Jason G. Craggs

Placebo analgesia is accompanied by large reductions in pain-related brain activity in irritable bowel syndrome patients

Abstract Previous experiments found that placebos produced small decreases in neural activity of pain‐related areas of the brain, yet decreases were only statistically significant after termination of stimuli and in proximity to when subjects rated them. These changes could reflect report bias rather than analgesia. This functional magnetic resonance imaging (fMRI) study examined whether placebo analgesia is accompanied by reductions in neural activity in pain‐related areas of the brain during the time of stimulation. Brain activity of irritable bowel syndrome patients was measured in response to rectal distension by a balloon barostat. Large reductions in pain and in brain activation within pain‐related regions (thalamus, somatosensory cortices, insula, and anterior cingulate cortex) occurred during the placebo condition. Results indicate that decreases in activity were related to placebo suggestion and a second factor (habituation/attention/conditioning). Although many factors influence placebo analgesia, it is accompanied by reduction in pain processing within the brain in clinically relevant conditions.

Brain Activity Related to Temporal Summation of C-fiber Evoked Pain

Abstract 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 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).

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 (≥0.33Hz) 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 11 healthy volunteers, the present study was designed to compare brain responses associated with TSSP across these healthy participants and 13 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 0.33Hz and 0.17Hz to the right foot. Stimulus intensities were adjusted to each individuals heat sensitivity to achieve comparable TSSP‐ratings of moderate pain in all subjects. Experimental pain ratings showed robust TSSP during 0.33Hz but not 0.17Hz 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.

Functional brain interactions that serve cognitive-affective processing during pain and placebo analgesia

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 dimensions 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 inter-regional 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, inter-regional relationships were dynamic and the network models varied across hemispheres 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 inter-regional 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.

Sleep and affect in older adults: using multilevel modeling to examine daily associations

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.

Time-varied characteristics of acupuncture effects in fMRI studies.

When studying the neural responses to acupuncture with a block‐designed paradigm, its temporal dynamics predicted by the general linear model (GLM) conforms to typical “on‐off” variations during a limited period of the experiment manipulation. Despite a lack of direct evidence associating its psychophysiological response, numerous clinical reports suggest that acupuncture can provide pain relief beyond a needling session. Therefore, a typical GLM analysis may be insensitive or inappropriate for identifying altered neural responses resulting from acupuncture. We developed a new approach to investigate the dynamics underlying sustained effects of acupuncture. Specifically, we designed two separate models to evaluate the baseline activities (prior to stimulation) and neural activities in sequential epochs, using three block‐designed functional runs: acupuncture at acupoint ST36, nonmeridian point (NMP) stimulation, and a visual task. We found that the activity patterns during rest were associated with the stimulus types and that the resting activities might be even higher than that of stimulation phases. Such effects of the elevated activity during rest may reduce or eliminate the activity during stimulus conditions or even reverse the sign of brain activation using conventional GLM analysis. Moreover, such sustained responses, followed by acupuncture at ST36 and NMP, exhibited distinct patterns in wide brain structures, particularly in the limbic system and brainstem. These findings may pose great implications for the design and interpretation of a range of acupuncture neuroimaging studies. Hum Brain Mapp, 2009.

Gray Matter Volumes of Pain-Related Brain Areas Are Decreased in Fibromyalgia Syndrome

UNLABELLED Fibromyalgia (FM) is a chronic, widespread musculoskeletal pain disorder that is very prevalent in the general population (approximately 5%). Accumulating evidence suggests that FM is associated with central pain processing abnormalities, ie, 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 3 of these brain regions, including the anterior and mid-cingulate, as well as mid-insular cortices. Importantly, FM patients demonstrated neither 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. PERSPECTIVE Increasing evidence supports the association of chronic pain with accelerated gray matter atrophy in pain disorders like low back pain, IBS, and FM syndrome. However, cause-effect relationships between chronic pain and decreased gray matter volumes have not been established yet and will require future prospective studies.

The dynamic mechanisms of placebo induced analgesia: Evidence of sustained and transient regional involvement

Abstract Previously, we demonstrated that placebo analgesia (PA) accompanies reductions in neural activity during painful stimulation. This study investigated areas of the brain where the neural activity was 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 processes. Identifying brain regions associated with pain‐modulation with different temporal profiles is consistent with the multidimensionality of PA and highlights the need for continued investigation of this construct.

Abnormal resting state functional connectivity in patients with chronic fatigue syndrome: an arterial spin-labeling fMRI study ☆

BACKGROUND Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder characterized by severe fatigue and neurocognitive dysfunction. Recent work from our laboratory and others utilizing arterial spin labeling functional magnetic resonance imaging (ASL) indicated that ME/CFS patients have lower resting state regional cerebral blood flow (rCBF) in several brain areas associated with memory, cognitive, affective, and motor function. This hypoperfusion may underlie ME/CFS pathogenesis and may result in alterations of functional relationships between brain regions. The current report used ASL to compare functional connectivity of regions implicated in ME/CFS between patients and healthy controls (HC). METHODS Participants were 17 ME/CFS patients (Mage=48.88years, SD=12) fulfilling the 1994 CDC criteria and 17 age/sex matched HC (Mage=49.82years, SD=11.32). All participants underwent T1-weighted structural MRI as well as a 6-min pseudo-continuous arterial spin labeling (pCASL) sequence, which quantifies CBF by magnetically labeling blood as it enters the brain. Imaging data were preprocessed using SPM 12 and ASL tbx, and seed-to-voxel functional connectivity analysis was conducted using the CONN toolbox. All effects noted below are significant at p<0.05 with cluster-wise FDR correction for multiple comparisons. RESULTS ME/CFS patients demonstrated greater functional connectivity relative to HC in bilateral superior frontal gyrus, ACC, precuneus, and right angular gyrus to regions including precuneus, right postcentral gyrus, supplementary motor area, posterior cingulate gyrus, and thalamus. In contrast, HC patients had greater functional connectivity than ME/CFS in ACC, left parahippocampal gyrus, and bilateral pallidum to regions including right insula, right precentral gyrus, and hippocampus. Connectivity of the left parahippocampal gyrus correlated strongly with overall clinical fatigue of ME/CFS patients. CONCLUSION This is the first ASL based connectivity analysis of patients with ME/CFS. Our results demonstrate altered functional connectivity of several regions associated with cognitive, affective, memory, and higher cognitive function in ME/CFS patients. Connectivity to memory related brain areas (parahippocampal gyrus) was correlated with clinical fatigue ratings, providing supporting evidence that brain network abnormalities may contribute to ME/CFS pathogenesis.

Psychometric properties of the community integration questionnaire in a heterogeneous sample of adults with physical disability.

OBJECTIVE To investigate the psychometric properties of the Community Integration Questionnaire (CIQ) in a mixed sample of adults with physical disabilities. DESIGN Cross-sectional, survey study. SETTING Academic and community medical clinics, national registry, and self-referral. PARTICIPANTS Community-dwelling adults with spinal cord injury (n=146), multiple sclerosis (n=174), limb loss (n=158), or muscular dystrophy (n=273). INTERVENTIONS 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. RESULTS 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. CONCLUSIONS 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.