Catherine S. Hubbard

Convergent validation of the Social Axioms Survey

Social axioms are generalized statement beliefs about oneself, the social and physical environment, or the spiritual world. A recently developed measure of social axioms was validated in a sample of female college students (N=182) from the USA. Five established measures were used to demonstrate convergent validity for the Social Axioms Survey (SAS). The five dimensions of the survey (Control by Fate, Reward for Application, Social Cynicism, Spirituality, and Social Flexibility) were predictably related to the established measures. In addition, a number of self-reported behaviors were also significantly correlated with the social axioms dimensions. While the USA data lend support to the validity of the SAS, validation in other cultures is needed. In addition, the emic aspects of social beliefs in individual cultures should be explored.

Corticotropin-releasing factor receptor 1 antagonist alters regional activation and effective connectivity in an emotional-arousal circuit during expectation of abdominal pain.

Alterations in corticotropin-releasing factor (CRF) signaling pathways have been implicated in irritable bowel syndrome (IBS) pathophysiology. We aimed to (1) determine the effect of the selective CRF receptor 1 antagonist (CRF1) GW876008 relative to placebo, on regional activation and effective connectivity of a stress-related emotional–arousal circuit during expectation of abdominal pain using functional magnetic resonance imaging in human subjects with a diagnosis of IBS and healthy controls (HCs), and (2) examine GW876008 effects on state–trait anxiety and hypothalamic–pituitary–adrenal (HPA) axis response. Although there were no drug-related effects on peripheral HPA activity, significant central effects were observed in brain regions associated with the stress response. Effective connectivity analysis showed drug-induced normalizations between key regions of the emotional–arousal circuit in patients. During pain expectation, orally administered GW876008 relative to placebo produced significant blood oxygen level-dependent (BOLD) signal reductions in the amygdala, hippocampus, insula, anterior cingulate, and orbitomedial prefrontal cortices across groups. Patients showed significantly greater BOLD responses in the left locus coeruleus and hypothalamus after placebo compared with HCs, and BOLD signal decreases in the left hypothalamus after drug. The inhibitory effects of GW876008 in the hypothalamus in patients were moderated by anxiety; patients having average and high levels of state anxiety showed drug-related BOLD decreases. GW876008 represents a novel tool for elucidating the neuronal mechanisms and circuitry underlying hyperactivation of CRF/CRF1 signaling and its role in IBS pathophysiology. The unique state anxiety effects observed suggest a potential pathway for therapeutic benefit of CRF1 receptor antagonism for patients with stress-sensitive disorders.

Altered Brain Structure and Function Correlate with Disease Severity and Pain Catastrophizing in Migraine Patients

Our study provides a new and comprehensive look at how migraine affects brain structure, how these changes in structure are related to functional brain networks, and how coping and disease severity influence both structure and functional networks. Specifically, we demonstrate concomitant functional and structural brain changes related to pain catastrophizing and disease severity in migraine patients. Abstract Cover Figure Migraine patients (Pts) show widespread structural and functional brain changes that are associated with symptoms and increased pain catastrophizing A, Migraine patients showed (i) increased gray matter volume (GMV) in the left (L) hippocampus and (ii) decreased cortical thickness in the L anterior midcingulate cortex (aMCC) compared to healthy control subjects. B, Pain catastrophizing correlated with GMV reductions in the (i) L primary somatosensory cortex (S1) and (ii) L medial prefrontal cortex (mPFC), and cortical thinning in the (iii) L dorsolateral prefrontal cortex (DLPFC) and middle temporal gyrus (MTG) in migraine patients. C, GMV reductions correlated with (i) disease duration (ii), attack frequency, and (iii) migraine pain intensity in patients. D, Whole-brain overlay maps for migraine patients and healthy controls for the (i) L PCC, (ii) L aINS, and (iii) aMCC seed regions rendered onto inflated brains. Red represents resting-state functional connectivity for healthy controls and green represents the same maps in migraine patients. Yellow represents areas showing overlap in functional connectivity in controls and migraineurs. Images are thresholded at T = 4.5 (cluster extent = 25) for visualization purposes. The schematic illustrates the relationship between disease severity measures and pain catastrophizing and disruptions in functional connectivity between the default mode network (DMN), central executive network (CEN), and salience network (SN) in migraine patients. In patients, pain catastrophizing correlated with increased coupling between DMN and CEN nodes (PCC-DLPFC), whereas disease duration and migraine pain intensity correlated with SN-DMN network decoupling (aINS/aMCC-mPFC), and increased SN-CEN (aMCC-aINS) network coupling, respectively. To investigate the neuroanatomical and functional brain changes in migraine patients relative to healthy controls, we used a combined analytical approach including voxel- and surface-based morphometry along with resting-state functional connectivity to determine whether areas showing structural alterations in patients also showed abnormal functional connectivity. Additionally, we wanted to assess whether these structural and functional changes were associated with group differences in pain catastrophizing and migraine-related disease variables in patients. We acquired T1-weighted anatomical and functional magnetic resonance imaging scans during rest in human subjects with a diagnosis of migraine and healthy controls. Structural analyses revealed greater left hippocampal gray matter volume and reduced cortical thickness in the left anterior midcingulate in patients compared with controls. We also observed negative associations between pain catastrophizing and migraine disease variables and gray matter in areas implicated in processing the sensory, affective, and cognitive aspects of pain in patients. Functional connectivity analyses showed that migraine patients displayed disrupted connectivity between default mode, salience, cognitive, visuospatial, and sensorimotor networks, which was associated with group differences in pain catastrophizing and migraine-related disease variables in patients. Together, our findings show widespread morphological and functional brain abnormalities in migraineurs in affective, cognitive, visual, and pain-related brain areas, which are associated with increased pain catastrophizing, disease chronicity, and severity of symptoms, suggesting that these structural and functional changes may be a consequence of repeated, long-term nociceptive signaling leading to increased pain sensitivity, mood disturbances, and maladaptive coping strategies to deal with unrelenting pain.

Impaired Emotional Learning and Involvement of the Corticotropin-Releasing Factor Signaling System in Patients with Irritable Bowel Syndrome

BACKGROUND & AIMS Alterations in central corticotropin-releasing factor signaling pathways have been implicated in the pathophysiology of anxiety disorders and irritable bowel syndrome (IBS). We aimed to characterize the effects of the corticotropin-releasing factor receptor 1 (CRF-R1) antagonist, GW876008, on brain and skin conductance responses during acquisition and extinction of conditioned fear to the threat of abdominal pain in subjects with IBS and healthy individuals (controls). METHODS We performed a single-center, randomized, double-blind, 3-period crossover study of 11 women with IBS (35.50 ± 12.48 years old) and 15 healthy women (controls) given a single oral dose (20 mg or 200 mg) of the CRF-R1 antagonist or placebo. Blood-oxygen level-dependent responses were analyzed using functional magnetic resonance imaging in a tertiary care setting. RESULTS Controls had greater skin conductance responses during acquisition than extinction, validating the fear-conditioning paradigm. In contrast, during extinction, women with IBS had greater skin conductance responses than controls-an effect normalized by administration of a CRF-R1 antagonist. Although the antagonist significantly reduced activity in the thalamus in patients with IBS and controls during acquisition, the drug produced greater suppression of blood-oxygen level-dependent activity in a wide range of brain regions in IBS patients during extinction, including the medial prefrontal cortex, pons, hippocampus, and anterior insula. CONCLUSIONS Although CRF signaling via CRF-R1 is involved in fear acquisition and extinction learning related to expected abdominal pain in patients with IBS and controls, this system appears to be up-regulated in patients with IBS. This up-regulation might contribute to the previously reported abnormal brain responses to expected abdominal pain.

Modulation of nociceptive and acoustic startle responses to an unpredictable threat in men and women.

&NA; The present study examined whether a moderately aversive abdominal threat would lead to greater enhancement in affect‐ and pain‐related defensive responding as indexed by the acoustic startle reflex (ASR) and nociceptive flexion reflex (NFR) in women compared to men. We also predicted sex differences in threat‐related autonomic arousal measured by skin conductance responses (SCRs) to acoustic startle and noxious sural nerve stimulation. Unpredictable threat was manipulated by alternating 30‐second safe (“no abdominal stimulation will be given”) and threat (“abdominal stimulation may occur at anytime”) periods. The experiment consisted of 2 blocks, each containing 4 safe and 4 threat periods in which the ASR or NFR was randomly probed 9–21 seconds following period onset. Unpredictable abdominal threat potentiated both ASR and NFR responses compared to periods signaling safety. SCRs to acoustic startle probes and noxious sural nerve stimulation were also significantly elevated during the threat vs safe periods. No sex differences in ASR or startle‐evoked SCRs emerged. However, nociceptive responding was moderated by sex; females showed significant increases in NFR magnitudes across both safe and threat periods compared to males. Females also showed greater threat‐potentiated SCRs to sural nerve stimulation than males. Our findings indicate that both affect‐ and pain‐related defense and arousal systems are strongly influenced by threat of an aversive, unpredictable event, a situation associated with anticipatory anxiety. Females, compared to males, showed greater nociceptive responding and pain modulation when exposed to an unpredictable threatening context, whereas affect‐driven ASR responses showed no such sex differentiation. Unpredictable threat enhanced arousal and affect‐related defensive responses across males and females, whereas nociceptive and sympathetic responses to noxious sural nerve stimulation showed sex‐dependent effects.

Behavioral, metabolic and functional brain changes in a rat model of chronic neuropathic pain: A longitudinal MRI study

Peripheral neuropathy often manifests clinically with symptoms of mechanical and cold allodynia. However, the neuroplastic changes associated with peripheral neuropathic pain and the onset and progression of allodynic symptoms remain unclear. Here, we used a chronic neuropathic pain model (spared nerve injury; SNI) to examine functional and metabolic brain changes associated with the development and maintenance of mechanical and cold hypersensitivity, the latter which we assessed both behaviorally and during a novel acetone application paradigm using functional MRI (fMRI). Female Sprague-Dawley rats underwent SNI (n=7) or sham (n=5) surgery to the left hindpaw. Rats were anesthetized and scanned using a 7 T MRI scanner 1 week prior to (pre-injury) and 4 (early/subchronic) and 20 weeks (late/chronic) post-injury. Functional scans were acquired during acetone application to the left hindpaw. (1)H magnetic resonance spectroscopy was also performed to assess SNI-induced metabolic changes in the anterior cingulate cortex (ACC) pre- and 4 weeks post-injury. Mechanical and cold sensitivity, as well as anxiety-like behaviors, were assessed 2 weeks pre-injury, and 2, 5, 9, 14, and 19 weeks post-injury. Stimulus-evoked brain responses (acetone application to the left hindpaw) were analyzed across the pre- and post-injury time points. In response to acetone application during fMRI, SNI rats showed widespread and functionally diverse changes within pain-related brain regions including somatosensory and cingulate cortices and subcortically within the thalamus and the periaqueductal gray. These functional brain changes temporally coincided with early and sustained increases in both mechanical and cold sensitivity. SNI rats also showed increased glutamate within the ACC that correlated with behavioral measures of cold hypersensitivity. Together, our findings suggest that extensive functional reorganization within pain-related brain regions may underlie the development and chronification of allodynic-like behaviors.

Gating of sensory information differs in patients with interstitial cystitis/painful bladder syndrome.

PURPOSE Altered sensory processing in interstitial cystitis/painful bladder syndrome cases may result from a deficiency of the central nervous system to adequately filter incoming visceral afferent information. We used prepulse inhibition as an operational measure of sensorimotor gating to examine early pre-attentive stages of information processing in females with interstitial cystitis/painful bladder syndrome and healthy controls. MATERIALS AND METHODS We assessed prepulse inhibition in 14 female patients with interstitial cystitis/painful bladder syndrome and 17 healthy controls at 60 and 120-millisecond prepulse-to-startle stimulus intervals. We evaluated group differences in prepulse inhibition, and relationships between prepulse inhibition, neuroticism and acute stress ratings. RESULTS Patients showed significantly decreased prepulse inhibition at 60 and 120-millisecond prepulse intervals. The prepulse inhibition deficit was related to acute stress ratings in the patients. However, increased neuroticism appeared to mitigate the prepulse inhibition deficit in those with interstitial cystitis/painful bladder syndrome, possibly reflecting greater vigilance. CONCLUSIONS Compared to healthy controls, female patients with interstitial cystitis/painful bladder syndrome had decreased ability to adequately filter incoming information and perform appropriate sensorimotor gating. These results suggest that a possible mechanism for altered interoceptive information processing in interstitial cystitis/painful bladder syndrome cases may be a general deficit in filtering mechanisms due to altered pre-attentive processing.

Identification of roughskin newt medullary vasotocin target neurons with a fluorescent vasotocin conjugate.

Arginine8 vasotocin (AVT), a neurohypophyseal peptide in nonmammalian vertebrates, plays a key role in the regulation of social behaviors related to reproduction. In male roughskin newts (Taricha granulosa), AVT is an important facilitator of several reproductive behaviors, including courtship clasping of females. Although AVT is known to act in certain brain regions and AVT receptors have been localized to some extent, specific target neurons for this peptide have not been identified in any species. Internalization of a receptor‐specific conjugate of AVT and the fluorescent dye Oregon green was used to identify AVT target cells in the medulla of male roughskin newts. Medullary neurons are of interest because they appear to mediate facilitation of clasping by AVT. Direct application of AVT‐Oregon green to the fourth ventricular surface of the medulla in vivo resulted in conjugate internalization by a widespread population of medullary neurons, particularly in the medial reticular formation and nuclei of cranial nerves V, VII, VIII, IX, and X. Some fourth‐ventricle ependymal cells were also labeled. Reticulospinal neurons, which play an important role in clasping, were identified by retrograde labeling with tetramethylrhodamine dextran amine. AVT‐Oregon green was internalized by 72% of these neurons. These results show that AVT can directly affect a very large and diverse medullary neuronal population, which may underlie the peptides role in multiple neuroendocrinological processes, including autonomic and behavioral regulation. Selectivity of the AVT action may arise through interactions between AVT and steroids such as corticosterone. J. Comp. Neurol. 491:381–389, 2005.

Increased attentional network functioning related to symptom severity measures in females with irritable bowel syndrome.

Increased attention to gastrointestinal (GI) symptoms and disease‐specific contexts may play an important role in the enhanced perception of visceral stimuli frequently reported in patients with irritable bowel syndrome (IBS). In this study, we test the hypothesis that altered attentional mechanisms underlie central pain amplification in IBS.

Altered cognition-related brain activity and interactions with acute pain in migraine

Little is known about the effect of migraine on neural cognitive networks. However, cognitive dysfunction is increasingly being recognized as a comorbidity of chronic pain. Pain appears to affect cognitive ability and the function of cognitive networks over time, and decrements in cognitive function can exacerbate affective and sensory components of pain. We investigated differences in cognitive processing and pain–cognition interactions between 14 migraine patients and 14 matched healthy controls using an fMRI block-design with two levels of task difficulty and concurrent heat (painful and not painful) stimuli. Across groups, cognitive networks were recruited in response to a difficult cognitive task, and a pain–task interaction was found in the right (contralateral to pain stimulus) posterior insula (pINS), such that activity was modulated by decreasing the thermal pain stimulus or by engaging the difficult cognitive task. Migraine patients had less task-related deactivation within the left dorsolateral prefrontal cortex (DLPFC) and left dorsal anterior midcingulate cortex (aMCC) compared to controls. These regions have been reported to have decreased cortical thickness and cognitive-related deactivation within other pain populations, and are also associated with pain regulation, suggesting that the current findings may reflect altered cognitive function and top-down regulation of pain. During pain conditions, patients had decreased task-related activity, but more widespread task-related reductions in pain-related activity, compared to controls, suggesting cognitive resources may be diverted from task-related to pain-reduction-related processes in migraine. Overall, these findings suggest that migraine is associated with altered cognitive-related neural activity, which may reflect altered pain regulatory processes as well as broader functional restructuring.