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1.  Effective connectivity among brain regions associated with slow temporal summation of C-fiber evoked pain in fibromyalgia patients and healthy controls 
The Journal of Pain  2012;13(4):390-400.
Temporal summation of “second pain” (TSSP) or “windup” results from the summation of C-fiber-evoked responses of dorsal-horn neurons. This phenomenon is dependent on stimulus frequency (>0.33 Hz) and relevant to central sensitization and chronic pain. Our previous neuroimaging studies characterized brain regions associated with TSSP in normal control (NC) and fibromyalgia (FM) groups. During an fMRI scan, subjects received sensitivity adjusted repetitive heat pulses at 0.33 on the right foot. FM subjects required significantly lower stimulus intensities than NC to achieve similar TSSP and no significant group differences in the pain-related brain activity were detected. In our current study, we asked whether the effective connectivity among a set of TSSP-related brain regions identified in our previous work differs amongst FM and NC groups. Structural equation modeling was used to characterize the effective connectivity amongst a-priori selected brain areas, including the thalamus, S1, S2, posterior insula, and the anterior mid-cingulate cortex (aMCC) within the left and right hemispheres. This analysis confirmed our a-priori models of effective connectivity among these regions mainly confirmed those hypothesized, yet some unpredicted connections were additionally identified (thalamus to aMCC and aMCC to S1). While the models of effective connectivity were not identical in the FM and NC groups, they were very similar. Additionally, the TSSP related effective connectivity of right and left hemisphere regions was very similar. These results provide evidence for significant overlap of the fundamental brain mechanisms that process sensory and affective information related to TSSP in NC and FM groups.
PMCID: PMC3321832  PMID: 22480771
Temporal summation; Second pain; Windup; fMRI; effective connectivity; fibromyalgia
2.  Fibromyalgia patients have reduced hippocampal volume compared with healthy controls 
Journal of Pain Research  2015;8:47-52.
Fibromyalgia patients frequently report cognitive abnormalities. As the hippocampus plays an important role in learning and memory, we determined whether individuals with fibromyalgia had smaller hippocampal volume compared with healthy control participants.
T1-weighted structural magnetic resonance imaging (MRI) scans were acquired from 40 female participants with fibromyalgia and 22 female healthy controls. The volume of the hippocampus was estimated using the software FreeSurfer. An analysis of covariance model controlling for potentially confounding factors of age, whole brain size, MRI signal quality, and Beck Depression Inventory scores were used to determine significant group differences.
Fibromyalgia participants had significantly smaller hippocampi in both left (F[1,56]=4.55, P=0.037, η2p=0.08) and right hemispheres (F[1,56]=5.89, P=0.019, η2p=0.10). No significant effect of depression was observed in either left or right hemisphere hippocampal volume (P=0.813 and P=0.811, respectively).
Potential mechanisms for reduced hippocampal volume in fibromyalgia include abnormal glutamate excitatory neurotransmission and glucocorticoid dysfunction; these factors can lead to neuronal atrophy, through excitotoxicity, and disrupt neurogenesis in the hippocampus. Hippocampal atrophy may play a role in memory and cognitive complaints among fibromyalgia patients.
PMCID: PMC4321661
hippocampus; MRI; brain atrophy; pain
3.  Functional Connectivity of the Default Mode Network and Its Association With Pain Networks in Irritable Bowel Patients Assessed via Lidocaine Treatment 
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 DMN’s internal connectivity and its temporal relationship (ie, functional network connectivity) with pain-related neural networks in chronic pain conditions is poorly understood, as is the DMN’s sensitivity to analgesic effects. The current study assessed how DMN functional connectivity and its temporal association with 3 pain-related networks changed after rectal lidocaine treatment in irritable bowel syndrome patients. Eleven females with irritable bowel syndrome underwent a rectal balloon distension paradigm during functional magnetic resonance imaging in 2 conditions: natural history (ie, baseline) 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 2 of the pain networks, those involved in cognitive and in affective pain processes, 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 DMN connectivity more similar to pain-free individuals. Findings show potential implications of this network as an approach for understanding clinical pain management techniques.
This study shows that lidocaine, a peripheral analgesic, significantly altered DMN connectivity and affected its relationship with pain-related networks. These findings suggest that the DMN, which is hypothesized to represent non-goal-oriented activity, is sensitive to analgesic effects and could be useful to understand pain treatment mechanisms.
PMCID: PMC3791210  PMID: 23743257
Default mode network; fMRI; irritable bowel syndrome; lidocaine; functional network connectivity
4.  Functional brain interactions that serve cognitive-affective processing during pain and placebo analgesia 
NeuroImage  2007;38(4):720-729.
Pain requires the integration of sensory, cognitive, and affective information. The use of placebo is a common methodological ploy in many fields, including pain. Neuroimaging studies of pain and placebo analgesia (PA) have yet to identify a mechanism of action. Because PA must result from higher-order processes, it is likely influenced by cognitive and affective dimension of the pain experience. A network of brain regions involved in these processes includes: the anterior and posterior insula (A-Ins, P-Ins), dorsal anterior cingulate cortex (DACC), dorsolateral prefrontal cortex (DLPFC), and the supplementary motor area (SMA). We used connectivity analyses to investigate the underlying mechanisms associated with placebo analgesia in a group of chronic pain patients. Structural equation models (SEM) of fMRI data evaluated the interregional connectivity of these regions across three conditions: 1) initial baseline (B1), 2) placebo (PA), and 3) placebo match (PM). SEM results of B1 data in the left hemisphere confirmed hypothesized regional relationships. However, interregional relationships were dynamic and the network models varied across hemisphere and conditions. Deviations from the B1 model in the PA and PM conditions correspond to our manipulation of expectation for pain. The dynamic changes in interregional influence across conditions are interpreted in the context of a self-reinforcing feedback loop involved in the induction and maintenance of PA. Although it is likely that placebo analgesia results partly from afferent inhibition of a nociceptive signal, the mechanisms likely involve the interaction of a cognitive-affective network with input from both hemispheres.
PMCID: PMC2100389  PMID: 17904390
5.  Temporal Summation of Second Pain: Variability in Responses to a Fixed Protocol 
Temporal summation of second pain (TSSP) is relevant for the study of central sensitization, and refers to increased pain evoked by repetitive stimuli at a constant intensity. While the literature reports on participants whose pain ratings increase with successive stimuli, response to a TSSP protocol can be variable. The aim of this study was to characterize the full range of responses to a TSSP protocol in pain-free adults.
Three hundred twelve adults received a train of brief, repetitive heat stimuli at a fixed temperature and rated the intensity of second pain after each pulse. TSSP response (Δ in pain ratings) was quantified using the most common methods in the literature, and response groups were formed: TSSP (Δ>0), no change (Δ=0), and temporal decrease in second pain (TDSP) (Δ<0). A cluster analysis was performed on the Δ values to empirically derive response groups.
Depending on how TSSP response was quantified, 61 – 72% of the sample demonstrated TSSP, 11 – 28% had no change in pain ratings, and 0 – 20% demonstrated TDSP. The cluster analysis found that the majority (59%) of participants fell in the no change cluster, 29% clustered into the TSSP group, and 12% in the TDSP cluster.
Using a fixed thermal paradigm, pain-free adults exhibit substantial variability in response to a TSSP protocol not well characterized by group-mean slopes. Studies are needed to determine TSSP response patterns in clinical samples, identify predictors of response, and determine the clinical implications of response variability.
PMCID: PMC3502719  PMID: 22899549
temporal summation of pain; wind-up; second pain; quantitative sensory testing; central sensitization
6.  Psychometric Properties of the Community Integration Questionnaire in a Heterogeneous Sample of Adults With Physical Disability 
To investigate the psychometric properties of the Community Integration Questionnaire (CIQ) in a mixed sample of adults with physical disabilities.
Cross-sectional, survey study.
Academic and community medical clinics, national registry, and self-referral.
Community-dwelling adults with spinal cord injury (n=146), multiple sclerosis (n=174), limb loss (n=158), or muscular dystrophy (n=273).
Not applicable.
Main Outcome Measures
CIQ, General Health item from the Medical Outcomes Study 36-Item Short-Form Health Survey, and Mental Health Scale from the Medical Outcomes Study 36-Item Short-Form Health Survey.
Based on the original scoring procedures, the CIQ Total scale and Home Integration subscale demonstrated acceptable internal consistency; however, reliability indices for the Social Integration and Productive Activities subscales were suboptimal. The exploratory factor analysis yielded a 4-factor solution (accounting for approximately 63% of the variance) that did not replicate the original factor structure of the CIQ. The results of the confirmatory factor analyses indicated that a modified 3-factor solution provided the best fit to the data from our samples. Using a revised scoring system based on these findings, the CIQ demonstrated improved reliability relative to the original scoring and good concurrent validity.
The results provide general support for the validity of the CIQ as a measure of participation in adults with physical disabilities. However, our results indicate that some small modifications to the original scoring system are needed to optimize its use in this patient group. Additional research is needed to refine the measurement of participation in these and other populations.
PMCID: PMC3371822  PMID: 21851927
Disabled persons; Outcome assessment (health care); Psychometrics; Quality of life; Rehabilitation
7.  Gray Matter Volumes of Pain Related Brain Areas are Decreased in Fibromyalgia Syndrome 
Fibromyalgia (FM) is a chronic widespread musculoskeletal pain disorder that is very prevalent in the general population (approx. 5%). Accumulating evidence suggests that FM is associated with central pain processing abnormalities, i.e. central sensitization. Several previous studies of chronic pain patients, including FM, have shown gray matter atrophy of brain areas associated with sensory and affective pain processing. These findings, however, have not been confirmed in all FM studies. In this study, we investigated gray matter volumes of brain areas associated with pain-related areas of FM patients identified by functional brain imaging. Using voxel-based morphometric (VBM) analysis of magnetic resonance brain images, we compared 19 pain related brain areas of 14 female FM patients and 11 healthy controls (NC). We found that FM patients had significantly less gray matter volumes than NC in three of these brain regions, including the anterior and mid-cingulate, as well as mid-insular cortices. Importantly, FM patients neither demonstrated global gray matter atrophy nor gray matter changes associated with depression, as shown in some studies. Using a more stringent analysis than other VBM studies, we provide evidence for decreased gray matter volumes in a number of pain related brain areas in FM. Although the mechanisms for these gray matter changes are presently unclear, they may contribute to some of the core features of this chronic disorder including affective disturbances and chronic widespread pain
PMCID: PMC3070837  PMID: 21146463
VBM; fibromyalgia; pain
8.  Relationship of intersession variation in negative pain-related affect and responses to thermally evoked pain 
The purpose of this study was to determine whether session specific measures of negative pain related affect would account for longitudinal variability in the ratings of the evoked thermal pain. Pain-free subjects rated pain evoked on the posterior leg using thermal stimuli of 45, 47, 49 and 51°C on three occasions, each separated by two weeks. Session specific negative pain related affect measures were collected at the first session in addition to. Ratings of pain decreased significantly with repeated testing demonstrating a systematic change in rating from the first to second sessions that ranged from a mean of 5.3 at 47°C to 9.1at 49°C. In addition, large random variation occurred across all sessions resulting in minimal detectable change ranging from 14 to 27. The least variability occurred when a mean rating of the four temperatures was used. Session specific measures of pain related affect decreased with repeated testing; however the significant between subject variability in both rating of pain and pain-related affect were not related to each other. No associations were identified between psychological measures and variability in rating of evoked pain. Future studies of the variability in ratings should consider other factors such as attentional focus.
The individual variability in thermal rating was not explained by individual variation in session specific measures of negative pain-related affect. The results of this study support the use of repeated baseline measures of thermal stimuli when feasible. When this is not possible, the variability in ratings of thermal stimuli over multiple sessions is reduced when the mean of multiple temperatures is used.
PMCID: PMC2822036  PMID: 19853524
fear; threat; challenge; quantitative sensory testing
9.  Virtual human technology: patient demographics and healthcare training factors in pain observation and treatment recommendations 
Journal of Pain Research  2010;3:241-247.
Patients’ sex, race, and age have been found to affect others’ perception of their pain. However, the influence of these characteristics on treatment recommendations from laypersons and healthcare providers is understudied.
To address this issue, 75 undergraduates and 107 healthcare trainees (HTs) used a web-based delivery system to view video clips of virtual human (VH) patients presenting with different standardized levels of pain. Subjects then rated the VHs’ pain intensity and recommended the amount of medical treatment the VHs should receive.
Results indicated that, compared with undergraduates, HTs perceived African Americans and older adults as having less pain but were more willing to recommend medical treatment for these patients than were undergraduate participants. HTs and undergraduates rated female, African American, older, and high-pain-expressing adults as having greater pain intensity than male, Caucasian, younger, and lower-pain-expressing adults. Moreover, they also recommended that female, older, and high-pain-expressing adults receive more medical treatment than male, younger, and lower-pain-expressing adults.
This study found that the characteristics of the VHs and whether the participants were undergraduates or HTs influenced the ratings of pain assessment and treatment recommendations. The findings are consistent with the previous VH literature showing that VH characteristics are important cues in the perception and treatment of pain. However, this is the first study to identify differences in pain-related decisions between individuals who are pursuing healthcare careers and those who are not. Finally, not only does this study serve as further evidence for the validity and potential of VH technology but also it confirms prior research that has shown that biases regarding patient sex, race, and age can affect pain assessment and treatment.
PMCID: PMC3033032  PMID: 21311717
pain; virtual human; race; age; gender; perception
10.  Widespread hyperalgesia in irritable bowel syndrome is dynamically maintained by tonic visceral impulse input and placebo/nocebo factors: Evidence from human psychophysics, animal models, and neuroimaging 
NeuroImage  2009;47(3):995-1001.
Irritable bowel syndrome (IBS) is a highly prevalent gastrointestinal disorder that is often accompanied by both visceral and somatic hyperalgesia (enhanced pain from colorectal and somatic stimuli). Neural mechanisms of both types of hyperalgesia have been analyzed by neuroimaging studies of IBS patients and animal analog studies of “IBS-like” rats with delayed rectal and somatic hypersensitivity. Results from these studies suggest that pains associated with both visceral and widespread secondary cutaneous hyperalgesia are dynamically maintained by tonic impulse input from the non-inflamed colon and/or rectum and by brain-to-spinal cord facilitation. Enhanced visceral and somatic pains are accompanied by enhanced pain-related brain activity in IBS patients as compared to normal control subjects; placebos can normalize both their hyperalgesia and enhanced brain activity. That pain in IBS which is likely to be at least partly maintained by peripheral impulse input from the colon/rectum is supported by results showing that local rectal–colonic anesthesia normalizes visceral and somatic hyperalgesia in IBS patients and visceral and somatic hypersensitivity in “IBS-like” rats. Yet these forms of hyperalgesia are also highly modifiable by placebo and nocebo factors (e.g., expectations of relief or distress, respectively). Our working hypothesis is that synergistic interactions occur between placebo/nocebo factors and enhanced afferent processing so as to enhance, maintain, or reduce hyperalgesia in IBS. This explanatory model may be relevant to other persistent pain conditions.
PMCID: PMC2844701  PMID: 19375508
Neuroimaging; Placebo analgesia; Irritable bowel syndrome; Hyperalgesia
11.  Sleep and affect in older adults: using multilevel modeling to examine daily associations 
Journal of sleep research  2008;17(1):42-53.
The main objective of the present study was to examine daily associations (intraindividual variability or IIV) between sleep and affect in older adults. Greater understanding of these associations is important, because both sleep and affect represent modifiable behaviors that can have a major influence on older adults’ health and well-being. We collected sleep diaries, actigraphy, and affect data concurrently for 14 days in 103 community-dwelling older adults. Multilevel modeling was used to assess the sleep–affect relationship at both the group (between-persons) and individual (within-person or IIV) levels. We hypothesized that nights characterized by better sleep would be associated with days characterized by higher positive affect and lower negative affect, and that the inverse would be true for poor sleep. Daily associations were found between affect and subjective sleep, only and were in the hypothesized direction. Specifically, nights with greater reported awake time or lower sleep quality ratings were associated with days characterized by less positive affect and more negative affect. Gender was not a significant main effect in the present study, despite previous research suggesting gender differences in the sleep–affect relationship. The fact that self-ratings of sleep emerged as the best predictors of affect may suggest that perceived sleep is a particularly important predictor. Finally, our results suggest exploration of affect as a potential intervention target in late-life insomnia is warranted.
PMCID: PMC2923492  PMID: 18275554
affect; daily variability; intraindividual variability; mood; older adults; sleep
12.  Brain Activity Associated with Slow Temporal Summation of C-fiber Evoked Pain in Fibromyalgia Patients and Healthy Controls 
Temporal summation of “second pain” (TSSP) is the result of C-fiber-evoked responses of dorsal-horn neurons, termed ‘windup’. This phenomenon is dependent on stimulus frequency (≥0.33 Hz) and relevant for central sensitization as well as chronic pain. Whereas our previous functional magnetic resonance imaging (fMRI) study characterized neural correlates of TSSP in eleven healthy volunteers, the present study was designed to compare brain responses associated with TSSP across these healthy participants and thirteen fibromyalgia (FM) patients. Volume-of-interest analysis was used to assess TSSP-related brain activation. All participants underwent fMRI-scanning during repetitive heat pulses at 0.33 Hz and 0.17 Hz to the right foot. Stimulus intensities were adjusted to each individual’s heat sensitivity to achieve comparable TSSP-ratings of moderate pain in all subjects. Experimental pain ratings showed robust TSSP during 0.33 Hz but not 0.17 Hz stimuli. When stimulus strength was adjusted to induce equivalent levels of TSSP, no differences in activation of pain-related brain regions occurred across NC and FM groups. Subsequently, the fMRI-data of both groups were combined to increase the power of our statistical comparisons. fMRI-statistical maps identified several brain regions with stimulus and frequency dependent activation consistent with TSSP, including ipsilateral and contralateral thalamus, medial thalamus, S1, bilateral S2, mid- and posterior insula, rostral and mid-anterior cingulate-cortex. However, the stimulus temperatures necessary to evoke equivalent levels of TSSP and corresponding brain activity were less in FM patients. These results suggest that enhanced neural mechanisms of TSSP in FM are reflected at all pain related brain areas, including posterior thalamus, and are not the result of selective enhancement at cortical levels.
PMCID: PMC2582560  PMID: 18367419
Temporal summation; Second pain; Windup; fMRI; Fibromyalgia
13.  The dynamic mechanisms of placebo induced analgesia: Evidence of sustained and transient regional involvement 
Pain  2008;139(3):660-669.
Previously, we demonstrated that placebo analgesia (PA) accompanies reductions in neural activity during painful stimulation. This study investigated areas of the brain where neural activity increased during PA. The literature has associated PA with two potential mechanisms of action; one sustained (e.g., engaged for the duration of PA), the other, transitory (e.g., a feedback mechanism). We propose that PA results from the engagement of two complementary pain-modulation mechanisms that are identified with fMRI data as a main-effect for condition or a time*condition interaction. The mechanism with sustained activity should activate the emotional regulation circuitry needed for memory formation of the event. The mechanism with transient activity should process cognitive and evaluative information of the stimuli in the context of the placebo suggestion to confirm the expectations set by it.
To identify regions involved with these mechanisms, we re-analyzed fMRI data from two conditions, baseline (B) and PA. Results support the presence of both mechanisms, identified as two neural-networks with different temporal characteristics. Regions with sustained activity primarily involved the temporal and parahippocampal cortices. Conversely, brain regions with transient activity included linguistic centers in the left hemisphere, and frontal regions of the right hemisphere generally associated with executive functioning. Together, these mechanisms likely engage analgesic processes and then simply monitor the system for unexpected stimuli, effectively liberating resources for other process. That brain regions associated with pain modulation have different temporal profiles is consistent with the multidimensionality of PA and highlights the need for continued investigation of this construct.
PMCID: PMC2723185  PMID: 18804916
Placebo analgesia; irritable bowel syndrome; brain imaging
14.  Brain Activity Related to Temporal Summation of C-fiber Evoked Pain 
Pain  2006;129(1-2):130-142.
Temporal summation of “second pain” (TSSP) is considered to be the result of C-fiber-evoked responses of dorsal horn neurons, termed ‘windup’. This phenomenon is dependent on stimulus frequency (≥ 0.33 Hz) and relevant for central sensitization and chronic pain. Previous brain imaging studies have only been used to characterize neural correlates of second pain but not its temporal summation. We utilized functional magnetic resonance imaging (fMRI) in healthy volunteers to measure brain responses associated with TSSP. Region of interest analysis was used to assess TSSP related brain activation. Eleven pain-free normal subjects underwent fMRI scanning during repetitive heat pulses to the right foot at 0.33 Hz and 0.17 Hz. Stimulus intensities were adjusted to each individual’s heat sensitivity to achieve comparable TSSP ratings of moderate pain in all subjects. As predicted, experimental pain ratings showed robust TSSP during 0.33 Hz but not 0.17 Hz stimuli. fMRI statistical maps identified several brain regions with stimulus and frequency dependent activation consistent with TSSP, including contralateral thalamus (THAL), S1, bilateral S2, anterior and posterior insula (INS), mid-anterior cingulate cortex (ACC), and supplemental motor areas (SMA). TSSP ratings were significantly correlated with brain activation in somatosensory areas (THAL, S1, left S2), anterior INS, and ACC. These results show that neural responses related to TSSP are evoked in somatosensory processing areas (THAL, S2), as well as in multiple areas that serve other functions related to pain, such as cognition (ACC, PFC), affect (INS, ACC, PAG), pre-motor activity (SMA, cerebellum), and pain modulation (rostral ACC).
PMCID: PMC1997296  PMID: 17156923
Temporal summation; Second pain; Windup; fMRI

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