Optimizing examination time and diagnostic performance of the histamine-induced axon-reflex flare response in diabetes.

INTRODUCTION/AIMS: The axon-reflex flare response is a reliable method for functional assessment of small fibers in diabetic peripheral neuropathy (DPN), but broad adoption is limited by the time requirement. The aims of this study were to (1) assess diagnostic performance and optimize time required for assessing the histamine-induced flare response and (2) associate with established parameters. METHODS: A total of 60 participants with type 1 diabetes with (n = 33) or without (n = 27) DPN participated. The participants underwent quantitative sensory testing (QST), corneal confocal microscopy (CCM), and flare intensity and area size assessments by laser-Doppler imaging (FLPI) following an epidermal skin-prick application of histamine. The flare parameters were evaluated each minute for 15 min, and the diagnostic performance compared to QST and CCM were assessed using area under the curve (AUC). Minimum time-requirements until differentiation and to achieve results comparable with a full examination were assessed. RESULTS: Flare area size had better diagnostic performance compared with CCM (AUC 0.88 vs. 0.77, p < 0.01) and QST (AUC 0.91 vs. 0.81, p = 0.02) than mean flare intensity, and could distinguish people with and without DPN after 4 min compared to after 6 min (both p < 0.01). Flare area size achieved a diagnostic performance comparable to a full examination after 6 and 7 min (CCM and QST respectively, p > 0.05), while mean flare intensity achieved it after 5 and 8 min (CCM and QST respectively, p > 0.05). DISCUSSION: The flare area size can be evaluated 6-7 min after histamine-application, which increases diagnostic performance compared to mean flare intensity.

Quantification of parenchymal fibrosis in chronic pancreatitis: relation to atrophy and pancreatic function.

BACKGROUND: Non-invasive modalities for assessing chronic pancreatitis (CP) are needed in clinical practice. PURPOSE: To investigate the correlation between magnetic resonance elastography (MRE)-derived stiffness and T1 relaxation times (as proxies of fibrosis) and explore their relationships to gland volume and pancreatic functions in patients with CP and healthy controls (HCs). MATERIAL AND METHODS: In 49 patients with CP and 35 HCs, pancreatic stiffness, T1 relaxation times, and gland volume were assessed. Fecal elastase and the presence of diabetes were used to evaluate pancreatic exocrine and endocrine functions. Uni- and multivariable linear regression models were used to analyze correlations between imaging parameters. RESULTS: There was a positive correlation between MRE-derived stiffness and T1 relaxation times in patients with CP (R2 = 0.42; P < 0.001) and HCs (R2 = 0.14; P = 0.028). There was no correlation between MRE-derived stiffness and gland volume in patients (R2 = 0.007; P = 0.065) or HCs (R2 = 0.010; P = 0.57). T1 relaxation time was correlated to gland volume (R2 = 0.19; P = 0.002) in patients with CP but not in the HCs (P = 0.056). Severity of pancreatic functional impairment was reflected by increased fibrosis-related parameters in patients without functional impairment, followed by a further increase in fibrosis-related parameters and reduction in gland volume in patients with pancreatic functional impairments. CONCLUSION: Pancreatic MRE-derived stiffness and T1 relaxation times might reflect early pathophysiological changes in CP. The dynamic correlation with pancreatic function suggests that these parameters may be useful for the non-invasive and early identification of CP.

White matter brain changes in chronic pancreatitis: A 7-year longitudinal follow-up study.

BACKGROUND/OBJECTIVES: The progression of cerebral white matter changes over time has not been explored in chronic pancreatitis (CP). We aimed to characterize such alterations in individuals with CP at baseline and after 7-years as compared with controls and to explore associations to risk factors and clinical parameters. METHODS: Diffusion tensor imaging was used to evaluate 20 individuals with CP and 13 healthy controls at baseline and after 7-years (CP: n = 9, controls: n = 11). Tract-based spatial statistics were used to assess whole-brain white matter structure, extract significant fractional anisotropy (FA) clusters between groups, mean FA skeleton, mean FA and mean diffusivity (MD). FA of the extracted significant clusters between groups were used for regression analyses with risk factors and clinical parameters, including duration of CP, smoking, and diabetes. RESULTS: At baseline, widespread reductions in FA were found in CP compared to controls involving corpus callosum, the anterior, posterior thalamic radiation, and superior and posterior corona radiata (cluster volume: 49,431 mm3, all P < 0.05). At baseline, also the mean FA (P = 0.004) and FA skeleton (P = 0.002) were reduced in CP compared to controls. FA of the extracted significant cluster was associated with the daily tobacco use (P = 0.001) and duration of CP (P = 0.010). At follow-up, the whole-brain FA skeleton was reduced by 1.7% for both CP individuals and controls (P = 0.878). CONCLUSION: Individuals with CP had widespread cerebral white matter alterations at baseline that can likely be explained by the CP disease and exposure to toxic substances. Otherwise, further progression resembles that in healthy controls.

Tapentadol and oxycodone reduce cingulate glutamate in healthy volunteers.

Tapentadol and oxycodone are commonly used analgesics. Preclinical studies have shown that oxycodone modulates brain metabolites related to opioid pathways, whereas tapentadol also affects noradrenergic activity. However, knowledge about the function of the medications in the human brain is limited. The aim was to investigate effects of tapentadol and oxycodone on brain glutamate, the most important neurotransmitter in pain processing. Magnetic resonance spectroscopy was obtained in 21 healthy subjects from the anterior cingulate cortex, prefrontal cortex, and insula at baseline and after 14 days of treatment with either 50 mg tapentadol, 10 mg oxycodone (equipotent dose, both extended release) or placebo twice daily in a randomized double-blind cross-over study. Compared to baseline, decreased glutamate/creatine levels were identified in anterior cingulate cortex after tapentadol (1.26 ± 0.14 vs. 1.35 ± 0.18, P = .04) and oxycodone (1.26 ± 0.10 vs. 1.35 ± 0.12, P = .05) treatments, both with 7% reduction. This indicates that both analgesics modulate the glutamatergic system at the supraspinal level in humans.

Influence of tapentadol and oxycodone on the spinal cord and brain using electrophysiology: a randomized, placebo-controlled trial.

AIMS: The aim of this study was to investigate the effects of tapentadol and oxycodone using the nociceptive withdrawal reflex and sensory evoked potentials. METHODS: Twenty-one healthy volunteers completed a cross-over trial with oxycodone (10 mg), tapentadol (50 mg) extended-release tablets, or placebo treatment administered orally BID for 14 days. Electrical stimulations were delivered on the plantar side of the foot to evoke a nociceptive withdrawal reflex at baseline and post-interventions. Electromyography, recorded at tibialis anterior, and electroencephalography were recorded for analysis of: number of reflexes, latencies, and area under the curve of the nociceptive withdrawal reflex as well as latencies, amplitudes and dipole sources of the sensory-evoked potential. RESULTS: Tapentadol decreased the odds ratio of eliciting nociceptive withdrawal reflex by -0.89 (P = .001, 95% confidence interval [CI] -1.46, -0.32), whereas oxycodone increased the latency of the N1 component of the sensory-evoked potential at the vertex by 12.5 ms (P = .003, 95% CI 3.35, 21.69). Dipole sources revealed that the anterior cingulate component moved caudally for all three interventions (all P < .02), and the insula components moved caudally in both the oxycodone and tapentadol arms (all P < .03). CONCLUSION: A decrease in the number of nociceptive withdrawal reflex was observed during tapentadol treatment, possibly relating to the noradrenaline reuptake inhibition effects on the spinal cord. Both oxycodone and tapentadol affected cortical measures possible due to µ-opioid receptor agonistic effects evident in the dipole sources, with the strongest effect being mediated by oxycodone. These findings could support the dual effect analgesic mechanisms of tapentadol in humans as previously shown in preclinical studies.

Two-Week Cervical Vagus Nerve Stimulation in Chronic Pancreatitis Patients Induces Functional Connectivity Changes of Limbic Structures.

OBJECTIVES: Noninvasive vagus nerve stimulation (nVNS) has not only shown antinociceptive effects, but also demonstrated anti-inflammatory and antidepressant effects. These effects could be beneficial in chronic pancreatitis (CP) patients suffering from chronic abdominal pain, even though the underlying central mechanisms remain unclear. The aim was to investigate the effect of cervical nVNS in patients with painful CP on brain functional connectivity and cerebral metabolites. MATERIALS AND METHODS: In a randomized double-blind, sham-controlled crossover trial, we used resting-state functional magnetic resonance imaging to investigate functional connectivity changes of limbic structures (seed-based analysis) after two weeks cervical nVNS treatment (GammaCore) as compared with two weeks sham treatment. Similarly, magnetic resonance spectroscopy was performed in the anterior cingulate cortex (ACC) with assessment of glutamate/creatine (Glu/cre) and N-acetylaspartate/creatine (NAA/cre). RESULTS: Sixteen CP patients (mean age 56.6 ± 9.4 years) completed the trial. nVNS induced reduced functional connectivity compared to sham treatment between 1) bilateral thalamus and bilateral superior frontal gyrus, 2) ACC and putamen, and 3) posterior cingulate cortex and right thalamus (all p < 0.05). No changes were observed in Glu/cre (p = 0.96) and NAA/cre (p = 0.43) levels between the nVNS and sham treatments. CONCLUSION: In our population of CP patients, cervical nVNS compared with sham treatment induced reduced functional connectivity of limbic structures, as also observed in other patient groups. The findings are relevant, since we have previously demonstrated an effect on pain scores in CP patients for both nVNS and sham treatment. Our results elucidate the effects in the central nervous system following nVNS treatment of CP patients, pointing at potential beneficial effects in this patient group.

Single- and multiparameter magnetic resonance imaging for diagnosing and severity grading of chronic pancreatitis.

PURPOSE: The study aimed to determine the performance of advanced magnetic resonance imaging (MRI), including a multiparametric MRI-index, for diagnosing and severity grading of chronic pancreatitis (CP) at various functional stages with focus on detection of CP with preserved pancreatic function. METHODS: Fifty-four CP patients and 35 healthy controls underwent MRI including assessment of pancreatic volume, main pancreatic duct (MPD) diameter, T1 relaxation time, magnetic resonance elastography (MRE) derived stiffness, and intravoxel incoherent motion (IVIM) diffusion-weighted imaging. Patients were categorized into three subgroups: Preserved pancreatic function (n = 14), partial pancreatic insufficiency (exocrine insufficiency or diabetes, n = 25), and complete pancreatic insufficiency (exocrine insufficiency and diabetes, n = 15). A multiparametric MRI-index was based on ordinal logistic regression analysis. Diagnostic performances of MRI parameters for diagnosing CP at different functional stages were determined using receiver operating characteristic (ROC) analysis. RESULTS: All MRI parameters differed across CP subgroups and healthy controls (all P < 0.001), except for IVIM. T1 relaxation time (ROC area under the curve (ROC-AUC) 0.82), MRE (ROC-AUC 0.88), and MRI-index (ROC-AUC 0.86) showed the highest performance for detecting patients with preserved pancreatic function (early CP) vs. healthy controls. For detecting preserved pancreatic function vs. partial insufficiency, pancreatic volume, MRI-index, and T1 relaxation time performed best (all ROC-AUC > 0.75), with the MRI-index tending to outperform MRE (ROC-AUC 0.77 vs. 0.63; P = 0.10). CONCLUSION: Quantitative assessments of T1 relaxation time and MRE-derived stiffness seem promising for diagnosing CP at different functional stages and may together with multiparametric MRI-index be used for early identification, staging and monitoring of CP.

The co-existence of sensory and autonomic neuropathy in type 1 diabetes with and without pain.

AIMS: To investigate the co-existence of diabetic peripheral neuropathy (DPN), painful diabetic peripheral neuropathy (PDPN), and cardiac autonomic neuropathy (CAN) and to establish a model to predict CAN based on peripheral measurements. METHODS: Eighty participants (20 type 1 diabetes (T1DM) + PDPN, 20 T1DM + DPN, 20 T1DM-DPN (without DPN), and 20 healthy controls (HC)) underwent quantitative sensory testing, cardiac autonomic reflex tests (CARTs), and conventional nerve conduction. CAN was defined as ≥ 2 abnormal CARTs. After the initial analysis, the participants with diabetes were re-grouped based on the presence or absence of small (SFN) and large fibre neuropathy (LFN), respectively. A prediction model for CAN was made using logistic regression with backward elimination. RESULTS: CAN was most prevalent in T1DM + PDPN (50%), followed by T1DM + DPN (25%) and T1DM-DPN and HC (0%). The differences in prevalence of CAN between T1DM + PDPN and T1DM-DPN/HC were significant (p < 0.001). When re-grouping, 58% had CAN in the SFN group and 55% in the LFN group, while no participants without either SFN or LFN had CAN. The prediction model had a sensitivity of 64%, a specificity of 67%, a positive predictive value of 30%, and a negative predictive value of 90%. CONCLUSION: This study suggests that CAN predominantly co-exists with concomitant DPN.

Perception threshold tracking: validating a novel method for assessing function of large and small sensory nerve fibers in diabetic peripheral neuropathy with and without pain.

ABSTRACT: It remains unknown why some people with diabetes develop painful neuropathies while others experience no pain. This study aimed to validate a novel method for assessing the function of small sensory nerves in diabetes to further elucidate this phenomenon. The function of large and small nerves was assessed using a novel perception threshold tracking technique in 3 well-characterized groups (n = 60) with type 1 diabetes, namely, (1) painful diabetic peripheral neuropathy (T1DM + PDPN), (2) painless diabetic peripheral neuropathy (T1DM + DPN), and (3) no neuropathy (T1DM - DPN), and healthy controls (n = 20). Electrical currents with different shapes, duration, and intensities were applied by 2 different skin electrodes activating large and small fibers, respectively. The minimal current needed to activate the fibers were analyzed as the rheobase of the stimulus-response function. Nerve fiber selectivity was measured by accommodation properties of stimulated nerves. The rheobase of both fiber types were highest for T1DM + PDPN, followed by T1DM + DPN, T1DM - DPN, and healthy controls, indicating that the nerve properties are specific in individuals with diabetes and pain. There was an overall significant difference between the groups ( P < 0.01). The accommodation properties of stimulated fibers were different between the 2 electrodes ( P < 0.05) apart from in the group with T1DM + PDPN, where both electrodes stimulated nerves displaying properties similar to large fibers. Perception threshold tracking reveals differences in large and small nerve fiber function between the groups with and without diabetes, DPN, and pain. This indicates that the methods have potential applications in screening DPN and explore further the features differentiating painful from nonpainful DPN.

Diagnostic Accuracy of Perception Threshold Tracking in the Detection of Small Fiber Damage in Type 1 Diabetes.

AIM: An objective assessment of small nerve fibers is key to the early detection of diabetic peripheral neuropathy (DPN). This study investigates the diagnostic accuracy of a novel perception threshold tracking technique in detecting small nerve fiber damage. METHODS: Participants with type 1 diabetes (T1DM) without DPN (n = 20), with DPN (n = 20), with painful DPN (n = 20) and 20 healthy controls (HCs) underwent perception threshold tracking on the foot and corneal confocal microscopy. Diagnostic accuracy of perception threshold tracking compared to corneal confocal microscopy was analyzed using logistic regression. RESULTS: The rheobase, corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), and corneal nerve fiber length (CNFL) (all P < .001) differed between groups. The diagnostic accuracy of perception threshold tracking (rheobase) was excellent for identifying small nerve fiber damage, especially for CNFL with a sensitivity of 94%, specificity 94%, positive predictive value 97%, and negative predictive value 89%. There was a significant correlation between rheobase with CNFD, CNBD, CNFL, and Michigan Neuropathy Screening Instrument (all P < .001). CONCLUSION: Perception threshold tracking had a very high diagnostic agreement with corneal confocal microscopy for detecting small nerve fiber loss and may have clinical utility for assessing small nerve fiber damage and hence early DPN. CLINICAL TRIALS: NCT04078516.

Altered functional connectivity between brain structures in adults with type 1 diabetes and polyneuropathy.

OBJECTIVE: Alterations of the central nervous system are increasingly being recognized as a part of diabetes, especially in the thalamus and the default mode network (DMN). However, the functional involvement in diabetic peripheral neuropathy (DPN) is poorly understood. This study aimed to investigate functional connectivity of thalamus and DMN in individuals with DPN and the associations to clinical characteristics. METHODS: Forty-seven type 1 diabetes mellitus (T1DM) individuals with DPN and 28 healthy controls underwent resting-state functional magnetic resonance imaging. Seed-to-voxel and ROI-to-ROI analyses were performed for thalamus and DMN. The connectivity for both thalamus and DMN were correlated to clinical parameters. RESULTS: Alterations in the functional connectivity of the thalamus and DMN were observed in individuals with T1DM and DPN. Thalamus showed decreased connectivity to the middle frontal, superior frontal, and precentral cortex (all pFWE-corrected<0.05). DMN ROIs showed increased connectivity to the superior frontal cortex (all puncorrected<0.05). A trend towards increased overall connectivity within DMN was observed in the T1DM compared to healthy controls (p=0.051). The subgroup with painful DPN had significantly increased overall connectivity compared to healthy controls (p=0.038). No associations were found to clinical parameters. CONCLUSION: Individuals with DPN had disrupted connectivity between thalamus/DMN and other brain structures and disrupted overall mean connectivity within DMN. Our findings support the existing knowledge of central nervous system involvement in diabetes and provide support for the involvement of thalamus and DMN in people with T1DM and DPN.

Disrupted white matter integrity in the brain of type 1 diabetes is associated with peripheral neuropathy and abnormal brain metabolites.

AIMS: We aimed to quantify microstructural white matter abnormalities using magnetic resonance imaging and examine their associations with 1) brain metabolite and volumes and 2) clinical diabetes-specific characteristics and complications in adults with type 1 diabetes mellitus (T1DM) and distal symmetric peripheral neuropathy (DSPN). METHODS: Diffusion tensor images (DTI) obtained from 46 adults with T1DM and DSPN and 28 healthy controls were analyzed using tract-based spatial statistics and were then associated with 1) brain metabolites and volumes and 2) diabetes-specific clinical characteristics (incl. HbA1c, diabetes duration, level of retinopathy, nerve conduction assessment). RESULTS: Adults with T1DM and DSPN had reduced whole-brain FA skeleton (P = 0.018), most prominently in the inferior longitudinal fasciculus and retrolenticular internal capsule (P < 0.001). Reduced fractional anisotropy (FA) was associated with lower parietal N-acetylaspartate/creatine metabolite ratio (r = 0.399, P = 0.006), brain volumes (P ≤ 0.002), diabetes duration (r = -0.495, P < 0.001) and sural nerve amplitude (r = 0.296, P = 0.046). Additionally, FA was reduced in the subgroup with concomitant proliferative retinopathy compared to non-proliferative retinopathy (P = 0.03). No association was observed between FA and HbA1c. CONCLUSIONS: This hypothesis-generating study provided that altered white matter microstructural abnormalities in T1DM with DSPN were associated with reduced metabolites central for neuronal communications and diabetes complications, indicating that peripheral neuropathic complications are often accompanied by central neuropathy.

Central neuronal transmission in response to tonic cold pain is modulated in people with type 1 diabetes and severe polyneuropathy.

AIMS: This study aimed to investigate cortical source activity and identify source generators in people with type 1 diabetes during rest and tonic cold pain. METHODS: Forty-eight participants with type 1 diabetes and neuropathy, and 21 healthy controls were investigated with electroencephalography (EEG) during 5-minutes resting and 2-minutes tonic cold pain (immersing the hand into water at 2 °C). EEG power was assessed in eight frequency bands, and EEG source generators were analyzed using standardized low-resolution electromagnetic tomography (sLORETA). RESULTS: Compared to resting EEG, cold pain EEG power differed in all bands in the diabetes group (all p < 0.001) and six bands in the controls (all p < 0.05). Source generator activity in the diabetes group was increased in delta, beta2, beta3, and gamma bands and decreased in alpha1 (all p < 0.006) with changes mainly seen in the frontal and limbic lobe. Compared to controls, people with diabetes had decreased source generator activity during cold pain in the beta2 and beta3 bands (all p < 0.05), mainly in the frontal lobe. CONCLUSIONS: Participants with type 1 diabetes had altered EEG power and source generator activity predominantly in the frontal and limbic lobe during tonic cold pain. The results may indicate modulated central transmission and neuronal impairment.

The Histamine-Induced Axon-Reflex Response in People With Type 1 Diabetes With and Without Peripheral Neuropathy and Pain: A Clinical, Observational Study.

Small nerve fibres are important when studying diabetic peripheral neuropathy (DPN) as they could be first affected. However, assessing their integrity and function adequately remains a major challenge. The aim of this study was to investigate the association between different degrees of DPN, the presence of neuropathic pain, and the intensity of the axon-reflex flare response provoked by epidermal histamine. Eighty adults were included and divided into 4 groups of 20 with type 1 diabetes and: painful DPN (T1DM+PDPN), non-painful DPN (T1DM+DPN), no DPN and no pain (T1DM-DPN), and 20 persons without diabetes or pain (HC). The vasomotor responses were captured by a Full-field Laser Speckle Perfusion Imager. The response was lowest in T1DM+DPN, followed by T1DM+PDPN, T1DM-DPN and HC. The response was significantly reduced in DPN (T1DM+DPN, T1DM+PDPN) compared with people without (T1DM-DPN, HC) (P < .001). The response was also attenuated in diabetes irrespective of the degree of DPN (T1DM+PDPN, T1DM+DPN, T1DM-DPN) (P < .001). There were no differences in the response between painful neuropathy (T1DM+PDPN) and painless DPN (T1DM+DPN) (P = .189). The method can distinguish between groups with and without diabetes and with and without DPN but cannot distinguish between groups with and without painful DPN. PERSPECTIVE: This study describes how diabetes attenuates the axon-reflex response, and how it is affected by neuropathy and pain clarifying previous findings. Furthermore, the study is the first to utilize histamine when evoking the response, thus providing a new and fast alternative for future studies into the pathophysiology of neuropathic pain.

Reduced gray matter brain volume and cortical thickness in adults with type 1 diabetes and neuropathy.

In this study we investigated brain morphology in adults with diabetic neuropathy. We aimed to characterize gray matter volume (GMV) and cortical thickness, and to explore associations between whole brain morphology and clinical characteristics. 46 adults with type 1 diabetes and distal symmetric peripheral neuropathy (DSPN) and 28 healthy controls underwent magnetic resonance imaging scans. GMV and cortical thickness were estimated using voxel-/surface-based morphometry. Associations between total GMV and clinical characteristics were explored. Adults with DSPN had reduced total GMV compared with controls (627.4 ± 4.1 mL vs. 642.5 ± 5.2 mL, P = 0.026). GMV loss was more pronounced for participants with painful neuropathy compared with controls (619.1±8.9 mL vs. 642.4±5.2 mL, P = 0.026) and for those with proliferative vs. non-proliferative retinopathy (609.9 ± 6.8 mL vs. 636.0 ± 4.7 mL, P = 0.003). Characteristics such as severity of neuropathy and decreased parietal N-acetylaspartate/creatine metabolite concentration seem to be related to GMV loss in this cohort. Regional GMV loss was confined to bilateral thalamus/putamen/caudate, occipital and precentral regions, and decreased cortical thickness was identified in frontal areas. Since the observed total GMV loss influenced with clinical characteristics, brain imaging could be useful for supplementary characterization of diabetic neuropathy. The regional brain changes could suggest that some areas are more vulnerable in this cohort.

Spectral and dynamic electroencephalogram abnormalities are correlated to psychometric test performance in hepatic encephalopathy.

OBJECTIVE: Alterations of the electroencephalogram (EEG) have been reported in patients with hepatic encephalopathy (HE). However, previous methods have not assessed transient phenomena in the EEG signal (dynamics) and associations to psychometric test performance have in general been poor. The aims were to quantify spectral and dynamic EEG abnormalities in patients with HE and to correlate putative findings to psychometric test performances. METHODS: Multichannel EEG (64 electrodes) was recorded in 24 cirrhotic patients with various grades of HE and 26 healthy volunteers. Spectral and dynamic EEG indices were quantified by continues wavelet analysis. In addition, the psychometric hepatic encephalopathy score (PHES), continues reaction time, and biochemical profile were assessed. RESULTS: Compared with healthy volunteers, patients had progressively slowing of the EEG (all p ≤ 0.004) (spectral EEG indices) and increased variability in the alpha [7.5-13.5 Hz] (p = 0.001) and beta bands [13.5-32 Hz] (p = 0.02) (dynamic EEG indices). In addition, anteriorization and dissociation of the basic posterior alpha rhythm, along with dissociation of frontal delta activities [1-3.5 Hz] were seen with worsening of HE. Spectral EEG indices (all frequency bands) as well as dynamic EEG indices (alpha and beta bands) were correlated to PHES scores (all p < 0.05). CONCLUSION: EEG analysis, based on continues wavelet transform, provides quantifiable information on static as well as dynamic features of the EEG in patients with HE. EEG abnormalities were correlated to psychometric test performance and may provide valuable clinical biomarkers for surveillance, prognostication and treatment of this entity.

T1 relaxation times and MR elastography-derived stiffness: new potential imaging biomarkers for the assessment of chronic pancreatitis.

PURPOSE: Non-invasive imaging methods to detect morphological changes of the pancreas in patients with mild chronic pancreatitis (CP) are needed. This study aimed to compare magnetic resonance imaging-based parameters, pancreatic volume, T1 mapping, magnetic resonance elastography (MRE), and proton density fat fraction between CP patients and controls, and determine the diagnostic performance for diagnosing different stages of CP. METHODS: Nineteen patients with mild CP (Cambridge grade 2 or less or recurring acute pancreatitis; n = 19), 30 with moderate/severe CP (Cambridge grade 3 and 4), and 35 healthy controls underwent pancreatic magnetic resonance imaging to assess the above mentioned magnetic resonance imaging-based parameters. The diagnostic performance of each parameter for detecting any mild and moderate/severe CP was determined using receiver operating characteristic analysis. RESULTS: Pancreatic volume, T1 relaxation times, MRE-derived stiffness, and proton density fat fraction differed significantly between patients with mild CP, moderate/severe CP, and healthy controls (all p < 0.05). T1 mapping and MRE showed a very high diagnostic performance for distinguishing the mild CP group from the control group (T1 mapping: receiver operating characteristic area under the curve (ROC-AUC): 0.94; sensitivity: 84%; specificity: 91%, MRE: ROC-AUC: 0.93; sensitivity: 89%; specificity: 94%). T1 mapping and MRE also had the highest performance for diagnosing the presence of any CP from the control group (ROC-AUCs of 0.98 and 0.97, respectively). CONCLUSION: Quantitative assessments of T1 relaxation time and MRE-derived stiffness had high performance in detecting mild CP and could probably reflect the early fibrotic changes in CP.

Although tapentadol and oxycodone both increase colonic volume, tapentadol treatment resulted in softer stools and less constipation: a mechanistic study in healthy volunteers.

OBJECTIVES: Opioids are often used in treatment of severe pain, although many patients experience gastrointestinal side-effects like constipation. The aim of the current study was to investigate changes in colonic volume, as the result of both colonic motility and fluid transport, in healthy volunteers during opioid treatment with tapentadol as compared with oxycodone and placebo. METHODS: In a randomized, double-blind, cross-over study, 21 healthy male volunteers were administered equianalgesic dosages of oral tapentadol (50 mg bid), oxycodone (10 mg bid) or corresponding placebo for 14 days. Segmental colonic volumes were quantified using T2-weighted magnetic resonance images, and gastrointestinal side-effects were assessed with questionnaires. RESULTS: Total colonic volume increase during treatment was higher during tapentadol and oxycodone treatment (median 48 and 58 mL) compared to placebo (median -14 mL, both p≤0.003). Tapentadol (and placebo) treatment resulted in more bowel movements (both p<0.05) and softer stool consistency as compared with oxycodone (both p<0.01). Only oxycodone treatment was associated with increased constipation, straining during defecation, and tiredness (all p≤0.01). The colonic volume increase during treatment was directly associated with softer stools during tapentadol treatment (p=0.019). CONCLUSIONS: Tapentadol treatment increased colonic volume without leading to harder stools, likely as the opioid sparing effects result in less water absorption from the gut lumen. Oxycodone treatment also increased colonic volume, but with a simultaneous increase in stool dryness and gastrointestinal and central nervous system side-effects. The results confirm that tapentadol treatment may be advantageous to oxycodone regarding tolerability to pain treatment.

The effects of tapentadol and oxycodone on central processing of tonic pain.

OBJECTIVE: The present study investigated differences between opioids to experimental tonic pain in healthy men. METHODS: Twenty-one males participated in this cross-over-trial. Interventions twice daily were oxycodone (10 mg), tapentadol (50 mg) and placebo for 14 days. Tonic pain was induced on day 1, 4 and 14 by immersing the hand in 2 °C water for 120 s. Electroencephalography was recorded during test pain at baseline and after 14 days. Spectral analysis and source localization were investigated in predefined frequency bands. RESULTS: A decreased perception of pain on day 4 persisted throughout the 14 days compared to baseline (p < 0.006). Oxycodone decreased the electroencephalography spectral power in the delta and theta bands and increased power in the alpha1, alpha2 and beta1 bands (p < 0.03). Tapentadol increased spectral power in the alpha1 band (p < 0.001). Source localization revealed that oxycodone decreased activity of the temporal and limbic region in the delta band, and frontal lobe in the alpha2 and beta1 bands, whereas tapentadol decreased alpha1 band activity in the temporal lobe compared to placebo. CONCLUSION: Oxycodone and tapentadol reduced pain perception and changed the central processing of tonic pain. SIGNIFICANCE: Different mechanisms of action were involved, where oxycodone affected cortical structures more than tapentadol.

Cervical transcutaneous vagal neuromodulation in chronic pancreatitis patients with chronic pain: A randomised sham controlled clinical trial.

BACKGROUND & AIMS: Chronic abdominal pain is the primary symptom of chronic pancreatitis, but unfortunately it is difficult to treat. Vagal nerve stimulation studies have provided evidence of anti-nociceptive effect in several chronic pain conditions. We investigated the pain-relieving effects of transcutaneous vagal nerve stimulation in comparison to sham treatment in chronic pancreatitis patients. METHODS: We conducted a randomised double-blinded, sham-controlled, crossover trial in patients with chronic pancreatitis. Patients were randomly assigned to receive a two-week period of cervical transcutaneous vagal nerve stimulation using the gammaCore device followed by a two-week sham stimulation, or vice versa. We measured clinical and experimental endpoints before and after each treatment. The primary clinical endpoint was pain relief, documented in a pain diary using a visual analogue scale. Secondary clinical endpoints included Patients' Global Impression of Change score, quality of life and Brief Pain Inventory questionnaire. Secondary experimental endpoints included cardiac vagal tone and heart rate. RESULTS: No differences in pain scores were seen in response to two weeks transcutaneous vagal nerve stimulation as compared to sham treatment (difference in average pain score (visual analogue scale): 0.17, 95%CI (-0.86;1.20), P = 0.7). Similarly, no differences were seen for secondary clinical endpoints, except from an increase in the appetite loss score (13.9, 95%CI (0.5:27.3), P = 0.04). However, improvements in maximum pain scores were seen for transcutaneous vagal nerve stimulation and sham treatments as compared to their respective baselines: vagal nerve stimulation (-1.3±1.7, 95%CI (-2.21:-0.42), P = 0.007), sham (-1.3±1.9, 95%CI (-2.28:-0.25), P = 0.018). Finally, heart rate was decreased after two weeks transcutaneous vagal nerve stimulation in comparison to sham treatment (-3.7 beats/min, 95%CI (-6.7:-0.6), P = 0.02). CONCLUSION: In this sham-controlled crossover study, we found no evidence that two weeks transcutaneous vagal nerve stimulation induces pain relief in patients with chronic pancreatitis. TRIAL REGISTRATION NUMBER: The study is registered at NCT03357029; www.clinicaltrials.gov.