important to inform whether this network is in fact sensitive to analgesic effects. We examined whether DMN connectivity and FNC with pain-related networks changed under lidocaine in irritable bowel syndrome (IBS) patients. Eleven females with IBS underwent a rectal balloon distension paradigm during fMRI in two conditions (i.e., natural history and lidocaine). Results showed increased DMN connectivity with pain-related regions during natural history and increased within-network connectivity of DMN structures under lidocaine. Further, there was a significantly greater lag time between two networks involved in cognitive and affective processes of pain, comparing lidocaine to natural history. These findings suggest that 1) DMN plasticity is sensitive to analgesic effects and 2) reduced pain ratings via analgesia reflect less DMN functional connectivity with pain-related regions. Findings show potential implications of this network as an approach for understanding clinical pain management techniques.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Janelle E Letzen.
Thesis: Thesis (M.S.)--University of Florida, 2013.
Local: Adviser: Robinson, Mike E.
Local: Co-adviser: Perlstein, William Michael.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2013
System ID: UFE0045467:00001


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1 DEFAULT MODE NETWORK FUNCTIONAL CONNECTIVITY AND ITS RELATIONSHIP WITH PAIN PROCESSING NETWORKS VIA LIDOCAINE By JANELLE ELIZABETH LETZEN A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE UNIVERSITY OF FLORIDA 2013

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2 2013 Janelle Elizabeth Letzen

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3 To my amazing family for their en dless support and encouragement Les quiero y adoro como la vaca quiere al toro

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4 ACKNOWLEDGMENTS I would like to thank my mentors, Drs. Michael Robinson and William Perlstein, for their support and guidance on this project. In addition, I want to thank Dr. J ason Craggs for his guidance in writing the journal article associated with my thesis. I also want to recognize the members of my supervisory committee: Dr. Vonetta Dotson, Dr. Christina McCr a e and Dr. Stephen Boggs. Finally, I want to thank my wonderful family, friends, and lab mates

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS .................................................................................................. 4 LIST OF TABLES ............................................................................................................ 6 LIST OF FIGURES .......................................................................................................... 7 LIST OF ABBREVIATIONS ............................................................................................. 8 ABSTRACT ..................................................................................................................... 9 CHAPTER 1 INTRODUCTION .................................................................................................... 11 The Default Mode Network (DMN) .......................................................................... 11 DMN Functional Connectivity in Chronic Pain Patients ........................................... 12 Temporal Relationships between the DMN and PainRelated Networks ................ 13 The Effects of Treatment on DMN Connectivity ...................................................... 13 2 METHODS .............................................................................................................. 15 Participants ............................................................................................................. 15 Experimental Materials ........................................................................................... 16 Experi mental Procedures ........................................................................................ 17 Data Acquisition and Image PreProcessing ........................................................... 17 Independent Component Analysis .......................................................................... 19 Condition Level Analyses ....................................................................................... 19 Functional Network Connectivity ............................................................................. 20 3 RESULTS ............................................................................................................... 22 Pain Ratings ........................................................................................................... 22 LidocaineRelated Changes in DMN Connectivity .................................................. 22 Functional Network Connectivity of the Default Mode and PainRelated Networks .............................................................................................................. 23 4 DISCUSSION ......................................................................................................... 35 DMN Functional Connectivity Under Lidocaine ....................................................... 35 Functional Network Connectivity ............................................................................. 36 Strengths and Limitations ....................................................................................... 38 Conclusion .............................................................................................................. 39 LIST OF REFERENCES ............................................................................................... 41 BIOGRAPHICAL SKETCH ............................................................................................ 46

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6 LIST OF TABLES Table page 3 1 Significant differences in functionally connected regions to the DMN, based on condition ( p .05, FDR ). ........................................................................ 25 3 2 Regions comprising the Sensorimotor Network in the NH condition ( p .05, FDR ) .......................................................................................................... 26 3 3 Regions comprising the Sensorimotor Network in the RL condition ( p .05, FDR ) .......................................................................................................... 27 3 4 Regions comprising the Insular Salience Network in the NH condition ( p .05, FDR ) .......................................................................................................... 28 3 5 Regions comprising the Insular Salience Network in the RL condition ( p .05, FDR ) .......................................................................................................... 29 3 6 Regions comprising the Cognitive Control Network in the NH condition ( p .05, FDR ) ................................................................................................. 30 3 7 Regions comprising the Cognitive Control Network in the RL condition ( p .05, FDR ) ................................................................................................. 31

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7 LIST OF FIGURES Figure page 2 1 The fMRI scanning session consisted of seven 40 sec runs ............................. 21 3 1 Significant differences ( p .05, FDR .05) between the NH and RL conditions emerged in the regions functionally connected with the DMN. .......... 32 3 2 Lag times reported in the FNC analyses were calculated based on the time course, or temporal waveform, of the DMN and three pain processing networks.. ........................................................................................................... 33 3 3 The temporal relationships between the DMN and pain related neural networks (i.e. independent components) are represented above, with A B denoting that network A precedes network B.. ................................................... 34

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8 LIST OF ABBREVIATIONS CCN Cognitive Control Network DMN Default Mode Network FNC Functional Network Connectivity IBS Irritable Bowel Syndrome NH Natural History RL Rectal Lidocaine SMN Sensorimotor Network

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9 Abstract of Thesis Presented to the Graduate School of the University of Florida in Partial Fulf illment of the Requirements for the Degree of Master of Science DEFAULT MODE NETWORK FUNCTIONAL CONNECTIVITY AND ITS RELATIONSHIP WITH PAIN PROCESSING NETWORKS VIA LIDOCAINE By Janelle Elizabeth Letzen May 2013 Chair: Michael Robinson C ochair: William Perlstein Major: Psychology The default mode network (DMN), a group of brain regions implicated in passive thought processes, has been proposed as a potentially informative neural marker to aid in novel treatment development. However, the effect of current analgesics on DMN functional connectivity and its temporal relationship (i.e. functional network connectivity, FNC) with pain related networks has not been explored, and therefore such research is important to inform whether this network is in fact sensi tive to analgesic effects. We examined whether DMN connectivity and FNC with painrelated networks changed under lidocaine in irritable bowel syndrome (IBS) patients. Eleven females with IBS underwent a rectal balloon distension paradigm during fMRI in two conditions (i.e., natural history and lidocaine). Results showed increased DMN connectivity with painrelated regions during natural history and increased withinnetwork connectivity of DMN structures under lidocaine. Further, there was a significantly gr eater lag time between two networks involved in cognitive and affective processes of pain, comparing lidocaine to natural history. These findings suggest that 1) DMN plasticity is sensitive to analgesic effects and 2) reduced pain ratings via analgesia ref lect less DMN functional

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10 connectivity with painrelated regions. Findings show potential implications of this network as an approach for understanding clinical pain management techniques.

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11 CHAPTER 1 INTRODUCTION Chronic pain is a major public health concern in the US, affecting approximately 100 million adults and costing about $635 billion per year in productivity loss and healthcare expenses.2 4 To better understand mechanisms underlying the sensory, affective, and cognitive processes involved in chronic pain, research has increasingly focused on neuroimaging paradigms exploring functional connections between brain regions Alterations in functional brain connectivity have been found across a variety of chronic pain populations .9, 39, 41 Although early fMRI studies of chronic pain focused on co activated brain regions during specific tasks, such as the processing of experimental pain, recent studies have examined how activity among task negative neural networks inf luences the experience of chronic and experimental pain. One such network, the default mode network (DMN) has been hypothesized to potential ly help highlight the complexities of pain mechanisms.12 Recent reviews have also proposed the DMN as a potential marker of treatment effects for chronic pain, with implications for analgesic development .2, 36, 49 However, there is little research on how current analgesics affect neural activity in the D MN or its temporal relationship (i.e. functional network connectivity, FNC) with painrelated neural networks. The Default Mode Network (DMN) The DMN is a set of cortical regions that have greater coherence of neural activity when an individual is not acti vely engaged in a goal directed task .21 The function of the DMN has been described as underlying processes in which an individual is awake and alert, but not actively engaged in a task that necessitates attention. Such processes include self referential mental activity23 and mind wandering8. Further,

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12 because patients under anesthesia show DMN activity, it has been proposed to be a network that is representative of baseline brain activity.14 In healthy participants, common regions of the DMN include the posterior cingulate cortex (PCC), the ventral anterior cingulate cortex, and the medial prefrontal cortex (mPFC). A cross a variety of clinical populations however, studies have demonstrated altered functional connectivity of the DMN suggesting that idiosyncratic patterns of the DMN might provide information about neural mechanisms underlying pathology and treatment effects .2, 20 DMN Functional Connectivity in Chronic Pain Patients Research has shown that chronic pain is associated with abnormal connectivity patterns among DMN regions. Tagliazucchi and colleagues44 found increased connectivity of DMN structures (orbitofrontal gyrus, right and left angular gyri ) with the insular cortex in chronic back pain patients, suggestive of an interaction between persistent pain and emotional processes during rest. Increased DMN functional connectivity with painand emotionrelated brain regions have also been reported in fibromyalgia and irritable bowel syndrome patients (IBS ) .36, 45 Conversely, another study showed that chronic back pain patients had decreased functional connectivity of the DMN during deactivation in an attention task, suggestive of persistent neuroplastic changes in basal brain activity caused by chronic pain.1 Cauda and colleagues7 also found decreased DMN functional connectivity in patients with diabetic neuropathy compared to controls. None of these studies, however, have reported the temporal relationship (i.e. FNC) between the DMN and painrelated networks, which might provide some insight about the aberrant DMN connectivity shown in chronic pain patients

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13 Temporal Relationships b etween the DMN and PainRelated Networks There has been one study that reported on the FNC between the DMN and painrelated neural networks. Otti and colleagues37 showed that patients with somatoform pain disorder had two distinct painrelated networks [cingular insular (affective reactions, CIN) and sensorimotor networks (sensory discriminative processing, SMN)] and two subsystems of the DMN [anterior DMN (self referential processing and cognitive control of emotions, aDMN) and posterior DMN (memory, pDMN)]. Whi le the overall FNC pattern of these networks was not significantly different between the somatoform pain disorder and control groups the authors suggested that their results might have been affected by the use of psychotropic medications in the patients w ith somatoform pain disorder because medication has been shown to alter DMN connectivity in clinical populations. The Effects of Treatment on DMN Connectivity Although there is little known about the effect s of analgesics on DMN functional connectivity i n chronic pain patients studies across a variety of clinical populations have shown modulation of DMN connectivity as a result of medication. Patients with schizophrenia showed increases in DMN connectivity with the ventromedial prefrontal cortex while taking olanzapine, suggestive of restoration to the brains temporal characteristics .40 Additionally, patients with ADHD showed improved suppression of the DMN during an attention task under psychostimulants .38 In patients with Alzhiemers disease, increased DMN connectivity with the precuneus under memantine treatment has been shown, providing additional evidence for neuroplasticity among DMN brain regions following treatment .29

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14 Few studies have reported treatment effects on abnormal DMN activity resulting from chronic pain. Therefore, the present study examined the effects of a peripheral analgesic intra rectal lidocaine, has on DMN coherence in patients with IBS. Additionally, we examined the temporal relationship between the DMN and painrelated networks to determine whether the administr ation of lidocaine altered the FNC between these networks. Based on studies that reported the restorative effects of medication on the DMN in other clinical populations we hypothesized that : 1) following the administration of a peripheral analgesic the c oherence of DMN activity would be more consistent with that typically seen in healthy controls; 2), w e also hypothesized that the within subject design of this protocol for clinically relevant pain would allow us to identify significant changes in FNC betw een baseline (i.e., natural history ) and analgesic conditions because lidocaine was expected to decrease visceral pain and subsequently alter the FNC between the DMN and neural networks associated with pain.

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15 CHAPTER 2 METHODS The present study is a secondary data analysis from a study investigating the effects of rectal lidocaine on pain in patients with irritable bowel syndrome (IBS). Although the original study was a double blind clinical trial involving three sessions of fMRI data collection (i.e., baseline, placebo, rectal lidocaine), only two of these conditions were included in the present analyses. The current study uses a withinsubjects design to examine task negative related functional brain connectivity during two conditions in w hich participants with IBS were exposed to a clinically relevant pain protocol (i.e., rectal distention). The first is a baseline, or natural history condition (NH), during which the rectal balloon was coated with a saline gel prior to insertion. In the se cond, rectal lidocaine (RL) condition, the rectal balloon was coated with lidocaine gel prior to insertion to produce peripheral ly induced analgesia. This study was approved by the University of Florida and Gainesville Veterans Administration Institutional Review Boards and performed at the University of Florida McKnight Brain Institute in Gainesville, FL. Prior to enrollment, all participants completed an informed consent form stating that they would receive either an active analgesic (i.e. lidocaine) or a placebo agent during the treatment sessions. Participants MRI data from 11 female patients with Irritable Bowel Syndrome (IBS) were used in this study (mean age = 31.26 years, SD = 7.55 years). Ethnically, e ight participants were Caucasian, two were Afri can American, and one was Hispanic. Inclusion criteria for the study was: 1) persistent spontaneous pain for at least six months, 2) a diagnosis of IBS based on ROME II criteria with the exclusion of organic disease,27 3) no history of

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16 medical or psychological comorbidities other than those closely related to IBS, and 4) the discontinued use of pain medications, serotonin uptake inhibitors, serotonin antagonists or tricyclic antidepressants at the time of the study. All patients were required to fast 12 hours before each MRI session and self administered one Fleets enema (CB Fleet Co., Inc., Lynchberg, VA) at least two hours prior to the session, which was confirmed by the gastroenterologist who administered study materials. Experimental Materials To induce visceral pain, we used a clinically relevant rectal balloon distention paradigm .46 A visceral stimulator (Metronics, Minn., MN) delivered distensions to the recta l balloon at a rapid rate (870mL/ min) and constant pressure plateau between 10 and 55mmHg. Pr essure, volume, and compliance measures were simultaneously monitored and recorded.32, 35, 50 The balloon was a 500ml polyethylene bag secured on a rectal catheter (Zinetics Medical, Inc., Salt Lake City, UT) using unwaxed dental floss and parafilm (Americ an National Can, Greenwich, CT) to ensure a tight seal. For both conditions, the balloon was lubricated (Surgilube, E fougera and CO, Melville, NY 11747) and placed into the rectum by a gastroenterologist. The balloon was inserted 4cm from the anal sphinct er to stimulate approximately 4cm of the rectum during the inflation period. The gastroenterologist who performed study procedures was the physician with whom the majority of the patients normally consulted in the clinic. In contrast to the NH condition, w hich used a lubricating saline gel, during the RL condition, 300mg of lidocaine gel (Astra USA, Inc., Westborough, MA) was applied to the entire area of the rectum that would be distended.

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17 Experimental Procedures During each testing session, patients were greeted in the waiting room at the Gastroenterology Clinic, escorted to an examination room, and introduced to study procedures. Then, each patients response to visceral stimuli was tested using different amounts of balloon distension pressure applied in ascending order (i.e., 10, 20, 30, 40, and 50mmHg). Patients rated their pain after each stimulus using a pain rating scale of 0 to 100, where 0 represented no pain and 100 represented the most intense pain imaginable.47 Once a pain rating of 40 or ab ove was reached, the corresponding pressure was recorded for use during the fMRI scans. All patients were hyperalgesic (i.e., none were excluded). Patients completed three MRI sessions with no more than one week between each session. The first session for all patients was the NH condition, during which they were informed that treatment would not be used. In the subsequent two sessions, the RL condition was counterbalanced with a placebo condition, wherein either lidocaine gel or saline gel was administered on a double blind basis. Prior to the start of scanning, patients were informed that they would receive either lidocaine or saline gel. The patients were not given any auditory or visual clues that they were to receive a stimulus. To maintain consistency in pain sensitivity across sessions, patients were only scanned on days when their spontaneous, ongoing abdominal pain ratings were at least 30. Data Acquisition and Image PreProcessing All structural and functional MRI data were collected using a resear ch dedicated head scanner with a standard 8 channel RF headcoil (Siemens Allegra, 3.0T). Each MRI session included collection of a highresolution 3D structural image, followed by 7 functional MRI (fMRI) scans. The high resolution 3D anatomical images were acquired

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18 using a T1weighted MP RAGE protocol with the following parameters: 128 1mm axial slices; repetition time (TR) = 2000ms, echo time (TE) = 4.13ms, flip angle (FA) = 8o, matrix = 256 x 256mm, field of view (FOV) = 24cm). Functional images were acquired from a T2 gradient echo planar imaging (EPI) sequence using 33 contiguous axial slices of the whole brain parallel to the anterior commissure posterior commissure (AC PC) plane. Additional parameters included: TR/TE = 2000ms/30ms, FA = 90o, FOV = 240 x 240mm, matrix = 64 x 64; 3.75mm3 isotropic voxels with 0.4mm slice gap. T he stimulus onset of all fMRI scans was TR timelocked to the onset of scan acquisition. Each scan lasted for 44s, during which the first 24s were a rest period followed by 20s of visceral pain caused by rectal distension. Immediately after each fMRI scan, patients provided ratings of pain and unpleasantness using a verbal rating (Figure 21 ). To reduce saturation effects from an inhomogeneous B0 field, the first two volumes of each functional run were discarded at the scanner and two additional volumes were discarded during preprocessing. Image preprocessing was carried out using AFNI ( http://afni.nimh.nih.gov/afni/) and consisted of temporal concatenation of the fMRI scans for each subject, 3D motion correction (motion censor limit = 0.3mm per TR), spatial smoothing (FWHM = 4mm), slice scan time correction, and spatial normalization to a standardized MNI template. To examine the possibility that movement artifacts might have on subsequent analyses, we examined the movement parameters and found that average displacement was less than the 2mm voxel dimension (NH = 1.615mm, RL = 1.675mm). Analysis of conditionrelated effects did not reveal any si gnificant differences (NH =

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19 0.124, RL = 0.129; p > .05) in movement, suggesting that observed conditionlevel differences in activation were not due to systematic differences in head movement. Independent Component Analysis The initial network analysis for this study was done with the Group ICA of fMRI Toolbox (GIFT v1.3b; http://icatb.sourceforge.net/ ) for Matlab v7. ICA is a datadriven statistical analysis technique that yields independent components (ICs), which isolate sources of variance within the data. Each IC represents a group of brain regions with synchronized activity over a unique temporal pattern (i.e., time course) and can be conceptualized as a neural network.5 The GIFT procedure occurred in three stages, and involved 1a) reduction of data di mensionality and 1b) estimation of the optimal number of components using the MDL algorithm (22 were estimated), 2) estimation of group signal sources and reduction of mutual information among those sources, and 3) back reconstruction of grouplevel ICs to single subject level. ConditionLevel Analyses Following the ICA analysis, each participants ICs from both conditions were correlated with the DMN template provided by the GIFT toolbox to identify the IC that best represented the DMN. Once the IC representing the DMN in each condition was identified, we used NeuroElf ( http://neuroelf.net/ ) to conduct a paired samples t test to identify significant spatial differences in the ICs representing the DMN in each condition (i.e., NH and RL). Differences in spatial patterns of the DMN comparing the conditions were considered significant at p 0.01 (corrected for family wise error) with a minimum cluster size of 30 contiguous voxels.

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20 Functional Network Connectivity Although each IC represents a group of brain regions that follows a specific temporal pattern over the course of the fMRI scan (i.e., time course), correlations can exist among the time courses of different ICs. In addition to producing a spatial map of each IC, GIFT outputs each ICs time course. This output shows a waveform, which represents fluctuations in the ICs activity over time, and correlations among the ICs time courses are calculated based on the pattern of each ICs waveform. Moreover, temporal lags can be calculated to show whether ther e is a significant relationship between the onsets of the ICs waveforms.25 These temporal relationships can be assessed with the Functional Network Connectivity Toolbox (FNC; http://mialab.mrn.org/software /#fnc ), an extension of GIFT. For this study, we identified three distinct ICs related to processes in the experience of pain (i.e., sensation, affect, cognition) in addition to the DMN. These painrelated ICs were selected based on their inclusion of brain regions typically associated with each respect ive pain process. Using the FNC toolbox, we examined: 1) correlations between the ICs time courses and 2) the amount of delay between time courses (i.e., lag values) in each condition. As Jafri and colleagues25 described, we used a bandpass Butterworth filter between 0.03Hz and 0.37Hz on the ICA data, which was interpolated to detect sub TR conditionlevel differences in hemodynamic delay. All within condition pairwise combinations were computed via the maximal lagged correlation algorithm, and tested usi ng a onesample t test (p < .05). Between condition differences in FNC were examined using a twotailed pairedsamples t test (p < .05) and corrected for multiple corrections [False Discovery Rate (FDR)17 = .05].

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21 Figure 21. The fMRI scanning session consisted of seven 40 sec runs, with 20 sec of rest and 20 sec of rectal balloon distension. Pain ratings were collected at the end of each run, and participants were given 20 sec before the start of the subsequent run. An example of the first two runs is portrayed above. Rest (20s) Scan Off (20s) Rest (20s) Scan Off (20s) Run 1 Distension (20s) Rate Pain Distension (20s) Rate Pain Run 2

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22 CHAPTER 3 RESULTS Pain Ratings To examine whether the lidocaine gel resul ted in the reduction of pain, we conducted a twotailed pairedsamples t test of the patients pain ratings collected during the fMRI sessions. There was a significant difference between pain ratings in the NH (M = 47.82, SD = 13.212) compared to the RL (M = 32.55, SD = 17.489) condition [ t (10) = 2.235, p < .05]. Results confirm that rectal lidocaine significantly decreased the patients average pain ratings in response to rectal distension. LidocaineRelated Changes in DMN Connectivity Among the ICs ident ified by the GIFT toolbox, the default mode network (DMN) was readily detectable by its high correlation with the GIFT template of the DMN in both the NH and RL conditions (r = .36 and r = .40, respectively). A pairedsamples t test of the DMN spatial maps (i.e., Z score maps) revealed significant conditionlevel differences of the DMN spatial patterns (Figure 3 1 ). In comparing the NH and RL spatial maps of the DMN, significantl y different regions were included in the map (p 0.05, FDR 0.05, cluster threshold = 30 voxels). These significant differences imply more functional connectivity between the DMN and regions listed in Table 3 1. Compared to the RL condition, the spatial map of the DMN for the NH condition showed significant activity of the insula and precentral gyrus. Conversely, patients showed increased functional connectivity of the DMN with the superior temporal gyrus, middle temporal gyrus, angular gyrus, and inferior parietal lobule in the RL condition compared to NH.

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23 Functional Network Connectivity of the Default Mode and PainRelated Networks In addition to the DMN, three ICs associated with discrete dimensions of pain (i.e. sensation, affect, and cognition) were identified in each condition. Specifically, we identified ICs representing: 1) a Sensorimotor Network (SMN), 2) an Insular Salience Network (ISN), and 3) a Cognitive Control Network (CCN). We included all four networks in subsequent FNC analyses to better understand how painrelated processes potentially interact and influence the coherence of the DMN. Tables 32 through 37 list the regions contained in each IC based on condition, and each ICs time course can be seen in Figure 32 Results of the FNC analyses showed significant withinand betweencondition correlations for the four networks, demonstrating temporal relationships between these n etworks during pain processing. Figure 3 3 shows the overall pattern of the FNC within and betweencondition results. The arrows symbolize networks with significantly correlated temporal relationships, where A B represents a relationship showing that network A precedes network B by a certain amount of time. In NH, significant temporal correlations emerged between DMN and all three painrelated networks (SMN, p .001; ISN, p .001; CCN, p .001), with activity in painrelated networks preceding DMN activity (Figure 33a) Additionally, there were significant temporal relationships among the painrelated network s, so that SMN preceded ISN (p < .001) and CCN (p < .001), and ISN preceded CCN (p < .001). In the RL condition, s ignificant relationships with similar lag times to NH were found between SMN DMN (p < .001) and ISN DMN [ (p < .001) Figure 33b)] Although s imilar patterns were evident under RL, there were notable differences in the amount of temporal lag between multiple network pairs. Among painrelated networks, however, overall lag times in the RL condition were

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24 longer compared to NH, with a significant difference in the lag time for the SMN ISN relationship (p < .001). Additionally, the FNC analysis revealed that there was an overall difference in the temporal order of interactions among the networks in the RL condition compared to NH Specifically under RL, neural activity in the CCN preceded that of the DMN (p .0 3c represents the significant betweencondition differences among the networks temporal correlations. When overall lag times between conditions were directly compared, the only significant difference was between ISN CCN ( p = .007) with a significantly longer lag time for this relationship in the RL condition.

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25 Table 31 Significant differences in functionally connected regions to the DMN, based on condition ( p .05, FDR ). Condition Region Brodmann Area TAL Coordinates Peak Z score Cluster size X Y Z NH > RL Left Insula 13 47 12 6 3.64 52 Left Precentral Gyrus 43 54 7 13 2.82 7 RL > NH Right Superior Temporal Gyrus 39 42 58 27 5.66 81 Right Middle Temporal Gyrus 39 48 66 26 3.53 9 Right Angular Gyrus 39 56 63 31 4.33 12 Right Inferior Parietal Lobule 40 47 46 40 4.72 23

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26 Table 32 Regions comprising the Sensorimotor Network in the NH condition ( p .05, FDR .05) Region Brodmann Area TAL Coordinates Peak Z score Cluster size X Y Z Left Postcentral Gyrus 43 53 10 22 3.07 56 Right Postcentral Gyrus 2 39 25 39 3.06 67 43 65 16 14 3.85 34 Right Insula 13 45 15 19 2.93 156 Right Precuneus 7 7 45 51 3.20 17 19 33 71 36 3.42 24 L. Inferior Parietal Lobule 39 36 63 38 2.88 40 R. Inferior Parietal Lobule 40 39 36 51 3.09 45 Right Thalamus 12 18 7 3.28 39 Right Declive 34 58 7 3.12 15 Right Culmen 0 36 19 3.55 28 Right Caudate 20 2 28 3.04 16 Left Middle Frontal Gyrus 6 8 4 22 15 22 62 47 2.70 3.02 31 18 R. Middle Frontal Gyrus 8 15 31 44 2.97 17 Left Cingulate Gyrus 24 7 14 41 2.87 46 Right Cingulate Gyrus 32 18 14 39 3.07 23 L. Superior Temporal Gyrus 13 41 34 42 46 29 13 14 2.96 2.81 15 24 22 41 51 50 14 32 6 16 3.14 3.00 643 41 R. Superior Temporal Gyrus Right Inferior Frontal Gyrus 9 53 5 30 3.21 46 Left Paracentral Lobule 5 19 32 50 3.21 46 Left Precentral Gyrus 3 4 33 36 28 17 45 37 2.85 2.99 68 207 Right Precentral Gyrus 4 6 28 10 29 18 44 65 2.92 3.02 35 53 Left Substania Nigra 11 23 6 3.25 16 Right Cuneus 17 19 72 8 2.70 35 R. Parahippocampal Gyrus 19 27 43 1 3.07 16

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27 Table 33 Regions comprising the Sensorimotor Network in the RL condition ( p .05, FDR ) Region Brodmann Area TAL Coordinates Peak Z score Cluster size X Y Z Left Postcentral Gyrus 3 43 41 53 20 13 35 15 3.22 3.81 933 27 Right Postcentral Gyrus 2 3 40 62 22 14 31 26 3.38 4.32 925 79 Left Insula 13 42 15 17 3.17 105 Right Insula 13 48 18 19 3.44 151 Right Precuneus 7 19 25 36 41 66 43 37 3.06 3.05 40 1 9 R. Inferior Parietal Lobule 40 42 40 38 2.98 34 Left Thalamus 19 23 18 2.89 21 Left Declive 19 68 9 2.92 34 Right Declive 21 59 12 2.99 21 Right Culmen 0 34 17 3.80 29 Left Caudate 20 8 24 2.90 26 Left Middle Frontal Gyrus 6 28 16 49 2.92 24 R. Middle Frontal Gyrus 6 7 18 50 2.96 97 Left Cingulate Gyrus 24 7 11 39 3.06 21 L. Superior Temporal Gyrus 41 40 34 14 3.44 24 Left Inferior Frontal Gyrus 45 47 44 41 35 16 4 14 2.70 2.34 36 32 Left Paracentral Lobule 6 3 29 58 2.90 25 Left Middle Temporal Gyrus 39 31 67 28 2.75 19 R. Middle Temporal Gyrus 39 45 66 22 3.04 55 Left Superior Frontal Gyrus 6 8 8 55 2.81 31 R. Superior Frontal Gyrus 6 18 22 65 2.97 20

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28 Table 34 Regions comprising the Insular Salience Network in the NH condition ( p .05, FDR ) Region Brodmann Area TAL Coordinates Peak Z score Cluster size X Y Z Left Insula 13 42 17 14 3.84 85 Right Insula 13 34 7 17 3.96 746 Left Cingulate Gyrus 32 4 12 36 3.98 59 L. Superior Temporal Gyrus 22 55 46 14 3.98 18 Right Superior Temporal Gyrus 22 56 46 13 3.84 29 Right Precentral Gyrus 44 46 2 9 4.40 69 Left Postcentral Gyrus 40 58 27 23 3.92 80 Left Inferior Frontal Gyrus 44 60 7 14 4.10 645 Left Inferior Parietal Lobule 40 57 38 25 3.50 20 Right Inferior Parietal Lobule 40 58 36 24 4.00 118 R. Superior Parietal Lobule 7 15 51 61 3.94 56 Left Claustrum 34 5 8 4.27 159 Right Claustrum 32 8 3 5.45 18 R. Transverse Temporal Gyrus 41 40 20 12 4.22 39 R. Middle Temporal Gyrus 19 45 58 15 3.81 48

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29 Table 35 Regions comprising the Insular Salience Network in the RL condition ( p .05, FDR ) Region Brodmann Area TAL Coordinates Peak Z score Cluster size X Y Z Left Insula 13 38 3 13 4.25 858 Right Insula 13 40 13 3 4.39 1121 Right Cingulate Gyrus 24 3 12 31 4.24 223 L. Superior Temporal Gyrus 22 59 3 6 5.97 26 R. Superior Temporal Gyrus 13 22 39 53 61 45 44 52 52 20 9 22 4.34 3.97 3.78 20 27 29 Left Precentral Gyrus 13 48 9 13 5.23 36 Left Postcentral Gyrus 40 50 24 16 4.21 101 Right Postcentral Gyrus 43 51 12 17 4.03 116 Right Inferior Frontal Gyrus 44 52 0 16 5.15 29 Right Inferior Parietal Lobule 40 56 33 22 4.56 33 Right Precuneus 31 9 69 18 4.05 71 Right Lentiform Nucleus 31 4 1 5.02 30

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30 Table 36 Regions comprising the Cognitive Control Network in the NH condition ( p .05, FDR ) Region Brodmann Area TAL Coordinates Peak Z score Cluster size X Y Z Left Superior Frontal Gyrus 6 8 9 2 2 19 8 37 43 58 44 38 3.75 5.64 5.10 137 23 41 Right Superior Frontal Gyrus 6 9 10 15 19 29 25 46 49 52 35 27 4.38 3.87 4.07 26 29 44 Left Middle Frontal Gyrus 6 8 9 47 4 45 8 46 11 43 38 35 4.07 4.19 3.99 198 1044 35 Right Middle Frontal Gyrus 6 8 9 15 15 54 14 34 18 57 44 30 4.27 3.78 3.76 52 21 50 Left Insula 13 47 9 3 3.44 20 R Superior Temporal Gyrus 22 44 55 15 3.53 30 Left Precuneus 31 3 46 30 3.83 32 Left Inferior Frontal Gyrus 44 53 13 16 3.89 27 Left Middle Temporal Gyrus 39 48 63 25 3.94 20 Left Inferior Parietal Lobule 39 40 41 55 63 54 40 38 3.88 3.83 43 156 Left Supramarginal Gyrus 40 53 52 25 4.02 27 Right Supramarginal Gyrus 40 53 55 37 3.53 37 Right Uvula 29 71 23 4.46 44

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31 Table 37 Regions comprising the Cognitive Control Network in the RL condition ( p .05, FDR ) Region Brodmann Area TAL Coordinates Peak Z score Cluster size X Y Z Left Superior Frontal Gyrus 6 9 19 4 22 47 52 30 5.20 5.30 166 710 Right Superior Frontal Gyrus 6 10 7 23 20 46 54 55 5.26 4.88 65 45 Left Middle Frontal Gyrus 6 8 50 41 8 9 49 43 5.18 5.11 23 89 Right Middle Frontal Gyrus 6 15 13 4 2 4. 37 45 Left Precuneus 31 3 46 30 4.13 71 Left Insula 13 42 12 0 3.98 151 Left Superior Temporal Gyrus 39 47 60 30 4.04 193

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32 Figure 31. Significant differences ( p .05, FDR .05) between the NH and RL conditions emerged in the regions functionally connected with the DMN. Regions identified as significantly more connected with the DMN in NH include the insula and (orange, pictured left) p recentral gyrus (not shown), whereas the superior and m iddle temporal gy ri (blue, pictured right ), angular gyrus (not shown) and inferior parietal lobule (blue, pictured right ) were significantly more connected with the DMN in RL.

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33 Figure 32. Lag times reported in the FNC analyses were calculated based on the time course, or temporal waveform, of the DMN and three pain processing networks. Time courses from the IC s in the NH condition are shown on the left, and time courses from th e ICs in the RL condition are shown on the right.

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34 Figure 33 The temporal relationships between the DMN and painrelated neural networks (i.e. independent components) are represented above, with A B denoting that network A precedes network B. Longer lag times are shown in arrows with darker colors. The only significant condition level differences were found for the ISN CCN relationship. In the RL condition, the CCN lagged the ISN significantly more than in the NH condition ( p .05, FDR .05). All images are in radiological convention, and Z pl ane coordinates for each network are located at : SMN = 32, CCN = 38; ISN = 7 DMN = 18. 3 3a. Natural History 3 3 b Rectal Lidocaine 3 3 c RL > NH

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35 CHAPTER 4 DISCUSSION Rectal lidocaine has been shown to significantly reduce visceral pain in irritable bowel syndrome patients (IBS).48 This study examined the effects of rectal lidocaine on: 1) the coherence of the default mode network (DMN) in patients with IBS, and 2) the dynamic interactions between the DMN and painrelated networks via functional network connectivity (FNC) analysis Overall, the results showed that, compared to a natural history (NH) baseline condition, rectal lidocaine produced a significant change in the functional and spatial patterns of the DMN in patients with IBS. Additionally, although the application of rectal lidocaine did not have a significant conditionbased effect on the FNC between the DMN and painrelated networks, the analgesic significantly altered the temporal characteristics defining the synergy between two discrete painrelated networks. DMN Functional Connectivity Under Lidocaine Although the IC representing the DMN was easily identifiable in patients with IBS under both conditions, our results suggest that this network is functionally connected with a number of brain regions not typically seen in the DMN of healthy individuals without rectal lidocaine administration. Specifically, we found that the insula and precentral gyrus were incorporated into the DMN during the NH condition. Both the insula and precentral gyrus have been associated with acute and chronic pain processing in IBS patients.31 Previously described functions of the insula related to pain processing include self reflection,33 bodily arousal,19 and bodily awareness .26 Our results of greater DMN connectivity with the insula during NH compared to RL are consistent with findings comparing DMN connectivity between healthy controls and

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36 other chronic pain populations, including fibromyalgia36 and diabetic neuropathy patients.7 Napadow and colleagues36 suggested that their findings in fibromyalgia patients demonstrate an association between increased spontaneous pain in patients and increased DMN connectivity to the insula; this association supports our results of increased pain ratings during NH. Further, increased interconnection of the DMN with the insula has been suggested as demonstra ting increased cognitiveemotional components of pain processing.6 Because these areas were significantly more connected to the DMN during NH compared to RL, our results suggest that increased nociceptive pain sensitivity contributes to chronically active painrelated brain structures T hus the disruption of normal DMN connectivity may represent one possible mechanism by which pain transitions from an acute to chronic state. Following the administration of RL, we identified several regions that showed in creased funct ional connectivity within the DMN. Compared to NH, there was higher coherence among the middle temporal gyrus, angular gyrus, and inferior parietal lobule. These regions have previously been described as key nodes of the DMN among healthy indi viduals and have been associated with mental exploration4 and episodic memory retrieval .16 Thus, the increased coherence of these regions in the DMN under RL suggests that as pain sensation is lowered, somatic focus also decreases, which in turn facilitates a pattern of DMN connectivity more consistent with painfree individuals Functional Network Connectivity The results from this study also suggest that in addition to the changes in DMN connectivity, the pain relief provided by rectal lidocaine was associated with changes in the temporal characteristics, or functional network connectivity (FNC), of the DMN and other painrelated networks. In this study, w e identified three ICs representing networks

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37 associated with discrete painrelated processes. The Sensorimotor Network (SMN) contained subcortical structures including the thalamus, declive, substantia nigra, and culmen. These structures have been ass ociated with receiving sensory and nociceptive input .30, 43 The Insular Salience Network (ISN) was comprised of regions associated with determining the salience of stimuli that threaten homeostasis, including the insula,22 temporal, and somatosensory regions .34 The Cognitive Control Network (CCN) contained structures associated with attention and cognitive processing of pain and included: 1) the left superior frontal gyrus, which has been linked to self reflections in decision making13 and working memory ,15 2) the dorsolateral prefrontal cortex, which is associated with attention to pain and pain catastrophizing,18 and 3) the inferior parietal lobule, which is associated with active, cognitive evaluation of pain sensation.28 During the NH condition, patients with IBS manifested high levels of neuronal coherence among network combinations. Examination of the temporal characteristics between the DMN and the painrelated networks were consistently negatively correlated and had short lag times. Specific ally, the neural activity among the painrelated network s preceded that of the DMN and, as expected, the DMN deactivated almost instantly w hen activity in the painrelated networks increased. These results suggest that upon feeling visceral stimulation from the rectal balloon distension, neuronal resources are allocated to painrelated structures and superfluous processes (such as DMN activity) are suppressed, which is consistent with prior work showing the deactivation of the DMN during acute pain sensation.42

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38 However w hen sensory information related to chronic pain was attenuated via rectal lidocaine, there was a significant decrease in individuals behavioral pain ratings. Additionally, the FNC results revealed that the attenuated sensory input was asso ciated with changes in the temporal characteristics (i.e., longer lag times ) between painrelated network pairs. For example, the SMN ISN relationship was slower during the RL condition, suggesting longer response time between stimulus detection and determ ination of salience. Because the intensity, and thus salience, of the visceral stimulus was diminished by the rectal lidocaine, the immediate attention and decisionmaking resources were less pertinent. Interestingly, the changes in temporal relationship between the ISN CCN emerged as the only significant difference between the conditions, with rectal lidocaine showing a longer lag time between the two networks compared to natural history. This result suggests that although rectal lidocaine resulted in long er lag times among painrelated network pairs compared to the NH condition, perhaps the crucial neural mechanism underlying the reduction of behavioral pain ratings occurs in the ISN CCN relationship. Future studies are needed, however, before an assumption about causality can be made. Strengths and Limitations To the best of our knowledge, this study is the first to examine the effect of lidocaine, or any active analgesic, on DMN functional connectivity in patients with IBS. The DMN has previously been suggested as a potential neural marker of treatment efficacy in chronic pain2 and our findings demonstrate that this networks plasticity is sensitive to treatment effects. However, the dat a provide correlational rather than causational information, thus more research is needed on mechanisms behind these analgesic related DMN changes (e.g. neurotransmitters affected, influence of

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39 expectation). A second strength of the study is that it appear s to be the first to explore functional network connectivity between the DMN and painrelated networks in patients with IBS and in response to an analgesic. Limitations to the present work are important to note. First, although the block design of our study proved valuable in understanding the temporal relationships between the DMN and painrelated networks, it is possible that patterns of DMN connectivity reflect anticipatory anxiety to painful stimuli or residual pain from the prior distension block. To address whether these processes confounded patterns of DMN connectivity, future studies could examine the effects of analgesics under pure restingstate conditions. Second, our study did not use a healthy control group, but rather a within subjects desi gn. Although this design was ideal for addressing the goals of the original study for which data were collected,11 the current study would have benefitted from a mixed design to better determine the degree to which lidocaine restored healthy DMN connecti vity. Finally, because the exact function of the DMN is still unclear,10 future studies should address how treatment influences behavioral variables during fMRI data collection (such as mood and level of anxiety) and the result of thes e changes on DMN functional and functional network connectivity. Conclusion In conclusion, our results support evidence of aberrant DMN functional connectivity under increased pain intensity, and demonstrated that this network has the potential to show wit hinpatient changes in plasticity as a result of an analgesic. Additionally, analgesic administration altered the temporal relationship between the DMN and networks related to sensory, salience, and cognitive processing of pain, suggesting slowed temporal relationships between painrelated networks. However,

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40 caution is advised in assuming that the DMN could be a potential biomarker for chronic pain, because neither sensitivity nor specificity of DMN activity has been established.

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46 BIOGRAPHICAL SKETCH Janelle Letzen was born and raised in Florida Prior to her current position as a graduate student in the University of Floridas C linical and H ealth p sychology program, she attended the University of Flor ida as an undergraduate student, where she m ajor ed in Psychology and conducted research in the Developmental Cognitive Neuroscience L ab. Subsequently, she worked as a research assistant at the Childrens Hospital of Philadelphia for two years Her research at the Center for Autism Research utilized functional neuroimaging, eyetracking, and psychophysiology methodologies to examine social perception in children with Autism Spectrum Disorders. Janelles broad research interests include investigating the neural c orrelates of treatment effects i n individuals with chronic pain. She aspires to work in an academic setting, predominantly conducting neuroimaging research and teaching coursework related to clinic al neuroscience.