Publications by authors named "Jennifer S Labus"

71 Publications

Dysregulation in sphingolipid signaling pathways is associated with symptoms and functional connectivity of pain processing brain regions in provoked vestibulodynia.

J Pain 2021 May 21. Epub 2021 May 21.

G. Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California, Los Angeles, 90095; Department of Obstetrics and Gynecology, David Geffen School of Medicine at the University of California, Los Angeles, 90095.

Provoked vestibulodynia (PVD) is a chronic pain disorder characterized by local hypersensitivity and severe pain with pressure localized to the vulvar vestibule. Despite decades of study, the lack of identified biomarkers has slowed the development of effective therapies. The primary aim of this study was to use metabolomics to identify novel biochemical mechanisms in vagina and blood underlying brain biomarkers and symptoms in PVD, thereby closing this knowledge gap. Using a cross-sectional case-control observational study design, untargeted and unbiased metabolomic profiling of vaginal fluid and plasma was performed in women with PVD compared to healthy controls. In women with PVD, we also obtained assessments of vulvar pain, vestibular and vaginal muscle tenderness, and 24-hour symptom intensity alongside resting-state brain functional connectivity of brain regions involved in pain processing and modulation. Compared to healthy controls, women with PVD demonstrated differences primarily in vaginal (but not plasma) concentrations of metabolites of the sphingolipid signaling pathways, suggesting localized effects in vagina and vulvar vestibule rather than systemic effects. Our findings reveal that dysregulation of sphingolipid metabolism in PVD is associated with increased vulvar pain and muscle tenderness, sexual dysfunction, and decreased functional connectivity strength in pain processing/modulatory brain regions. This data collectively suggests that alterations in sphingolipid signaling pathways are likely an important molecular biomarker in PVD that could lead to new targets for therapeutic intervention.
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http://dx.doi.org/10.1016/j.jpain.2021.04.017DOI Listing
May 2021

Effect of Exclusion Diets on Symptom Severity and the Gut Microbiota in Patients with Irritable Bowel Syndrome.

Clin Gastroenterol Hepatol 2021 May 19. Epub 2021 May 19.

G Oppenheimer Center for Neurobiology of Stress and Resilience; Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, United States,. Electronic address:

Background & Aims: Altered fecal microbiota have been reported in IBS, although studies vary which could be due to dietary effects. Many IBS patients may eliminate certain foods because of their symptoms, which in turn may alter fecal microbiota diversity and composition. This study aims were to determine if dietary patterns were associated with IBS, symptoms, and fecal microbiota differences reported in IBS.

Methods: 346 IBS participants and 170 healthy controls (HCs) completed a Diet Checklist reflecting the diet(s) consumed most frequently. An exclusion diet was defined as a diet that eliminated food components by choice. Within this group, a gluten-free, dairy-free, or low FODMAP diet was further defined as restrictive as they are often implicated to reduce symptoms. Stool samples were obtained from 171 IBS patients and 98 HCs for 16S rRNA gene sequencing and microbial composition analysis.

Results: Having IBS symptoms was associated with consuming a restrictive diet (27.17% of IBS patients vs 7.65% of HCs; OR 3.25; 95% CI 1.66-6.75; p-value 0.006). IBS participants on an exclusion or restrictive diet reported more severe IBS symptoms (p=0.042 and p=0.029 respectively). The composition of the microbiota in IBS patients varied depending on the diet consumed. IBS participants on an exclusion diet had a greater abundance of Lachnospira and a lower abundance of Eubacterium (q-values<0.05) and those on a restrictive diet had a lower abundance of Lactobacillus (q-value <0.05).

Conclusions: Restrictive diets are likely consumed more by IBS patients than HCs to reduce GI symptom severity. Dietary patterns influence the composition of fecal microbiota and may explain some of the differences between IBS and HCs.
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http://dx.doi.org/10.1016/j.cgh.2021.05.027DOI Listing
May 2021

Altered brain structural connectivity in patients with longstanding gut inflammation is correlated with psychological symptoms and disease duration.

Neuroimage Clin 2021 9;30:102613. Epub 2021 Mar 9.

G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA, United States; Vatche and Tamar Manoukian Division of Digestive Diseases at UCLA, United States; UCLA Microbiome Center, United States. Electronic address:

Objective: We aimed to identify differences in network properties of white matter microstructure between asymptomatic ulcerative colitis (UC) participants who had a history of chronic gut inflammation, healthy controls (HCs) and a disease control group without gut inflammation (irritable bowel syndrome; IBS).

Design: Diffusion weighted imaging was conducted in age and sex-matched participants with UC, IBS, and HCs (N = 74 each), together with measures of gastrointestinal and psychological symptom severity. Using streamline connectivity matrices and graph theory, we aimed to quantify group differences in brain network connectivity. Regions showing group connectivity differences were correlated with measures showing group behavioral and clinical differences.

Results: UC participants exhibited greater centrality in regions of the somatosensory network and default mode network, but lower centrality in the posterior insula and globus pallidus compared to HCs (q < 0.05). Hub analyses revealed compromised hubness of the pallidus in UC and IBS compared to HCs which was replaced by increased hubness of the postcentral sulcus. Surprisingly, few differences in network matrices between UC and IBS were identified. In UC, centrality measures in the secondary somatosensory cortex were associated with depression (q < 0.03), symptom related anxiety (q < 0.04), trait anxiety (q < 0.03), and symptom duration (q < 0.05).

Conclusion: A history of UC is associated with neuroplastic changes in several brain networks, which are associated with symptoms of depression, trait and symptom-related anxiety, as well as symptom duration. When viewed together with the results from IBS subjects, these findings suggest that chronic gut inflammation as well as abdominal pain have a lasting impact on brain network organization, which may play a role in symptoms reported by UC patients, even when gut inflammation has subsided.
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http://dx.doi.org/10.1016/j.nicl.2021.102613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050027PMC
March 2021

Association between pain sensitivity and gray matter properties in the sensorimotor network in women with irritable bowel syndrome.

Neurogastroenterol Motil 2021 04 10;33(4):e14027. Epub 2020 Nov 10.

Department of Internal Medicine & Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background: Enhanced perception of visceral stimuli is an important feature of Irritable Bowel Syndrome (IBS), but it is not known whether visceral sensitivity is associated with regional structural brain properties in IBS.

Methods: Structural brain magnetic resonance imaging data from 216 women with IBS and 138 healthy women were parcellated with FreeSurfer to define regional gray matter morphometry (volume, cortical thickness, surface area and mean curvature) in the sensorimotor network. General linear models were used to detect group differences between IBS and health. In a second set of 48 female IBS patients, pain threshold, pain intensity ratings during rectal balloon distension, and reported levels of abdominal pain and bloating were correlated with brain regions that showed differences between IBS and health in the first data set.

Key Results: Several statistically significant differences between IBS patients and healthy controls were found, mainly higher gray matter volume and cortical thickness in primary somatosensory cortex, secondary somatosensory cortex, and subcortical regions, and lesser gray matter volume, surface area and cortical thickness in posterior insula and superior frontal gyrus. Pain intensity ratings during rectal distension were associated with left primary somatosensory cortical thickness, and pain threshold was associated with right nucleus accumbens volume.

Conclusions And Inferences: Regional gray matter differences in sensorimotor network are associated with visceral sensitivity and may represent neuroplastic changes in female IBS patients.
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http://dx.doi.org/10.1111/nmo.14027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047895PMC
April 2021

Analysis of brain networks and fecal metabolites reveals brain-gut alterations in premenopausal females with irritable bowel syndrome.

Transl Psychiatry 2020 11 2;10(1):367. Epub 2020 Nov 2.

G. Oppenheimer Center for Neurobiology of Stress and Resilience, University of California, Los Angeles, Los Angeles, CA, USA.

Alterations in brain-gut-microbiome (BGM) interactions have been implicated in the pathogenesis of irritable bowel syndrome (IBS). Here, we apply a systems biology approach, leveraging neuroimaging and fecal metabolite data, to characterize BGM interactions that are driving IBS pathophysiology. Fecal samples and resting state fMRI images were obtained from 138 female subjects (99 IBS, 39 healthy controls (HCs)). Partial least-squares discriminant analysis (PLS-DA) was conducted to explore group differences, and partial correlation analysis explored significantly changed metabolites and neuroimaging data. All correlational tests were performed controlling for age, body mass index, and diet; results are reported after FDR correction, with q < 0.05 as significant. Compared to HCs, IBS showed increased connectivity of the putamen with regions of the default mode and somatosensory networks. Metabolite pathways involved in nucleic acid and amino acid metabolism differentiated the two groups. Only a subset of metabolites, primarily amino acids, were associated with IBS-specific brain changes, including tryptophan, glutamate, and histidine. Histidine was the only metabolite positively associated with both IBS-specific alterations in brain connectivity. Our findings suggest a role for several amino acid metabolites in modulating brain function in IBS. These metabolites may alter brain connectivity directly, by crossing the blood-brain-barrier, or indirectly through peripheral mechanisms. This is the first study to integrate both neuroimaging and fecal metabolite data supporting the BGM model of IBS, building the foundation for future mechanistic studies on the influence of gut microbial metabolites on brain function in IBS.
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http://dx.doi.org/10.1038/s41398-020-01071-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608552PMC
November 2020

Mindfulness-based stress reduction improves irritable bowel syndrome (IBS) symptoms via specific aspects of mindfulness.

Neurogastroenterol Motil 2020 09 7;32(9):e13828. Epub 2020 Apr 7.

G Oppenheimer Center for Neurobiology of Stress and Resilience, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.

Background: Irritable bowel syndrome (IBS) is a common and often debilitating chronic gastrointestinal disorder characterized by abdominal pain and altered bowel habits. Pharmacological treatments are often ineffective, leading to the development of a variety of behavioral interventions. Mindfulness-based stress reduction (MBSR) is one such program that has shown efficacy in reducing gastrointestinal (GI) symptoms and improving quality of life (QOL). This single-arm intervention study examines the association of clinical outcomes with changes in specific aspects of mindfulness.

Methods: Adults with IBS (53 women, 15 men) participated in an 8-week MBSR class. Primary outcomes of GI symptom severity, quality of life, and GI-specific anxiety, as well as specific aspects of mindfulness using the Five Factor Mindfulness Questionnaire (FFMQ), were assessed at baseline, post-treatment, and 6-month follow-up.

Key Results: Gastrointestinal symptom responder rate was 71%, and there was a significant pre-post treatment change for three of the five FFMQ scales. Regression analysis indicated that change in the Act with Awareness (P = .02) facet of mindfulness was the strongest predictor of GI symptom and QOL improvement.

Conclusions & Inferences: Mindfulness-based stress reduction training was associated with robust improvements in GI symptoms and associated problems in participants with IBS. Although significant increases in 3 of the 5 measured facets of mindfulness were found, regression analyses suggest that increases in the ability to retain present moment focus and act with awareness may be particularly important for improving outcomes in individuals with IBS. These results may inform the refinement of mindfulness-based protocols specifically for treatment of IBS.
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http://dx.doi.org/10.1111/nmo.13828DOI Listing
September 2020

Brain Resting-State Network Alterations Associated With Crohn's Disease.

Front Neurol 2020 18;11:48. Epub 2020 Feb 18.

IBD Clinical and Research Centre, University of Manitoba, Winnipeg, MB, Canada.

Inflammatory bowel disease (IBD) is a chronic disease that is associated with aspects of brain anatomy and activity. In this preliminary MRI study, we investigated differences in brain structure and in functional connectivity (FC) of brain regions in 35 participants with Crohn's disease (CD) and 21 healthy controls (HC). Voxel-based morphometry (VBM) analysis was performed to contrast CD and HC structural images. Region of interest (ROI) analyses were run to assess FC for resting-state network nodes. Independent component analysis (ICA) identified whole brain differences in FC associated with resting-state networks. Though no structural differences were found, ROI analyses showed increased FC between the frontoparietal (FP) network and salience network (SN), and decreased FC between nodes of the default mode network (DMN). ICA results revealed changes involving cerebellar (CER), visual (VIS), and SN components. Differences in FC associated with sex were observed for both ROI analysis and ICA. Taken together, these changes are consistent with an influence of CD on the brain and serve to direct future research hypotheses.
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http://dx.doi.org/10.3389/fneur.2020.00048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040490PMC
February 2020

Impact of early adverse life events and sex on functional brain networks in patients with urological chronic pelvic pain syndrome (UCPPS): A MAPP Research Network study.

PLoS One 2019 20;14(6):e0217610. Epub 2019 Jun 20.

G. Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA, Los Angeles, CA, United States of America.

Pain is a highly complex and individualized experience with biopsychosocial components. Neuroimaging research has shown evidence of the involvement of the central nervous system in the development and maintenance of chronic pain conditions, including urological chronic pelvic pain syndrome (UCPPS). Furthermore, a history of early adverse life events (EALs) has been shown to adversely impact symptoms throughout childhood and into adulthood. However, to date, the role of EAL's in the central processes of chronic pain have not been adequately investigated. We studied 85 patients (56 females) with UCPPS along with 86 healthy controls (HCs) who had resting-state magnetic resonance imaging scans (59 females), and data on EALs as a part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network Study. We used graph theory methods in order to investigate the impact of EALs on measures of centrality, which characterize information flow, communication, influence, and integration in a priori selected regions of interest. Patients with UCPPS exhibited lower centrality in the right anterior insula compared to HCs, a key node in the salience network. Males with UCPPS exhibited lower centrality in the right anterior insula compared the HC males. Females with UCPPS exhibited greater centrality in the right caudate nucleus and left angular gyrus compared to HC females. Males with UCPPS exhibited lower centrality in the left posterior cingulate, angular gyrus, middle temporal gyrus, and superior temporal sulcus, but greater centrality in the precuneus and anterior mid-cingulate cortex (aMCC) compared to females with UCPPS. Higher reports of EALs was associated with greater centrality in the left precuneus and left aMCC in females with UCPPS. This study provides evidence for disease and sex-related alterations in the default mode, salience, and basal ganglia networks in patients with UCPPS, which are moderated by EALs, and associated with clinical symptoms and quality of life (QoL).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217610PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586272PMC
February 2020

Evidence for an association of gut microbial Clostridia with brain functional connectivity and gastrointestinal sensorimotor function in patients with irritable bowel syndrome, based on tripartite network analysis.

Microbiome 2019 03 21;7(1):45. Epub 2019 Mar 21.

G. Oppenheimer Center for Neurobiology of Stress & Resilience, UCLA Vatche and Tamar Manoukian Division of Digestive Diseases, UCLA CHS 42-210, MC737818, 10833 Le Conte Avenue, Los Angeles, CA, 90095-7378, USA.

Background And Aims: Evidence from preclinical and clinical studies suggests that interactions among the brain, gut, and microbiota may affect the pathophysiology of irritable bowel syndrome (IBS). As disruptions in central and peripheral serotonergic signaling pathways have been found in patients with IBS, we explored the hypothesis that the abundance of serotonin-modulating microbes of the order Clostridiales is associated with functional connectivity of somatosensory brain regions and gastrointestinal (GI) sensorimotor function.

Methods: We performed a prospective study of 65 patients with IBS and 21 healthy individuals (controls) recruited from 2011 through 2013 at a secondary/tertiary care outpatient clinic in Sweden. Study participants underwent functional brain imaging, rectal balloon distension, a nutrient and lactulose challenge test, and assessment of oroanal transit time within a month. They also submitted stool samples, which were analyzed by 16S ribosomal RNA gene sequencing. A tripartite network analysis based on graph theory was used to investigate the interactions among bacteria in the order Clostridiales, connectivity of brain regions in the somatosensory network, and GI sensorimotor function.

Results: We found associations between GI sensorimotor function and gut microbes in stool samples from controls, but not in samples from IBS patients. The largest differences between controls and patients with IBS were observed in the Lachnospiraceae incertae sedis, Clostridium XIVa, and Coprococcus subnetworks. We found connectivity of subcortical (thalamus, caudate, and putamen) and cortical (primary and secondary somatosensory cortices) regions to be involved in mediating interactions among these networks.

Conclusions: In a comparison of patients with IBS and controls, we observed disruptions in the interactions between the brain, gut, and gut microbial metabolites in patients with IBS-these involve mainly subcortical but also cortical regions of brain. These disruptions may contribute to altered perception of pain in patients with IBS and may be mediated by microbial modulation of the gut serotonergic system.
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http://dx.doi.org/10.1186/s40168-019-0656-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429755PMC
March 2019

Altered gray matter volume in sensorimotor and thalamic regions associated with pain in localized provoked vulvodynia: a voxel-based morphometry study.

Pain 2019 07;160(7):1529-1540

Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress, UCLA, Los Angeles, CA, United States.

Multimodal neuroimaging studies provide support for a role of alterations in sensory processing circuits and endogenous pain modulatory systems in provoked vestibulodynia (PVD). In this study, we tested the hypotheses that PVD compared with healthy controls (HCs) would demonstrate gray matter volume (GMV) alterations in regions associated with sensorimotor, corticothalamic, and basal ganglia circuits. We also tested the replicability of previously reported gray matter increases in basal ganglia and hippocampal volumes in PVD vs HCs. In addition, disease specificity of GMV alterations were examined by comparing PVD with another chronic pain disorder. Finally, we examine whether GMV alterations are correlated with symptom measures. Structural magnetic resonance imaging was obtained in 119 premenopausal women (45 PVD, 45 HCs, and 29 irritable bowel syndrome [IBS]). A voxel-based morphometry analysis was applied to determine group differences in the hypothesized regions of interest. Compared with HCs, PVD women exhibited greater GMV in the basal ganglia, hippocampus, and sensorimotor cortices. Compared to patients with IBS, women with PVD had greater GMV in the hippocampus, and sensorimotor network, but lower GMV in the thalamus and precentral gyrus. Regional GMV alterations were associated with patient reports of pain during intercourse and muscle tenderness. The current findings provide further evidence that GMV is increased in PVD compared with HCs in several regions of the sensorimotor network and the hippocampus in patients with PVD. In addition, GMV distinct alterations in the sensorimotor network were identified between 2 pelvic pain disorders, PVD compared with IBS.
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http://dx.doi.org/10.1097/j.pain.0000000000001532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586504PMC
July 2019

Patients with sickle-cell disease exhibit greater functional connectivity and centrality in the locus coeruleus compared to anemic controls.

Neuroimage Clin 2019 22;21:101686. Epub 2019 Jan 22.

Center for Neurobiology of Stress and Resilience, Department of Medicine, Vatche and Tamar Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

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http://dx.doi.org/10.1016/j.nicl.2019.101686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356008PMC
January 2020

Altered Brain Structure and Functional Connectivity and Its Relation to Pain Perception in Girls With Irritable Bowel Syndrome.

Psychosom Med 2019 Feb/Mar;81(2):146-154

From the Pediatric Pain and Palliative Care Program (Bhatt, Zeltzer, Tsao), Department of Pediatrics at UCLA, Los Angeles, California; David Geffen School of Medicine at UCLA (Bhatt, Gupta, Labus, Zeltzer, Tsao, Tillisch), Los Angeles, California; G. Oppenheimer Family Center for Neurobiology of Stress and Resilience at UCLA (Gupta, Labus, Tillisch), Los Angeles, California; Vatche and Tamar Manoukian Division of Digestive Diseases at UCLA (Gupta, Labus, Tillisch); VA Greater Los Angeles Healthcare System (Tillisch), Los Angeles, California; and Department of Pediatrics (Shulman), Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas.

Objective: Imaging studies in adults with irritable bowel syndrome (IBS) have shown both morphological and resting state (RS) functional connectivity (FC) alterations related to cortical modulation of sensory processing. Because analogous differences have not been adequately investigated in children, this study compared gray matter volume (GMV) and RS-FC between girls with IBS and healthy controls (HC) and tested the correlation between brain metrics and laboratory-based pain thresholds (Pth).

Methods: Girls with Rome III criteria IBS (n = 32) and matched HCs (n = 26) were recruited. In a subset of patients, Pth were determined using a thermode to the forearm. Structural and RS scans were acquired. A voxel-based general linear model, adjusting for age, was applied to compare differences between groups. Seeds were selected from regions with group GMV differences for a seed-to-voxel whole brain RS-FC analysis. Significance for analyses was considered at p < .05 after controlling for false discovery rate. Significant group differences were correlated with Pth.

Results: Girls with IBS had lower GMV in the thalamus, caudate nucleus, nucleus accumbens, anterior midcingulate (aMCC), and dorsolateral prefrontal cortex. They also exhibited lower RS-FC between the aMCC and the precuneus, but greater connectivity between the caudate nucleus and precentral gyrus. Girls with IBS had higher Pth with a moderate effect size (t(22.81) = 1.63, p = .12, d = 0.64) and lower thalamic GMV bilaterally was correlated with higher Pth (left: r = -.62, p(FDR) = .008; right: r = -.51, p(FDR) = .08).

Conclusions: Girls with IBS had lower GMV in the PFC, basal ganglia, and aMCC, as well as altered FC between multiple brain networks, suggesting that structural changes related to IBS occur early in brain development. Girls with IBS also showed altered relationships between pain sensitivity and brain structure.
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http://dx.doi.org/10.1097/PSY.0000000000000655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355369PMC
April 2020

Changes in brain white matter structure are associated with urine proteins in urologic chronic pelvic pain syndrome (UCPPS): A MAPP Network study.

PLoS One 2018 5;13(12):e0206807. Epub 2018 Dec 5.

Department of Radiological Science, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, United States of America.

The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network has yielded neuroimaging and urinary biomarker findings that highlight unique alterations in brain structure and in urinary proteins related to tissue remodeling and vascular structure in patients with Urological Chronic Pelvic Pain Syndrome (UCPPS). We hypothesized that localized changes in diffusion tensor imaging (DTI) measurements might be associated with corresponding changes in urinary protein levels in UCPPS. To test this hypothesis, we created statistical parameter maps depicting the linear correlation between DTI measurements (fractional anisotropy (FA) and apparent diffusion coefficient (ADC)) and urinary protein quantification (MMP2, MMP9, NGAL, MMP9/NGAL complex, and VEGF) in 30 UCPPS patients from the MAPP Research Network, after accounting for clinical covariates. Results identified a brainstem region that showed a strong correlation between both ADC (R2 = 0.49, P<0.0001) and FA (R2 = 0.39, P = 0.0002) with urinary MMP9 levels as well as a correlation between both ADC (R2 = 0.42, P = 0.0001) and FA (R2 = 0.29, P = 0.0020) and urinary MMP9/NGAL complex. Results also identified significant correlations between FA and urinary MMP9 in white matter adjacent to sensorimotor regions (R2 = 0.30, P = 0.002; R2 = 0.36, P = 0.0005, respectively), as well as a correlation in similar sensorimotor regions when examining ADC and urinary MMP2 levels (R2 = 0.42, P<0.0001) as well as FA and urinary MMP9/NGAL complex (R2 = 0.33, P = 0.0008). A large, diffuse cluster of white matter was identified as having a strong correlation between both ADC (R2 = 0.35, P = 0.0006) and FA (R2 = 0.43, P<0.0001) with urinary NGAL levels. In contrast, no significant association between DTI measurements and VEGF was observed. Results suggest that elevated MMP9 or MMP9/NGAL in UCPPS may be related to degenerative neuronal changes in brainstem nuclei through excitotoxicity, while also facilitating synaptic plasticity in sensorimotor regions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0206807PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281196PMC
April 2019

Correlation of tryptophan metabolites with connectivity of extended central reward network in healthy subjects.

PLoS One 2018 6;13(8):e0201772. Epub 2018 Aug 6.

G. Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA Vatche and Tamar Manoukian Division of Digestive Diseases, Los Angeles, CA, United States of America.

Objective: A growing body of preclinical and clinical literature suggests that brain-gut-microbiota interactions play an important role in human health and disease, including hedonic food intake and obesity. We performed a tripartite network analysis based on graph theory to test the hypothesis that microbiota-derived fecal metabolites are associated with connectivity of key regions of the brain's extended reward network and clinical measures related to obesity.

Methods: DTI and resting state fMRI imaging was obtained from 63 healthy subjects with and without elevated body mass index (BMI) (29 males and 34 females). Subjects submitted fecal samples, completed questionnaires to assess anxiety and food addiction, and BMI was recorded.

Results: The study results demonstrate associations between fecal microbiota-derived indole metabolites (indole, indoleacetic acid, and skatole) with measures of functional and anatomical connectivity of the amygdala, nucleus accumbens, and anterior insula, in addition to BMI, food addiction scores (YFAS) and anxiety symptom scores (HAD Anxiety).

Conclusions: The findings support the hypothesis that gut microbiota-derived indole metabolites may influence hedonic food intake and obesity by acting on the extended reward network, specifically the amygdala-nucleus accumbens circuit and the amygdala-anterior insula circuit. These cross sectional, data-driven results provide valuable information for future mechanistic studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201772PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6078307PMC
January 2019

Disease-Related Microstructural Differences in the Brain in Women With Provoked Vestibulodynia.

J Pain 2018 05 31;19(5):528.e1-528.e15. Epub 2018 Jan 31.

G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA, Los Angeles, California; Vatche and Tamar Manoukian Division of Digestive Diseases at UCLA, Los Angeles, California; David Geffen School of Medicine at UCLA, Los Angeles, California. Electronic address:

Provoked vestibulodynia (PVD) is a chronic pelvic pain disorder affecting 16% of the female population. Neuroimaging studies have highlighted central abnormalities in PVD, similar to other chronic pelvic pain disorders, including brain regions involved in sensory processing and modulation of pain. The aim of the study was to determine alterations in the subvoxel, microstructural organization within tissues in PVD compared with healthy control participants (HCs) and a disease control group (irritable bowel syndrome [IBS]). Diffusion tensor imaging magnetic resonance imaging was conducted in 87 age-matched premenopausal women (29 PVD, 29 HCs, 29 IBS). Statistical parameter mapping of fractional anisotropy (FA) and mean diffusivity (MD) maps were used to identify microstructural difference in the brain specific to PVD or shared with IBS. PVD alterations in microstructural organization of the brain were predominantly observed in fibers associated with sensorimotor integration and pain processing that relay information between the thalamus, basal ganglia, sensorimotor, and insular cortex. PVD, compared with HCs, showed extensive increases in the FA of somatosensory and basal ganglia regions. In contrast, PVD and IBS subjects did not show any FA-related group differences. PVD subjects showed greater MD in the basal ganglia compared with HCs (higher MD in the internal capsule and pallidum) and IBS (higher MD in the putamen and pallidum). Increases in MD were associated with increased vaginal muscle tenderness and vulvar pain. The current findings highlight possible shared mechanisms between 2 different pelvic pain disorders, but also highlight the widespread alterations observed specifically in PVD compared with HCs.

Perspective: Alterations in microstructure in PVD were observed in fibers associated with sensorimotor integration and pain processing, which were also associated with increased vaginal muscle tenderness and vulvar pain. These alterations may be contributing to increased pain sensitivity and tenderness, highlighting the need for new therapies targeting the central nervous system.
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http://dx.doi.org/10.1016/j.jpain.2017.12.269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5927835PMC
May 2018

Sex Commonalities and Differences in Obesity-Related Alterations in Intrinsic Brain Activity and Connectivity.

Obesity (Silver Spring) 2018 02 27;26(2):340-350. Epub 2017 Dec 27.

Ingestive Behavior and Obesity Program, Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress and Resilience, Los Angeles, California, USA.

Objective: This study aimed to characterize obesity-related sex differences in the intrinsic activity and connectivity of the brain's reward networks.

Methods: Eighty-six women (n = 43) and men (n = 43) completed a 10-minute resting functional magnetic resonance imaging scan. Sex differences and commonalities in BMI-related frequency power distribution and reward seed-based connectivity were investigated by using partial least squares analysis.

Results: For whole-brain activity in both men and women, increased BMI was associated with increased slow-5 activity in the left globus pallidus (GP) and substantia nigra. In women only, increased BMI was associated with increased slow-4 activity in the right GP and bilateral putamen. For seed-based connectivity in women, increased BMI was associated with reduced slow-5 connectivity between the left GP and putamen and the emotion and cortical regulation regions, but in men, increased BMI was associated with increased connectivity with the medial frontal cortex. In both men and women, increased BMI was associated with increased slow-4 connectivity between the right GP and bilateral putamen and the emotion regulation and sensorimotor-related regions.

Conclusions: The stronger relationship between increased BMI and decreased connectivity of core reward network components with cortical and emotion regulation regions in women may be related to the greater prevalence of emotional eating. The present findings suggest the importance of personalized treatments for obesity that consider the sex of the affected individual.
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http://dx.doi.org/10.1002/oby.22060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783781PMC
February 2018

Systemic sclerosis is associated with specific alterations in gastrointestinal microbiota in two independent cohorts.

BMJ Open Gastroenterol 2017 1;4(1):e000134. Epub 2017 Apr 1.

Department of Pathology and Laboratory Medicine, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, California, USA.

Objective: To compare faecal microbial composition in patients with systemic sclerosis (SSc) from 2 independent cohorts with controls and to determine whether certain genera are associated with SSc-gastrointestinal tract (GIT) symptoms.

Design: Adult patients with SSc from the University of California, Los Angeles (UCLA) and Oslo University Hospital (OUH) and healthy controls participated in this study (1:1:1). All participants provided stool specimens for 16S rRNA sequencing. Linear discriminant analysis effect size demonstrated genera with differential expression in SSc. Differential expression analysis for sequence count data identified specific genera associated with GIT symptoms as assessed by the GIT 2.0 questionnaire.

Results: The UCLA-SSc and OUH-SSc cohorts were similar in age (52.1 and 60.5 years, respectively), disease duration (median (IQR): 6.6 (2.5-16.4) and 7.0 (1.0-19.2) years, respectively), gender distribution (88% and 71%, respectively), and GIT symptoms (mean (SD) total GIT 2.0 scores of 0.7 (0.6) and 0.6 (0.5), respectively). Principal coordinate analysis illustrated significant microbial community differences between SSc and controls (UCLA: p=0.001; OUH: p=0.002). Patients with SSc had significantly lower levels of commensal genera deemed to protect against inflammation, such as (UCLA and OUH), (UCLA), (OUH); and significantly higher levels of pathobiont genera, such as (UCLA), compared with controls. Increased abundance of was associated with less severe GIT symptoms in both cohorts.

Conclusions: The present analysis detected specific aberrations in the lower GIT microbiota of patients with SSc from 2 geographically and ethnically distinct cohorts. These findings suggest that GIT dysbiosis may be a pathological feature of the SSc disease state.
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http://dx.doi.org/10.1136/bmjgast-2017-000134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5508636PMC
April 2017

Brain signature and functional impact of centralized pain: a multidisciplinary approach to the study of chronic pelvic pain (MAPP) network study.

Pain 2017 Oct;158(10):1979-1991

aDivision of Biokinesiology and Physical Therapy, University of Southern California, Los Angeles, CA, USAbDepartment of Anesthesiology, Chronic Pain and Fatigue Research Center, University of Michigan, Ann Arbor, MI, USAcOppenheimer Center for Neurobiology of Stress, Pain and Interoception Network (PAIN), David Geffen School of Medicine at UCLA, Los Angeles, CA, USAdDepartment of Physiology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USAeDepartment of Anesthesiology, Perioperative and Pain Medicine, Division of Pain Medicine, Stanford University Medical Center, Stanford, CA, USAfDepartments of Radiology and Anesthesiology, University of Alabama, Birmingham Medical Center, Birmingham, AL, USAgDepartment of Urology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USAhDepartment of Urology, University of Southern California, Los Angeles, CA, USAiDepartment of Urology, University of Iowa, Iowa City, IA, USAjCollege of Medicine, Washington State University, Seattle, WA, USAkDepartment of Urology, Washington University, Saint Louis, MO, USAlNational Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USAmDepartment of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USAnDepartment of Urology, University of Michigan, Ann Arbor, MI, USA.

Chronic pain is often measured with a severity score that overlooks its spatial distribution across the body. This widespread pain is believed to be a marker of centralization, a central nervous system process that decouples pain perception from nociceptive input. Here, we investigated whether centralization is manifested at the level of the brain using data from 1079 participants in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network (MAPP) study. Participants with a clinical diagnosis of urological chronic pelvic pain syndrome (UCPPS) were compared to pain-free controls and patients with fibromyalgia, the prototypical centralized pain disorder. Participants completed questionnaires capturing pain severity, function, and a body map of pain. A subset (UCPPS N = 110; fibromyalgia N = 23; healthy control N = 49) underwent functional and structural magnetic resonance imaging. Patients with UCPPS reported pain ranging from localized (pelvic) to widespread (throughout the body). Patients with widespread UCPPS displayed increased brain gray matter volume and functional connectivity involving sensorimotor and insular cortices (P < 0.05 corrected). These changes translated across disease diagnoses as identical outcomes were present in patients with fibromyalgia but not pain-free controls. Widespread pain was also associated with reduced physical and mental function independent of pain severity. Brain pathology in patients with centralized pain is related to pain distribution throughout the body. These patients may benefit from interventions targeting the central nervous system.
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http://dx.doi.org/10.1097/j.pain.0000000000001001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964335PMC
October 2017

Brain Structure and Response to Emotional Stimuli as Related to Gut Microbial Profiles in Healthy Women.

Psychosom Med 2017 Oct;79(8):905-913

From the Oppenheimer Center for Neurobiology of Stress and Resilience (Tillisch, Mayer, Gupta, Gill, Labus), Departments of Medicine (Tillisch, Mayer, Gupta, Labus), Psychiatry (Mayer, Gupta), Division of Digestive Diseases, David Geffen School of Medicine at UCLA (Tillisch, Mayer, Gupta, Labus), UCLA Microbiome Center, Ahmanson-Lovelace Brain Mapping Center, UCLA (Mayer), Integrative Medicine, GLA VHA (Tillisch), UCLA Brain Research Institute (Labus), Los Angeles, CA; Danone Research (Brazeilles, Le Nevé, Derrien), Palaiseau, France; Microbiome & Human Health Innovation (van Hylckama Vlieg), Hoersholm, Denmark; and Symrise Group (Guyonnet), Clichy-la-Garenne, France.

Objective: Brain-gut-microbiota interactions may play an important role in human health and behavior. Although rodent models have demonstrated effects of the gut microbiota on emotional, nociceptive, and social behaviors, there is little translational human evidence to date. In this study, we identify brain and behavioral characteristics of healthy women clustered by gut microbiota profiles.

Methods: Forty women supplied fecal samples for 16S rRNA profiling. Microbial clusters were identified using Partitioning Around Medoids. Functional magnetic resonance imaging was acquired. Microbiota-based group differences were analyzed in response to affective images. Structural and diffusion tensor imaging provided gray matter metrics (volume, cortical thickness, mean curvature, surface area) as well as fiber density between regions. A sparse Partial Least Square-Discrimination Analysis was applied to discriminate microbiota clusters using white and gray matter metrics.

Results: Two bacterial genus-based clusters were identified, one with greater Bacteroides abundance (n = 33) and one with greater Prevotella abundance (n = 7). The Prevotella group showed less hippocampal activity viewing negative valences images. White and gray matter imaging discriminated the two clusters, with accuracy of 66.7% and 87.2%, respectively. The Prevotella cluster was associated with differences in emotional, attentional, and sensory processing regions. For gray matter, the Bacteroides cluster showed greater prominence in the cerebellum, frontal regions, and the hippocampus.

Conclusions: These results support the concept of brain-gut-microbiota interactions in healthy humans. Further examination of the interaction between gut microbes, brain, and affect in humans is needed to inform preclinical reports that microbial modulation may affect mood and behavior.
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http://dx.doi.org/10.1097/PSY.0000000000000493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089374PMC
October 2017

Surgically Induced Changes in Gut Microbiome and Hedonic Eating as Related to Weight Loss: Preliminary Findings in Obese Women Undergoing Bariatric Surgery.

Psychosom Med 2017 Oct;79(8):880-887

From the Ingestive Behavior and Obesity Program (Sanmiguel, Gupta, Ju, Stains, Coveleskie, Mayer, Labus), Oppenheimer Center for Neurobiology of Stress & Resilience; Department of Surgery (Balioukova, Chen, Dutson), Center for Obesity and Metabolic Health; UCLA Microbiome Center (Sanmiguel, Jacobs, Lagishetty, Mayer, Labus); and David Geffen School of Medicine at UCLA (Sanmiguel, Jacobs, Gupta, Ju, Stains, Lagishetty, Balioukova, Chen, Dutson, Mayer, Labus), Los Angeles, California.

Objective: Weight loss surgery results in significant changes in the anatomy, function, and intraluminal environment of the gastrointestinal tract affecting the gut microbiome. Although bariatric surgery results in sustained weight loss, decreased appetite, and hedonic eating, it is unknown whether the surgery-induced alterations in gut microbiota play a role in the observed changes in hedonic eating. We explored the following hypotheses: (1) laparoscopic sleeve gastrectomy (LSG) results in changes in gut microbial composition; (2) alterations in gut microbiota are related to weight loss; (3) alterations in gut microbiome are associated with changes in appetite and hedonic eating.

Methods: Eight obese women underwent LSG. Their body mass index, body fat mass, food intake, hunger, hedonic eating scores, and stool samples were obtained at baseline and 1-month postsurgery. 16S ribosomal RNA gene sequencing was performed on stool samples. DESeq2 changes in microbial abundance. Multilevel-sparse partial least squares discriminant analysis was applied to genus-level abundance for discriminative microbial signatures.

Results: LSG resulted in significant reductions in body mass index, food intake, and hedonic eating. A microbial signature composed of five bacterial genera discriminated between pre- and postsurgery status. Several bacterial genera were significantly associated with weight loss (Bilophila, q = 3E-05; Faecalibacterium q = 4E-05), lower appetite (Enterococcus, q = 3E-05), and reduced hedonic eating (Akkermansia, q = .037) after surgery.

Conclusions: In this preliminary analysis, changes in gut microbial abundance discriminated between pre- and postoperative status. Alterations in gut microbiome were significantly associated with weight loss and with reduced hedonic eating after surgery; however, a larger sample is needed to confirm these findings.
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http://dx.doi.org/10.1097/PSY.0000000000000494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5628115PMC
October 2017

Differences in gut microbial composition correlate with regional brain volumes in irritable bowel syndrome.

Microbiome 2017 05 1;5(1):49. Epub 2017 May 1.

Division of Digestive Diseases, David Geffen School at UCLA, Los Angeles, CA, 90095, USA.

Background: Preclinical and clinical evidence supports the concept of bidirectional brain-gut microbiome interactions. We aimed to determine if subgroups of irritable bowel syndrome (IBS) subjects can be identified based on differences in gut microbial composition, and if there are correlations between gut microbial measures and structural brain signatures in IBS.

Methods: Behavioral measures, stool samples, and structural brain images were collected from 29 adult IBS and 23 healthy control subjects (HCs). 16S ribosomal RNA (rRNA) gene sequencing was used to profile stool microbial communities, and various multivariate analysis approaches were used to quantitate microbial composition, abundance, and diversity. The metagenomic content of samples was inferred from 16S rRNA gene sequence data using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt). T1-weighted brain images were acquired on a Siemens Allegra 3T scanner, and morphological measures were computed for 165 brain regions.

Results: Using unweighted Unifrac distances with hierarchical clustering on microbial data, samples were clustered into two IBS subgroups within the IBS population (IBS1 (n = 13) and HC-like IBS (n = 16)) and HCs (n = 23) (AUROC = 0.96, sensitivity 0.95, specificity 0.67). A Random Forest classifier provided further support for the differentiation of IBS1 and HC groups. Microbes belonging to the genera Faecalibacterium, Blautia, and Bacteroides contributed to this subclassification. Clinical features distinguishing the groups included a history of early life trauma and duration of symptoms (greater in IBS1), but not self-reported bowel habits, anxiety, depression, or medication use. Gut microbial composition correlated with structural measures of brain regions including sensory- and salience-related regions, and with a history of early life trauma.

Conclusions: The results confirm previous reports of gut microbiome-based IBS subgroups and identify for the first time brain structural alterations associated with these subgroups. They provide preliminary evidence for the involvement of specific microbes and their predicted metabolites in these correlations.
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http://dx.doi.org/10.1186/s40168-017-0260-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410709PMC
May 2017

Resting-state functional connectivity predicts longitudinal pain symptom change in urologic chronic pelvic pain syndrome: a MAPP network study.

Pain 2017 06;158(6):1069-1082

aDivision of Biokinesiology and Physical Therapy, University of Southern California, Los Angeles, CA, USA bG Oppenheimer Center for Neurobiology of Stress and Resilience, Pain and Interoception Network (PAIN), David Geffen School of Medicine at UCLA, Los Angeles, CA, USA cDepartment of Anesthesiology, Chronic Pain and Fatigue Research Center, University of Michigan, Ann Arbor, MI, USA dDepartment of Anesthesiology, Perioperative and Pain Medicine, Division of Pain Medicine, Stanford University Medical Center, Stanford, CA, USA eDepartment of Physiology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA fNeuroscience Graduate Program, University of Southern California, Los Angeles, CA, USA gFunctional MRI Laboratory, University of Michigan, Ann Arbor, MI, USA hDepartment of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA iNational Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA.

Chronic pain symptoms often change over time, even in individuals who have had symptoms for years. Studying biological factors that predict trends in symptom change in chronic pain may uncover novel pathophysiological mechanisms and potential therapeutic targets. In this study, we investigated whether brain functional connectivity measures obtained from resting-state functional magnetic resonance imaging at baseline can predict longitudinal symptom change (3, 6, and 12 months after scan) in urologic chronic pelvic pain syndrome. We studied 52 individuals with urologic chronic pelvic pain syndrome (34 women, 18 men) who had baseline neuroimaging followed by symptom tracking every 2 weeks for 1 year as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study. We found that brain functional connectivity can make a significant prediction of short-term (3 month) pain reduction with 73.1% accuracy (69.2% sensitivity and 75.0% precision). In addition, we found that the brain regions with greatest contribution to the classification were preferentially aligned with the left frontoparietal network. Resting-state functional magnetic resonance imaging measures seemed to be less informative about 6- or 12-month symptom change. Our study provides the first evidence that future trends in symptom change in patients in a state of chronic pain may be linked to functional connectivity within specific brain networks.
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http://dx.doi.org/10.1097/j.pain.0000000000000886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435510PMC
June 2017

Early adverse life events are associated with altered brain network architecture in a sex- dependent manner.

Neurobiol Stress 2017 Dec 17;7:16-26. Epub 2017 Feb 17.

G. Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA, Los Angeles, CA, United States; Department of Medicine, UCLA, Los Angeles, CA, United States; Department of Psychiatry, UCLA, Los Angeles, CA, United States; UCLA Vatche and Tamar Manoukian Division of Digestive Diseases, UCLA, Los Angeles, CA, United States; UCLA Brain Research Institute, Los Angeles, CA, United States.

Introduction: Early adverse life events (EALs) increase the risk for chronic medical and psychiatric disorders by altering early neurodevelopment. The aim of this study was to examine associations between EALs and network properties of core brain regions in the emotion regulation and salience networks, and to test the influence of sex on these associations.

Methods: Resting-state functional and diffusion tensor magnetic resonance imaging were obtained in healthy individuals (61 men, 63 women). Functional and anatomical network properties of centrality and segregation were calculated for the core regions of the two networks using graph theory. Moderator analyses were applied to test hypotheses.

Results: The type of adversity experienced influences brain wiring differently, as higher EALs were associated with decreased functional and anatomical in salience and emotion regulation regions, while and EALs were associated with increased anatomical and in emotion regulation regions. Sex moderated the associations between EALs and measures of ; with decreased of salience and emotion regulation regions with increased EALs in females, and increased in salience regions with higher physical and emotional EALs in males. Increased of salience regions was associated with increased EALs in males. Centrality of the amygdala was associated with physical symptoms, and segregation of salience regions was correlated with higher somatization in men only.

Conclusions: Emotion regulation and salience regions are susceptible to topological brain restructuring associated with EALs. The male and female brains appear to be differently affected by specific types of EALs.
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http://dx.doi.org/10.1016/j.ynstr.2017.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5318542PMC
December 2017

Morphological brain measures of cortico-limbic inhibition related to resilience.

J Neurosci Res 2017 09 28;95(9):1760-1775. Epub 2016 Dec 28.

G Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA.

Resilience is the ability to adequately adapt and respond to homeostatic perturbations. Although resilience has been associated with positive health outcomes, the neuro-biological basis of resilience is poorly understood. The aim of the study was to identify associations between regional brain morphology and trait resilience with a focus on resilience-related morphological differences in brain regions involved in cortico-limbic inhibition. The relationship between resilience and measures of affect were also investigated. Forty-eight healthy subjects completed structural MRI scans. Self-reported resilience was measured using the Connor and Davidson Resilience Scale. Segmentation and regional parcellation of images was performed to yield a total of 165 regions. Gray matter volume (GMV), cortical thickness, surface area, and mean curvature were calculated for each region. Regression models were used to identify associations between morphology of regions belonging to executive control and emotional arousal brain networks and trait resilience (total and subscales) while controlling for age, sex, and total GMV. Correlations were also conducted between resilience scores and affect scores. Significant associations were found between GM changes in hypothesized brain regions (subparietal sulcus, intraparietal sulcus, amygdala, anterior mid cingulate cortex, and subgenual cingulate cortex) and resilience scores. There were significant positive correlations between resilience and positive affect and negative correlations with negative affect. Resilience was associated with brain morphology of regions involved in cognitive and affective processes related to cortico-limbic inhibition. Brain signatures associated with resilience may be a biomarker of vulnerability to disease. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jnr.24007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5512424PMC
September 2017

Sex-based differences in brain alterations across chronic pain conditions.

J Neurosci Res 2017 01;95(1-2):604-616

Oppenheimer Center for Neurobiology of Stress and Resilience, University of California, Los Angeles, Los Angeles, California.

Common brain mechanisms are thought to play a significant role across a multitude of chronic pain syndromes. In addition, there is strong evidence for the existence of sex differences in the prevalence of chronic pain and in the neurobiology of pain. Thus, it is important to consider sex when developing general principals of pain neurobiology. The goal of the current Mini-Review is to evaluate what is known about sex-specific brain alterations across multiple chronic pain populations. A total of 15 sex difference and 143 single-sex articles were identified from among 412 chronic pain neuroimaging articles. Results from sex difference studies indicate more prominent primary sensorimotor structural and functional alterations in female chronic pain patients compared with male chronic pain patients: differences in the nature and degree of insula alterations, with greater insula reactivity in male patients; differences in the degree of anterior cingulate structural alterations; and differences in emotional-arousal reactivity. Qualitative comparisons of male-specific and female-specific studies appear to be consistent with the results from sex difference studies. Given these differences, mixed-sex studies of chronic pain risk creating biased data or missing important information and single-sex studies have limited generalizability. The advent of large-scale neuroimaging databases will likely aid in building a more comprehensive understanding of sex differences and commonalities in brain mechanisms underlying chronic pain. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jnr.23856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120652PMC
January 2017

Multisite, multimodal neuroimaging of chronic urological pelvic pain: Methodology of the MAPP Research Network.

Neuroimage Clin 2016 6;12:65-77. Epub 2016 Jan 6.

UCLA Brain Research Institute, David Geffen School of Medicine at UCLA, USA; UCLA Ahmanson-Lovelace Brain Mapping Center, David Geffen School of Medicine at UCLA, USA; Department of Internal Medicine, David Geffen School of Medicine at UCLA, USA; Oppenheimer Center for Neurobiology of Stress at UCLA, David Geffen School of Medicine at UCLA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, USA.

The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network is an ongoing multi-center collaborative research group established to conduct integrated studies in participants with urologic chronic pelvic pain syndrome (UCPPS). The goal of these investigations is to provide new insights into the etiology, natural history, clinical, demographic and behavioral characteristics, search for new and evaluate candidate biomarkers, systematically test for contributions of infectious agents to symptoms, and conduct animal studies to understand underlying mechanisms for UCPPS. Study participants were enrolled in a one-year observational study and evaluated through a multisite, collaborative neuroimaging study to evaluate the association between UCPPS and brain structure and function. 3D T1-weighted structural images, resting-state fMRI, and high angular resolution diffusion MRI were acquired in five participating MAPP Network sites using 8 separate MRI hardware and software configurations. We describe the neuroimaging methods and procedures used to scan participants, the challenges encountered in obtaining data from multiple sites with different equipment/software, and our efforts to minimize site-to-site variation.
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http://dx.doi.org/10.1016/j.nicl.2015.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4925887PMC
November 2017

Placebo analgesia: Self-report measures and preliminary evidence of cortical dopamine release associated with placebo response.

Neuroimage Clin 2016 14;10:107-14. Epub 2015 Nov 14.

Department of Physiology, UCLA, Los Angeles, CA, United States; VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

Placebo analgesia is measured by self-report, yet current, expected, and recalled efficacy may be differentially related to brain function. Here we used a human thermal pain model to compare self-reports of expected, concurrent, and recalled efficacy of a topical placebo analgesic, and tested associations of the three measures of efficacy with changes in dopamine D2/D3 receptor availability in brain using [(18)F]fallypride with positron emission tomography (PET). Participants (15 healthy women) were assessed on three test days. The first test day included a laboratory visit, during which the temperature needed to evoke consistent pain was determined, placebo analgesia was induced via verbal and experience-based expectation, and the placebo response was measured. On two subsequent test days, PET scans were performed in Control and Placebo conditions, respectively, in counterbalanced order. During Visit 1, concurrent and recalled placebo efficacy were unrelated; during the Placebo PET visit, expected and recalled efficacy were highly correlated (ρ = 0.68, p = 0.005), but concurrent efficacy was unrelated to expected or recalled efficacy. Region of interest analysis revealed dopamine D2/D3 receptor availability was lower in left ventrolateral prefrontal cortex in the Placebo condition (p < 0.001, uncorrected), and greater change in this measure was associated with higher levels of recalled analgesic efficacy (ρ = 0.58, p = 0.02). These preliminary findings underscore the need to consider how self-reported symptom improvement is assessed in clinical trials of analgesics and suggest that dopaminergic activity in the ventrolateral prefrontal cortex may promote recalled efficacy of placebo.
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http://dx.doi.org/10.1016/j.nicl.2015.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683423PMC
October 2016

Unique Microstructural Changes in the Brain Associated with Urological Chronic Pelvic Pain Syndrome (UCPPS) Revealed by Diffusion Tensor MRI, Super-Resolution Track Density Imaging, and Statistical Parameter Mapping: A MAPP Network Neuroimaging Study.

PLoS One 2015 13;10(10):e0140250. Epub 2015 Oct 13.

Department of Radiological Science, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America; Department of Biomedical Physics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America; Oppenheimer Center for the Neurobiology of Stress, and PAIN, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America; Department of Bioengineering, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.

Studies have suggested chronic pain syndromes are associated with neural reorganization in specific regions associated with perception, processing, and integration of pain. Urological chronic pelvic pain syndrome (UCPPS) represents a collection of pain syndromes characterized by pelvic pain, namely Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) and Interstitial Cystitis/Painful Bladder Syndrome (IC/PBS), that are both poorly understood in their pathophysiology, and treated ineffectively. We hypothesized patients with UCPPS may have microstructural differences in the brain compared with healthy control subjects (HCs), as well as patients with irritable bowel syndrome (IBS), a common gastrointestinal pain disorder. In the current study we performed population-based voxel-wise DTI and super-resolution track density imaging (TDI) in a large, two-center sample of phenotyped patients from the multicenter cohort with UCPPS (N = 45), IBS (N = 39), and HCs (N = 56) as part of the MAPP Research Network. Compared with HCs, UCPPS patients had lower fractional anisotropy (FA), lower generalized anisotropy (GA), lower track density, and higher mean diffusivity (MD) in brain regions commonly associated with perception and integration of pain information. Results also showed significant differences in specific anatomical regions in UCPPS patients when compared with IBS patients, consistent with microstructural alterations specific to UCPPS. While IBS patients showed clear sex related differences in FA, MD, GA, and track density consistent with previous reports, few such differences were observed in UCPPS patients. Heat maps illustrating the correlation between specific regions of interest and various pain and urinary symptom scores showed clustering of significant associations along the cortico-basal ganglia-thalamic-cortical loop associated with pain integration, modulation, and perception. Together, results suggest patients with UCPPS have extensive microstructural differences within the brain, many specific to syndrome UCPPS versus IBS, that appear to be localized to regions associated with perception and integration of sensory information and pain modulation, and seem to be a consequence of longstanding pain.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0140250PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604194PMC
June 2016

Sex commonalities and differences in the relationship between resilient personality and the intrinsic connectivity of the salience and default mode networks.

Biol Psychol 2015 Dec 9;112:107-15. Epub 2015 Oct 9.

Oppenheimer Family Center for Neurobiology of Stress, UCLA, Los Angeles, CA, United States; Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, CA, United States; Department of Psychiatry, UCLA, Los Angeles, CA, United States; Department of Physiology, UCLA, Los Angeles, CA, United States; Pain and Interoception Network (PAIN), UCLA, Los Angeles, CA, United States.

Increased resilience is associated with better health outcomes and reduced morbidity in response to injury and homeostatic perturbations. Proper functioning of the salience network (SN) and modulation of the default mode network (DMN) by SN may play a role in adaptively responding to stress. Here, we demonstrate that resilient personality in healthy subjects is associated with SN and DMN connectivity patterns and that these patterns are influenced by sex. While connectivity of SN with several brain regions including right anterior insula was significantly associated with resilient personality in both men and women, results suggest that increased functional integration of anterior DMN preferentially benefits women while increased functional integration of posterior DMN preferentially benefits men in terms of resilience. These findings may relate to previous demonstrations that men and women engage different information processing and behavioral strategies to achieve resilience and highlight the importance of considering sex in resilience research.
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http://dx.doi.org/10.1016/j.biopsycho.2015.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5012423PMC
December 2015

Towards a systems view of IBS.

Nat Rev Gastroenterol Hepatol 2015 Oct 25;12(10):592-605. Epub 2015 Aug 25.

Institute for Genomics and Bioinformatics, University of California at Irvine, 4038 Bren Hall, Irvine, CA 92697-3435, USA.

Despite an extensive body of reported information about peripheral and central mechanisms involved in the pathophysiology of IBS symptoms, no comprehensive disease model has emerged that would guide the development of novel, effective therapies. In this Review, we will first describe novel insights into some key components of brain-gut interactions, starting with the emerging findings of distinct functional and structural brain signatures of IBS. We will then point out emerging correlations between these brain networks and genomic, gastrointestinal, immune and gut-microbiome-related parameters. We will incorporate this new information, as well as the reported extensive literature on various peripheral mechanisms, into a systems-based disease model of IBS, and discuss the implications of such a model for improved understanding of the disorder, and for the development of more-effective treatment approaches in the future.
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http://dx.doi.org/10.1038/nrgastro.2015.121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5001844PMC
October 2015
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