Publications by authors named "Tine Maria Hansen"

21 Publications

  • Page 1 of 1

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

Abdom Radiol (NY) 2021 Sep 15. Epub 2021 Sep 15.

Mech-Sense, Department of Radiology, Aalborg University Hospital, Hobrovej 18-22, PO. Box 365, 9000, Aalborg, Denmark.

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.
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http://dx.doi.org/10.1007/s00261-021-03276-5DOI Listing
September 2021

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

Clin Neurophysiol 2021 Aug 17;132(10):2342-2350. Epub 2021 Aug 17.

Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark. Electronic address:

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.
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http://dx.doi.org/10.1016/j.clinph.2021.07.021DOI Listing
August 2021

Tapentadol and oxycodone reduce cingulate glutamate in healthy volunteers.

Br J Clin Pharmacol 2021 Aug 24. Epub 2021 Aug 24.

Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.

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.
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http://dx.doi.org/10.1111/bcp.15050DOI Listing
August 2021

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

Neuromodulation 2021 Jun 14. Epub 2021 Jun 14.

Mech-Sense, Department of Radiology, Aalborg University Hospital, Aalborg, Denmark.

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.
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http://dx.doi.org/10.1111/ner.13482DOI Listing
June 2021

Practical and clinical applications of pancreatic magnetic resonance elastography: a systematic review.

Abdom Radiol (NY) 2021 10 2;46(10):4744-4764. Epub 2021 Jun 2.

Mech-Sense, Department of Radiology, Aalborg University Hospital, Hobrovej 18-22, PO. Box 365, 9000, Aalborg, Denmark.

Magnetic resonance elastography (MRE) is a non-invasive technique suitable for assessing mechanical properties of tissues, i.e., stiffness. MRE of the pancreas is relatively new, but recently an increasing number of studies have successfully assessed pancreas diseases with MRE aiming to differentiate healthy from pathological pancreatic tissue with or without fibrosis. This review will systematically describe the practical and clinical applications of pancreatic MRE. We conducted a systematic literature search with a pre-specified search strategy using PubMed and Embase according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. English peer-reviewed articles applying MRE of the pancreas were included. Two independent reviewers assessed the studies. The literature search yielded 14 studies. The pancreatic stiffness for healthy volunteers ranged from 1.11. to 1.21 kPa at a driver frequency of 40 Hz. In benign tumors, the stiffness values were slightly higher or sometimes even lower (range 0.78 to 2.00 kPa), compared to the healthy pancreas parenchyma whereas, in malignant tumors, the stiffness values tended to be higher (1.42 to 6.06 kPa). The pancreatic stiffness was increased in both acute (median: 1.99 kPa) and chronic pancreatitis (> 1.50 kPa). MRE is a promising technique for detecting and quantifying pancreatic stiffness. It is related to fibrosis and seems to be useful in assessing treatment response and clinical follow-up of pancreatic diseases. However, most of the described practical settings were characterized by a lack of uniformity and inconsistency in reporting standards across studies. Harmonization between centers is necessary to achieve more consensus and optimization of pancreatic MRE protocols.
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http://dx.doi.org/10.1007/s00261-021-03143-3DOI Listing
October 2021

Tapentadol results in less deterioration of gastrointestinal function and symptoms than standard opioid therapy in healthy male volunteers.

Neurogastroenterol Motil 2021 May 29:e14131. Epub 2021 May 29.

Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark.

Background: Tapentadol is a combined opioid agonist and norepinephrine reuptake inhibitor with fewer gastrointestinal side effects at equianalgesic doses compared with classical strong opioids. Previous studies on tapentadol have included multi-morbid patients in whom confounders exclude detailed assessment of the mechanistic effects and strict comparison with other opioids or placebo. This study aimed at investigating the effects of tapentadol and oxycodone on gastrointestinal motility and gastrointestinal side effects.

Methods: 21 healthy males participated in a randomized, double-blind, placebo-controlled, crossover study. Tapentadol (50 mg twice daily), oxycodone (10 mg twice daily), or placebo tablets were administered for 14 days. Segmental gastrointestinal transit times and colonic motility parameters were measured with electromagnetic capsules. Gastrointestinal side effects were assessed using questionnaires.

Key Results: During dosing with tapentadol, gastrointestinal side effects and motility parameters were on placebo level. Compared with tapentadol, oxycodone increased whole gut transit time by 17.9 hours (p = .015) and rectosigmoid transit time by 6.5 hours (p = .005). Compared with tapentadol, oxycodone also reduced long, fast antegrade colonic movements (p = .001). In comparison with placebo, oxycodone prolonged whole gut transit time by 31.6 hours, (p < .001). Moreover, less long, fast antegrade colonic movements (p = .002) were observed during oxycodone. For oxycodone only, slow colonic movements were associated with gastrointestinal side effects.

Conclusions & Inferences: In this mechanistic study, tapentadol caused significantly less colonic dysmotility and gastrointestinal side effects as compared with oxycodone in equianalgesic doses.
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http://dx.doi.org/10.1111/nmo.14131DOI Listing
May 2021

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

PLoS One 2021 26;16(2):e0247653. Epub 2021 Feb 26.

Mech-Sense, Department of Radiology, Aalborg University Hospital, Aalborg, Denmark.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247653PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909707PMC
August 2021

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

Scand J Pain 2021 Apr 22;21(2):406-414. Epub 2021 Feb 22.

Department of Gastroenterology and Hepatology, Mech-Sense, Aalborg University Hospital, Aalborg, Denmark.

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.
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http://dx.doi.org/10.1515/sjpain-2020-0151DOI Listing
April 2021

Pancreatic magnetic resonance imaging texture analysis in chronic pancreatitis: a feasibility and validation study.

Abdom Radiol (NY) 2020 05;45(5):1497-1506

Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.

Purpose: This feasibility and validation study addresses the potential use of magnetic resonance imaging (MRI) texture analysis of the pancreas in patients with chronic pancreatitis (CP).

Methods: Extraction of 851 MRI texture features from diffusion weighted imaging (DWI) of the pancreas was performed in 77 CP patients and 22 healthy controls. Features were reduced to classify patients into subgroups, and a Bayes classifier was trained using a tenfold cross-validation forward selection procedure. The classifier was optimized to obtain the best average m-fold accuracy, sensitivity, specificity, and positive predictive value. Classifiers were: presence of disease (CP vs. healthy controls), etiological risk factors (alcoholic vs. nonalcoholic etiology of CP and tobacco use vs. no tobacco use), and complications to CP (presumed pancreatogenic diabetes vs. no diabetes and pancreatic exocrine insufficiency vs. normal pancreatic function).

Results: The best classification performance was obtained for the disease classifier selecting only five of the original features with 98% accuracy, 97% sensitivity, 100% specificity, and 100% positive predictive value. The risk factor classifiers obtained good performance using 9 (alcohol: 88% accuracy) and 10 features (tobacco: 86% accuracy). The two complication classifiers obtained similar accuracies with only 4 (diabetes: 83% accuracy) and 3 features (exocrine pancreatic function: 82% accuracy).

Conclusion: Pancreatic texture analysis demonstrated to be feasible in patients with CP and discriminate clinically relevant subgroups based on etiological risk factors and complications. In future studies, the method may provide useful information on disease progression (monitoring) and detection of biomarkers characterizing early-stage CP.
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http://dx.doi.org/10.1007/s00261-020-02512-8DOI Listing
May 2020

Disrupted functional connectivity of default mode and salience networks in chronic pancreatitis patients.

Clin Neurophysiol 2020 05 10;131(5):1021-1029. Epub 2020 Feb 10.

Mech-Sense, Department of Radiology, Aalborg University Hospital, Hobrovej 18-22, 9000 Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Søndre Skovvej 11, 9000 Aalborg, Denmark. Electronic address:

Objective: The functional connectivity of the brain in chronic pancreatitis (CP) remains unknown. This study aimed to investigate functional connectivity in CP patients using resting state functional magnetic resonance imaging (fMRI) and explore the associations to clinical parameters and altered cerebral metabolites.

Methods: Seed-based and ROI-to-ROI analyses were performed to assess connectivity within and between the default mode network (DMN) and salience network (SN). Additionally, functional connectivity in these networks were investigated in relation to clinical parameters (CP etiology, pain, medication, etc.) and cerebral glutamate/creatine level in the anterior cingulate cortex.

Results: Thirty CP patients and 23 healthy controls were analyzed. CP patients showed hyper-connectivity in DMN and SN as compared to healthy controls. Furthermore, CP patients had reduced anti-correlated functional connectivity between DMN and SN (all P ≤ 0.009). The altered DMN connectivity correlated to glutamate/creatine level (r = 0.503, P = 0.020) in patients with pain, but not to the clinical parameters.

Conclusions: CP patients had altered functional connectivity within and between brain networks. Altered DMN functional connectivity had an association to cerebral metabolic changes.

Significance: Altered functional connectivity in CP share similarities with other chronic pain conditions, and support our understanding of altered brain circuitry associated with the CP disease.
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http://dx.doi.org/10.1016/j.clinph.2020.01.016DOI Listing
May 2020

Progression of parenchymal and ductal findings in patients with chronic pancreatitis: A 4-year follow-up MRI study.

Eur J Radiol 2020 Apr 7;125:108868. Epub 2020 Feb 7.

Mech-Sense, Department of Radiology, Aalborg University Hospital, Hobrovej 18-22, 9000 Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Søndre Skovvej 11, 9000 Aalborg, Denmark. Electronic address:

Purpose: Knowledge of the underlying mechanisms behind progression of chronic pancreatitis (CP) is needed to identify targets for new mechanism-based treatments. There is an urgent need for imaging biomarkers that can detect early morphological and functional pancreatic damage in order to initiate intervention and reduce the progression of CP at an early stage. The aim of our study was to assess and explore the potential role of structural magnetic resonance imaging (MRI) biomarkers for characterisation of disease progression in a CP patient cohort over a 4-year period.

Methods: This longitudinal MRI study included twenty-five patients with definitive CP. Assessments of morphological imaging parameters at baseline and after 4 years included pancreatic gland volume, apparent diffusion coefficient (ADC) values, fat signal fraction (FSF) and main pancreatic duct (MPD) diameter. Patients were classified according to the modified Cambridge classification.

Results: CP patients developed significantly reduced pancreatic gland volume, which decreased from mean 50.3 ± 19.6 ml at baseline to 43.5 ± 20.8 ml at follow-up (P < 0.001), decreased ADC values, meaning a higher degree of fibrosis (P < 0.001), increased FSF, meaning more fat infiltration (P < 0.001) and higher Cambridge classification scores (P = 0.033). The MPD diameter in the pancreatic head, body and tail did not change significantly over time (all P > 0.05). Only few, but no clear and systematic, associations were found between the progressions of the individual MRI measures.

Conclusions: Morphological progression in patients with established CP seems to be primarily parenchymal-related. The different parenchymal changes were mostly unrelated and probably reflect diverse pathophysiological processes.
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http://dx.doi.org/10.1016/j.ejrad.2020.108868DOI Listing
April 2020

Study protocol for a randomised double-blinded, sham-controlled, prospective, cross-over clinical trial of vagal neuromodulation for pain treatment in patients with chronic pancreatitis.

BMJ Open 2019 08 23;9(7):e029546. Epub 2019 Aug 23.

Mech-Sense, Department of Radiology, Aalborg University Hospital, Aalborg, Denmark.

Introduction: The management of chronic pancreatitis (CP) is challenging and requires a personalised approach focused on the individual patient's main symptoms. Abdominal pain is the most prominent symptom in CP, where central pain mechanisms, including sensitisation and impaired pain modulation, often are involved. Recent clinical studies suggest that vagal nerve stimulation (VNS) induces analgesic effects through the modulation of central pain pathways. This study aims to investigate the effect of 2 weeks transcutaneous VNS (t-VNS) on clinical pain in patients with CP, in comparison to the effect of sham treatment.

Methods And Analysis: Twenty-one patients with CP will be enrolled in this randomised, double-blinded, single-centre, sham-controlled, cross-over study. The study has two treatment periods: A 2-week active t-VNS using GammaCore device and a 2-week treatment with a sham device. During both treatment periods, the patients are instructed to self-administer VNS bilaterally to the cervical vagal area, three times per day. Treatment periods will be separated by 2 weeks. During the study period, patients will record their daily pain experience in a diary (primary clinical endpoint). In addition, all subjects will undergo testing which will include MRI, quantitative sensory testing, cardiac vagal tone assessment and collecting blood samples, before and after the two treatments to investigate mechanisms underlying VNS effects. The data will be analysed using the principle of intention to treat.

Ethics And Dissemination: The regional ethics committee has approved the study: N-20170023. Results of the trial will be submitted for publication in peer-reviewed journals.

Trial Registration Number: The study is registered at www.clinicaltrials.gov: NCT03357029.
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http://dx.doi.org/10.1136/bmjopen-2019-029546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720238PMC
August 2019

Cingulate glutamate levels associate with pain in chronic pancreatitis patients.

Neuroimage Clin 2019 2;23:101925. Epub 2019 Jul 2.

Mech-Sense, Department of Radiology, Aalborg University Hospital, Hobrovej 18-22, 9000 Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Søndre Skovvej 11, 9000 Aalborg, Denmark. Electronic address:

Aims: Emerging evidence show that patients with chronic pancreatitis (CP) and abdominal pain have structural and functional alterations in the central nervous system. The aim was to investigate cerebral metabolic signatures in CP and the associations to various risk factors/clinical characteristics and patient outcomes.

Methods: Magnetic resonance spectroscopy was used to measure brain metabolites in the anterior cingulate cortex (ACC), insula, prefrontal cortex and the parietal region in patients with CP and healthy controls. Subgroup analyses based on disease characteristics (alcoholic etiology of CP, diabetes and opioid treatment) were performed. Finally, relations to abdominal pain symptoms and quality of life scores were explored.

Results: Thirty-one patients with CP (mean age 58.5 ± 9.2 years) and 23 healthy controls (54.6 ± 7.8 years) were included. Compared to healthy controls, patients had increased glutamate/creatine (glu/cre) levels in the ACC (1.24 ± 0.17 vs. 1.13 ± 0.21, p = .045) and reduced parietal N-acetylaspartate/creatine (NAA/cre) levels (1.44 ± 0.18 vs. 1.54 ± 0.12, p = .027). Patients with alcoholic etiology of CP had significant lower levels of parietal NAA/cre as compared to patients without alcoholic etiology and healthy controls (p < .006). Patients with a high level of ACC glu/cre reported more severe abdominal pain than their counterparts with a low level of ACC glu/cre (pain score 4.1 ± 2.7 vs.1.9 ± 2.3, p = .039).

Conclusions: Cerebral spectroscopy revealed novel and complementary information on central pain mechanisms and alcohol mediated toxic effects in patients with CP. Our data suggest that cingulate glutamate levels associate with the patients clinical pain symptoms, while parietal NAA levels more likely associate with an alcoholic etiology of CP.
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http://dx.doi.org/10.1016/j.nicl.2019.101925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627035PMC
August 2020

Brain spectroscopy reveals that N-acetylaspartate is associated to peripheral sensorimotor neuropathy in type 1 diabetes.

J Diabetes Complications 2019 04 4;33(4):323-328. Epub 2019 Jan 4.

Department of Clinical Medicine, Aalborg University, Søndre Skovvej 11, 9000 Aalborg, Denmark; Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Mølleparkvej 4, 9000 Aalborg, Denmark; Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.

Aims: Emerging evidence shows, that distal symmetric peripheral neuropathy (DSPN) also involves alterations in the central nervous system. Hence, the aims were to investigate brain metabolites in white matter of adults with diabetes and DSPN, and to compare any cerebral disparities with peripheral nerve characteristics.

Methods: In type 1 diabetes, brain metabolites of 47 adults with confirmed DSPN were compared with 28 matched healthy controls using proton magnetic resonance spectroscopy (H-MRS) in the parietal region including the sensorimotor fiber tracts.

Results: Adults with diabetes had 9.3% lower ratio of N-acetylaspartate/creatine (NAA/cre) in comparison to healthy (p < 0.001). Lower NAA/cre was associated with lower sural (p = 0.01) and tibial (p = 0.04) nerve amplitudes, longer diabetes duration (p = 0.03) and higher age (p = 0.03). In addition, NAA/cre was significantly lower in the subgroup with proliferative retinopathy as compared to the subgroup with non-proliferative retinopathy (p = 0.02).

Conclusions: The association to peripheral nerve dysfunction, indicates concomitant presence of DSPN and central neuropathies, supporting the increasing recognition of diabetic neuropathy being, at least partly, a disease leading to polyneuropathy. Decreased NAA, is a potential promising biomarker of central neuronal dysfunction or loss, and thus may be useful to measure progression of neuropathy in diabetes or other neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.jdiacomp.2018.12.016DOI Listing
April 2019

Progression of Structural Brain Changes in Patients With Chronic Pancreatitis and Its Association to Chronic Pain: A 7-Year Longitudinal Follow-up Study.

Pancreas 2018 Nov/Dec;47(10):1267-1276

Objectives: Temporal information about the structural brain changes in chronic pancreatitis (CP) and its relation to the clinical manifestations is lacking. This study investigated changes in morphological brain parameters over 7 years in painful CP patients, compared with controls.

Methods: In this 7-year longitudinal magnetic resonance imaging study, we included 23 CP patients and 14 controls. Gray matter volume (GMV) and cortical thickness were examined using voxel-based and surface-based morphometry. In addition, patients completed pain questionnaires and diary.

Results: At baseline, patients had reduced GMV and cortical thickness in widespread brain areas compared with controls. After 7 years of follow-up, the GMV loss was more pronounced in patients compared with controls, particularly in precentral gyrus and putamen. Moreover, an increase in pain scores was associated with a less reduction of thalamic GMV (P = 0.046), whereas an increase in brief pain inventory score was associated with more reduction in cortical thickness of precentral (P = 0.005) and superior temporal gyri (P = 0.019), indicating that brain morphological alterations are associated with the pain.

Conclusions: Chronic pancreatitis pain is associated with morphological brain changes over time in several areas, reflecting that brain plasticity may be a consequence of repeated long-term nociceptive signaling.
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http://dx.doi.org/10.1097/MPA.0000000000001151DOI Listing
March 2019

Characterization of cortical source generators based on electroencephalography during tonic pain.

J Pain Res 2017 7;10:1401-1409. Epub 2017 Jun 7.

Department of Clinical Medicine, Aalborg University.

Objective: The aim of the present study was to characterize the cortical source generators evoked by experimental tonic pain.

Methods: Electroencephalography (EEG) was recorded on two separate days during rest and with immersion of the hand in ice water for 2 minutes (cold pressor test). Exact low-resolution brain electromagnetic tomography source localization was performed in 31 healthy volunteers to characterize the cortical source generators.

Results: Reliability was high in all eight frequency bands during rest and cold pressor conditions (intraclass coefficients =0.47-0.83 in the cingulate and insula). Tonic pain increased cortical activities in the delta (1-4 Hz), theta (4-8 Hz), beta1 (12-18 Hz), beta2 (18-24 Hz), beta3 (24-32 Hz), and gamma (32-60 Hz) bands (all <0.011) in widespread areas mainly in the limbic system, whereas decreased cortical activities were found in cingulate and pre- and postcentral gyri in the alpha2 (10-12 Hz) band (=0.007). The pain intensity was correlated with cingulate activity in the beta2, beta3, and gamma bands (all <0.04).

Conclusion: Source localization of EEG is a reliable method to estimate cortical source generators. Activities in different brain regions, mainly in the limbic system, showed fluctuations in various frequency bands. Cingulate changes were correlated with pain intensity.

Significance: This method might add information to the objective assessment of the cortical pain response in future experimental pain studies.
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http://dx.doi.org/10.2147/JPR.S132909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5476635PMC
June 2017

Acute Metabolic Changes Associated With Analgesic Drugs: An MR Spectroscopy Study.

J Neuroimaging 2016 09 30;26(5):545-51. Epub 2016 Mar 30.

Mech-Sense, Department of Radiology, Aalborg University Hospital, Aalborg, Denmark.

Background And Purpose: Magnetic resonance spectroscopy (MRS) is used to measure brain metabolites. Limited data exist on the analgesic-induced spectroscopy response. This was an explorative study with the aims to investigate the central effects of two analgesic drugs, an opioid and a selective serotonin and norepinephrine reuptake inhibitor, and to explore the association between metabolite changes and the analgesic effect and side effects.

Methods: Single voxel proton spectroscopy measurements were performed in the anterior cingulate cortex, insula and prefrontal cortex in 20 healthy subjects before and after treatment for 5 days with oxycodone (eight doses of 10 mg extended release), venlafaxine (eight doses of 37.5 mg extended release) or placebo in a randomized double-blind fashion. The metabolites of glutamate, N-acetylaspartate, and myo-inositol were analyzed in ratios to creatine.

Results: Including all areas, the glutamate/creatine ratio was decreased (P < .05) with 8.4% ± 0.3% after oxycodone treatment (P = .02) and 6.6% ± 0.4% after venlafaxine treatment (P = .07) as compared to placebo. No statistical significant differences in treatment effects across the areas were found (P = .6). No treatment effect was seen for N-acetylaspartate/creatine or myo-inositol/creatine ratios (all P > .05). No associations between treatment induced glutamate/creatine changes and the analgesic effect and side effects were demonstrated (all P > .05).

Conclusions: MRS can be used to detect brain metabolites following acute analgesic treatments and glutamate is central in these mechanisms. Consequently, MRS might be a valuable tool to objectively evaluate analgesic effects and a potential biomarker to predict treatment outcomes and more research is needed.
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http://dx.doi.org/10.1111/jon.12345DOI Listing
September 2016

The Effect of Oral Morphine on Pain-Related Brain Activation - An Experimental Functional Magnetic Resonance Imaging Study.

Basic Clin Pharmacol Toxicol 2015 Nov 29;117(5):316-22. Epub 2015 May 29.

Mech-Sense, Department of Radiology, Aalborg University Hospital, Aalborg, Denmark.

Knowledge about cerebral mechanisms underlying pain perception and effect of analgesic drugs is important for developing methods for diagnosis and treatment of pain. The aim was to explore altered brain activation before and after morphine treatment using functional magnetic resonance imaging recorded during experimental painful heat stimulation. Functional magnetic resonance imaging data were recorded and analysed in 20 healthy volunteers (13 men and 7 women, 24.9 ± 2.6 years) in a randomized, double-blind, placebo-controlled, cross-over study. Painful stimulations were applied to the right forearm using a contact heat evoked potential stimulator (CHEPS) before and after treatment with 30 mg oral morphine and placebo. CHEPS stimulations before treatment induced activation in the anterior cingulate cortex, secondary somatosensory cortex/insula, thalamus and cerebellum (n = 16, p < 0.05). In response to morphine treatment, the spatial extent of these pain-specific areas decreased (n = 20). Reduced pain-induced activation was seen in the right insula, anterior cingulate cortex and inferior parietal cortex after morphine treatment compared to before treatment (n = 16, p < 0.05), and sensory ratings of pain perception were significantly reduced after morphine treatment (p = 0.02). No effect on pain-induced brain activation was seen after placebo treatment compared to before treatment (n = 12, p > 0.05). In conclusion, heat stimulation activated areas in the 'pain matrix' and a clinically relevant dose of orally administered morphine revealed significant changes in brain areas where opioidergic pathways are predominant. The method may be useful to investigate the mechanisms of analgesics.
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http://dx.doi.org/10.1111/bcpt.12415DOI Listing
November 2015

Cingulate metabolites during pain and morphine treatment as assessed by magnetic resonance spectroscopy.

J Pain Res 2014 19;7:269-76. Epub 2014 May 19.

Mech-Sense, Department of Radiology, Aalborg University, Aalborg, Denmark.

Background: Experimental investigation of cerebral mechanisms underlying pain and analgesia are important in the development of methods for diagnosis and treatment of pain. The aim of the current study was to explore brain metabolites in response to pain and treatment with morphine.

Methods: Proton magnetic resonance spectroscopy of the anterior cingulate cortex was performed in 20 healthy volunteers (13 males and seven females, aged 24.9±2.6 years) during rest and acute pain before and during treatment with 30 mg of oral morphine or placebo in a randomized, double-blinded, cross-over study design. Pain was evoked by skin stimulation applied to the right upper leg using a contact heat-evoked potential stimulator.

Results: Data from 12 subjects were valid for analysis. Painful stimulation induced an increase in N-acetylaspartate/creatine compared with rest (F=5.5, P=0.04). During treatment with morphine, painful stimulation induced decreased glutamate/creatine (F=7.3, P=0.02), myo-inositol/creatine (F=8.38, P=0.02), and N-acetylaspartate/creatine (F=13.8, P=0.004) concentrations, whereas an increase in the pain-evoked N-acetylaspartate/creatine concentration (F=6.1, P=0.04) was seen during treatment with placebo.

Conclusion: This explorative study indicates that neuronal metabolites in the anterior cingulate cortex, such as N-acetylaspartate, glutamate, and myo-inositol, could be related to the physiology of pain and treatment with morphine. This experimental method has the potential to enable the study of brain metabolites involved in pain and its treatment, and may in the future be used to provide further insight into these mechanisms.
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http://dx.doi.org/10.2147/JPR.S61193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038455PMC
June 2014

Morphological and functional evaluation of chronic pancreatitis with magnetic resonance imaging.

World J Gastroenterol 2013 Nov;19(42):7241-6

Tine Maria Hansen, Jens Brøndum Frøkjær, Mech-Sense, Department of Radiology, Aalborg University Hospital, 9000 Aalborg, Denmark.

Magnetic resonance imaging (MRI) techniques for assessment of morphology and function of the pancreas have been improved dramatically the recent years and MRI is very often used in diagnosing and follow-up of chronic pancreatitis (CP) patients. Standard MRI including fat-suppressed T1-weighted and T2-weighted imaging techniques reveal decreased signal and glandular atrophy of the pancreas in CP. In contrast-enhanced MRI of the pancreas in CP the pancreatic signal is usually reduced and delayed due to decreased perfusion as a result of chronic inflammation and fibrosis. Thus, morphological changes of the ductal system can be assessed by magnetic resonance cholangiopancreatography (MRCP). Furthermore, secretin-stimulated MRCP is a valuable technique to evaluate side branch pathology and the exocrine function of the pancreas and diffusion weighted imaging can be used to quantify both parenchymal fibrotic changes and the exocrine function of the pancreas. These standard and advanced MRI techniques are supplementary techniques to reveal morphological and functional changes of the pancreas in CP. Recently, spectroscopy has been used for assessment of metabolite concentrations in-vivo in different tissues and may have the potential to offer better tissue characterization of the pancreas. Hence, the purpose of the present review is to provide an update on standard and advanced MRI techniques of the pancreas in CP.
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http://dx.doi.org/10.3748/wjg.v19.i42.7241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3831205PMC
November 2013

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

Scand J Gastroenterol 2011 Jul 25;46(7-8):988-96. Epub 2011 May 25.

Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg Hospital, Aarhus University Hospital, Denmark.

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.
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http://dx.doi.org/10.3109/00365521.2011.579160DOI Listing
July 2011
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