This pain drives me crazy: Psychiatric symptoms in women with interstitial cystitis/bladder pain syndrome

Table 3 Neuroimaging studies in urologic chronic pelvic pain syndrome, i.e. interstitial cystitis/bladder pain syndrome or chronic prostatitis/chronic pelvic pain syndrome and other pelvic or chronic pain conditions by year of publication

Ref.	Population	Technique	Findings
Farmer et al[123], 2011	Male 19 with CP/CPPS vs 16 HCs	fMRI during pain rating task; NMR, VBM; DTI	↑ FC in right anterior insula correlating with pain intensity; no GM differences between groups, but GM density in anterior insula and ACC correlated with pain intensity and chronicity; the normal correlation between WM FA and neocortex GM volume lost in CP/CPPS Pts
Bagarinao et al[124], 2014	Female 33 with IC/BPS (mean age = 39.51 ± 12.09 yr, 7 with vulvodynia and 8 with TMJD) vs 33 HCs (mean age = 38.95 ± 11.64 yr)	NMR, T1-weighted analysed with SPM8; used SVM algorithm; ROI approach	SVM predicted accurately to which group cases belonged in 73% of cases. SVM identified ↑ GM density areas in bilateral PSC, left preSMA, bilateral hippocampus, left amygdala. Correlation of ↑ cortical GM density with pain, symptom and mood self-ratings
Kilpatrick et al[125], 2014	Female 82 IC/BPS vs 85 HCs	fMRI, RS	Oscillation frequency power at lower frequencies ↑ in IC/BPS vs HCs in postcentral gyrus, anterior paracentral lobule, ventral and medial SMA and ↓ in right posterior insula; ↑ FC in Pts vs HCs between medial SMA and right midbrain, ventral SMA and cerebellum/bilateral midbrain, between anterior paracentral lobule and superior parietal Cx/cerebellum/right midbrain; ↓ FC in Pts vs HCs between right posterior insula and right medial insula
Farmer et al[126], 2015	Female 22 with IC/BPS (mean age = 37.73 ± 12.98 yr; no comorbidity or abnormal pelvis) vs 32 HCs (mean age = 32.84 ± 10.29 yr)	DTI, NMR T1-weighted, voxel-wise analysis	IC/BPS vs HCs ↓ WM density in left cerebellar corticospinal tract, right cerebellar ATR, right IFOF in right frontal orbital Cx, right ILF in lateral occipital Cx, left forceps major adjacent to precuneus, right ATR in right frontal pole, SLF in parietal Cx, and 8) temporal part of left SLF near ACC; ↑ FA in ILF, IFOF at right insula border, forceps major near left ACC, SLF in right postcentral gyrus and left PSC, and corticospinal tract passing through left PSC
Kutch et al[127], 2015	Male 28 with CP/CPPS vs 27 HCs	fMRI, RS	↓ FC between precentral gyrus/STG/IFG and right posterior insula in CP/CPPS Pts vs HCs
Gupta et al[128], 2015	Female 29 LPVD, 29 HCs, and 29 IBS	fMRI	Intrinsic connectivity LPVD > HCs in SMA, LPVD > IBS in left PMC, left and right SMA, IBS > LPVD in right STC and left and right PSC
Martucci et al[129], 2015	Female 45 UCPPS vs 45 HCs	fMRI, RS	↓ FC in DMN in PoMeCx (left precuneus and PCC); ↑ FC between PCC and insula, DLPFC, thalamus, pallidum, putamen, amygdala and hippocampus; ↓ FC between left precuneus and OFC, ACC, VMPFC, AG, SPL, IPL
Kairys et al[47], 2015	Female 33 with IC/BPS (mean age = 39.5 ± 12 yr; no comorbidity) vs 33 HCs (mean age = 39 ± 11.6 yr)	VBM, NMR, T1-weighted analysed with SPM8 under MATLAB® 7.6	↑ GM volume in IC/BPS vs HCs; SVM identified ↑ GM density areas in bilateral PSC, left preSMA, bilateral hippocampus, left amygdala. Correlation of ↑ cortical GM density with pain, symptom and mood self-ratings
Woodworth et al[130], 2015	45 UCPPS (19 female IC/BPS, 26 male CP/CPPS; mean age = 40 ± 14 yr) 56 HCs (26 female, 30 male, mean age = 38 ± 13 yr), 39 IBS (23 female, 16 male, mean age = 35 ± 12 yr)	DTI, 3T NMR post-bladder emptying; voxel-wise SPM; Pts were administered McGPQ and PANAS	↑ MD in UCPPS vs HCs in left/right putamen, left globus pallidus, right posterior coronal radiate, right left forceps minor and GCC, SplCC, right/left sensorimotor integration fibres, right ACC, right external and internal capsules, left posterior SLF, right left ILF, left precentral gyrus association fibres, right prefrontal WM projections; ↑ MD in UCPPS vs IBS in basal ganglia, right periventricular WM, temporal lobe projections, and fibres projecting to right primary motor cortex and association fibres in right hemisphere frontal areas; longer symptom duration correlated with MD and FA in WM clusters differing in MD between UCPPS and HCs
Kleinhans et al[131], 2016	Female 10 twins (5 mono- and 5 dizygotic) discordant for UCPPS (10 UCCPS vs 10 asymptomatic)	fMRI, RS after urination and 50 minutes after drinking 1/2 Lt of water; 3T NMR. ROIs bilateral PAG and amygdala	The symptomatic twins reported more pain at all timepoints and more urgency before scan; ↑ FC in symptomatic twins following water consumption and stable thereafter; in asymptomatic twins, ↑ FC only after bladder distention; ↑ FC in in asymptomatic twins between right PAG and cerebellar/cortical regions involved in sensorimotor planning; ↑ FC between laterobasal amygdala to ACC, insula, somatosensory, premotor Cxs, thalamus and VMPFC
Wei et al[132], 2016	Female 46 PDM vs 49 HCs	fMRI during menstruation and periovulatory phase	PDM, adaptive hyperconnectivity between PAG and SMCx during painful menstruation; maladaptive hypoconnectivity between PAG and DLPFC and DMN during menstruation or periovulatory phase
Deutsch et al[133], 2016	Female 11 with IC/BPS (4 non-comorbid; 5 comorbid with fibromyalgia, 5 vulvodynia, 4 IBS, 3 chronic fatigue) vs 11 HCs	ASL fMRI rCBF at BL, empty bladder and heat pain; 3T NMR	At empty bladder, ↓ rCBF in bilateral insula, middle and PCC in Pts with IC/BPS vs HCs. Bladder distension associated with ↑ rCBF in IC/BPS vs HCs SMA, motor and sensory Cxs, bilateral insula, hippocampus, and middle and PCC in Pts with IC/BPS. During heat pain, ↓ rCBF in IC/BPS Pts vs HCs, who showed ↑ rCBF in bilateral amygdala
Huang et al[134], 2016	52 UCPPS (23 female, 29 male), 39 IBS (24 female, 15 male), 61 HCs (32 female, 29 male)	3T NMR, T1-weighted; DTI, FA	↑ FA in UCPPS in left corticospinal tract, left forceps major, left SLF at precentral gyrus; left superior corona radiata at ACC; forceps major, right IFOF, ILF and cingulum projecting to parahippocampal gyri at precuneous compared to IBS and HCs; ↑ FA in right ATR in IBS compared to HCs; regional changes independent of local grey matter FA and density
Kutch et al[135], 2017	52 UCPPS (34 female IC/BPS; 18 male CP/CPPS), mean age = 38.8 ± 11.9 yr	fMRI, RS; 3T NMR; clinical reassessment after 3, 6, and 12 mo	Strong BL FC, particularly in the fronto-parietal network, was associated with symptom improvement at 3 mo, but not at 6 mo or 12 mo. FC data predicted accurately the improver/non-improver status at 3 mo for 73.1% of the sample, with 69.2% sensitivity and 75.0% specificity; improver status was not maintained at later timepoints
Kutch et al[136], 2017	48 female (IC/BPS) 24 male (CP/CPPS) with UCPPS (n = 110) vs 23 female fibromyalgia vs 49 female HCs	fMRI, NMR	Pts with UCPPS and widespread pain show ↑ GM volume in right SMA and cingulate Cx and bilateral SMCx as well as ↑ FC between SMCx and insula with the salience circuit, compared to UCPPS Pts with localised pain and controls
Harper et al[137], 2018	Female 18 UCPPS (mean age = 34.8 ± 11.0 yr) vs 20 HCs (mean age = 34.7 ± 12.3 yr)	1H-MRS, T1-weighted scans; McGPQ, PANAS, HADS	UCPPS Pts had ↓ GABA and ↑ choline and choline-to-total creatine ratio than HCs in the ACC; the two groups did not differ for other metabolites (glutamate + glutamine; glutamate; N-acetylaspartate; and inositol); ↑ ACC choline level correlated with McGPQ pain, HADS Depression and PANAS negative affect scores
Woodworth et al[138], 2018	30 UCPPS (13 female IC/BPS; 17 male CP/CPPS); mean age = 39.9 ± 13.5 yr	DTI (FA, ADC), correlations with urinary proteins	ADC in a small WM cluster adjacent to right motor cortex correlated with urinary MMP2; ADC in a WM cluster in DRN and LCC correlated with MMP9 and MMP9/NGAL complex; FA in SMCx-connecting areas correlated with MMP9 as did midbrain areas and left SMCx with MMP9/NGAL complex; large WM clusters’ ADC and FA correlated with NGAL urinary concentrations; no correlations with VEGF
Gupta et al[139], 2019	85 UCPPS mean age = 39.36 ± 12.80 yr (56 female IC/BPS, mean age = 38.96 ± 12.41 yr; 29 male CP/CPPS; mean age = 40.11 ± 13.71 yr) vs 86 HCs mean age = 37.90 ± 12.23 (59 female mean age = 35.44 ± 10.82 yr; 27 males; mean age = 49.60 ± 13.55 yr)	fMRI, RS; CTES to measure EALEs. Network centrality was measured for each of the main brain networks* (DMN, basal ganglia, sensorimotor, executive control and salience) using graph theory	UCPPS Pts with → ↓ centrality in right anterior insula than HCs (salience network hub). UCPPS male → ↓ centrality in right anterior insula than male HCs. UCPPS female → ↑ centrality in right caudate nucleus and left angular gyrus than female HCs [condition effects]. UCPPS male → ↓ centrality in left PCC (DMN), angular gyrus, middle temporal gyrus, and superior temporal sulcus; UCPPS male → ↑ centrality in precuneus and anterior mid-cingulate Cx than UCPPS female [sex effect]. ↑ reports of EALEs associated with ↑ centrality in left precuneus and left anterior mid-cingulate Cx in UCPPS female. Moderating effect of CTES on condition effect on betweenness centrality of right anterior insula (salience network hub); EALEs moderated centrality in amygdala at high CTES scores
Fenske et al[140], 2020	100 UCPPS mean age = 39.2 ± 13.3 male/female = 34/66 vs 109 HCs mean age = 36.7 ± 12.2 male/female = 34/75	fMRI, RS; PAG characterisation as a ROI according to the MNI	↑ FC in HCs vs Pts in right (pars triangularis) and left IFG (pars opercularis); right PCC, left IFG (pars orbitalis) and left IPL shown when Pts and HCs were compared on the MNI-trace ROI compared to the MNI-sphere ROI

These studies probably used the same sample, but one reported some pain disorder comorbidity and the other no comorbidity. Sensorimotor Network: Superior Frontal Gyrus; Superior Frontal Sulcus; Precentral Gyrus; Precentral Sulcus; Postcentral Gyrus; Postcentral Sulcus; Supramarginal Gyrus; Posterior ramus (or segment) of the lateral sulcus (or fissure); Thalamus; Superior segment of the circular sulcus of the insula; Long insular gyrus and central sulcus of the insula. Basal-Ganglia Network: Nucleus Accumbens; Putamen; Caudate Nucleus; Pallidum/Globus Pallidus. Emotion Regulation Network: Pregenual Anterior Cingulate; Subgenual Anterior Cingulate; Parahippocampal Gyrus; Hippocampus; Amygdala. Executive Control Network: Inferior Frontal Sulcus; Triangular Part of the Inferior Frontal Gyrus; Superior Frontal Gyrus; Superior Parietal Lobule. Salience Network: Anterior Mid Cingulate Cortex; Anterior segment of the circular sulcus of the insula; Inferior segment of the circular sulcus of the insula. Default Mode Network: Marginal branch (or part) of the Cingulate Sulcus; Middle Temporal Gyrus; Superior Temporal Sulcus; Superior Temporal Gyrus Precuneus; Posterior Cingulate Cortex Angular Gyrus. H-MRS: Proton magnetic resonance spectroscopy; ACC: Anterior cingulate cortex; ADC: Apparent diffusion concentration; AG: Angular gyrus of the parietal cortex; ASL: Arterial spin labelling; ATR: Anterior thalamic radiation; BL: Baseline; CP/CPPS: Chronic Prostatitis/Chronic Pelvic Pain Syndrome; CTES: Childhood Traumatic Events Scale; Cx: Cortex; DMN: Default mode network; DLPFC: Dorsolateral prefrontal cortex; DRN: Dorsal raphé nucleus; DTI: Diffusion tensor imaging; EALEs: Early adverse life events; FA: Fractional anisotropy; FC: Functional connectivity; fMRI: Functional magnetic neuroimaging; GABA: γ-aminobutyric acid; GCC: Genu Corpus Callosum; GM: Grey matter; HADS: Hospital Anxiety and Depression Scale; HCs: Healthy controls; IBS: Irritable bowel syndrome; IC/BPS: Interstitial cystitis/bladder pain syndrome; IFG: Inferior frontal gyrus; IFOF: Inferior fronto–occipital fasciculus; ILF: Inferior longitudinal fasciculus; IPL: Inferior parietal lobule; LCC: Locus cœruleus and Barrington’s nucleus complex; LPVD: Localized provoked vulvodynia; MD: Mean diffusivity; McGPQ: McGill Pain Questionnaire-Short form; MMP2: Matrix metalloproteinase-2; MMP9: Matrix metalloproteinase-2; MNI: Montréal Neurological Institute; NGAL: Neutrophil gelatinase-associated lipocalin: lipocalin-2; NMR: Nuclear magnetic resonance; OFC: Orbitofrontal cortex; PAG: Periaqueductal grey; PANAS: Positive and Negative Affect Schedule; PCC: Posterior cingulate cortex; PDM: Primary dysmenorrhea; PMC: Primary motor cortex; PoMeCx: Posterior medial cortex; Pts: Patients; PSC: Primary somatosensory cortex; rCBF: Regional cerebral blood flow; ROI: Region-of-interest; RS: Resting state; SLF: Superior longitudinal fasciculus; SMA: Supplementary motor area; SMCx: Sensorimotor cortex; SPL: Superior parietal lobule; SplCC: Splenium of the corpus callosum; SPM: Statistical Parametric Mapping; STC: Superior temporal cortex; STG: Superior temporal gyrus; SVM: Support vector machine; T: Tesla; TMJD: Temporomandibular joint dysfunction; UCPPS: Urologic chronic pelvic pain syndrome; VBM: Voxel-based morphometry; VEGF: Vascular endothelial growth factor; VMPFC: Ventromedial prefrontal cortex; WM: White matter; ↓: Decrease(d); ↑: Increase(d); →: Leads to: Show(ed).