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Hansen TM, Croosu SS, Røikjer J, Mørch CD, Ejskjaer N, Frøkjær JB. Neuropathic phenotypes of type 1 diabetes are related to different signatures of magnetic resonance spectroscopy-assessed brain metabolites. Clin Neurophysiol 2024; 166:11-19. [PMID: 39084155 DOI: 10.1016/j.clinph.2024.06.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 12/30/2023] [Accepted: 06/15/2024] [Indexed: 08/02/2024]
Abstract
OBJECTIVES The study aimed to investigate brain metabolites in type 1 diabetes and the associations with disease characteristics. We explored the metabolic profiles predicting different neuropathic phenotypes using multiple linear regression analyses. METHODS We compared brain metabolites in 55 adults with type 1 diabetes (including painful diabetic peripheral neuropathy (DPN), painless DPN, without DPN) with 20 healthy controls. Proton magnetic resonance spectroscopy measurements (N-acetylaspartate (NAA), glutamate (glu), myo-inositol (mI), and glycerophosphocholine (GPC) were obtained in ratios to creatine (cre)) from the parietal region, anterior cingulate cortex and thalamus. RESULTS The overall diabetes group revealed decreased parietal NAA/cre compared to healthy controls (1.41 ± 0.12 vs. 1.55 ± 0.13,p < 0.001) and increased mI/cre (parietal: 0.62 ± 0.08 vs. 0.57 ± 0.07,p = 0.025, cingulate: 0.65 ± 0.08 vs. 0.60 ± 0.08,p = 0.033). Reduced NAA/cre was associated with more severe DPN (all p ≤ 0.04) whereas increased mI/cre was associated with higher hemoglobin A1c (HbA1c) (p = 0.02). Diabetes was predicted from decreased parietal NAA/cre, increased parietal ml/cre, and decreased thalamic glu/cre. DPN was predicted from decreased parietal NAA/cre and increased GPC/cre. Painful DPN was predicted from increased parietal GPC/cre and thalamic glu/cre. CONCLUSIONS Specific metabolic brain profiles were linked to the different phenotypes of diabetes, DPN and painful DPN. SIGNIFICANCE Assessment of metabolic profiles could be relevant for detailed understanding of central neuropathy in diabetes.
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Affiliation(s)
- Tine M Hansen
- Department of Radiology, Aalborg University Hospital, Hobrovej 18-22, 9000 Aalborg, Denmark; Department of Clinical Medicine, Faculty of Medicine, Aalborg University, Søndre Skovvej 15, 9000 Aalborg, Denmark
| | - Suganthiya S Croosu
- Department of Radiology, Aalborg University Hospital, Hobrovej 18-22, 9000 Aalborg, Denmark; Department of Clinical Medicine, Faculty of Medicine, Aalborg University, Søndre Skovvej 15, 9000 Aalborg, Denmark; Steno Diabetes Center North Denmark, Aalborg University Hospital, Mølleparkvej 4, 9000 Aalborg, Denmark
| | - Johan Røikjer
- Steno Diabetes Center North Denmark, Aalborg University Hospital, Mølleparkvej 4, 9000 Aalborg, Denmark; Integrative Neuroscience, Aalborg University, Selma Lagerlöfs Vej 249, 9260 Gistrup, Denmark
| | - Carsten D Mørch
- Integrative Neuroscience, Aalborg University, Selma Lagerlöfs Vej 249, 9260 Gistrup, Denmark; Center for Neuroplasticity and Pain (CNAP), SMI, Department of Health Science and Technology, Aalborg University, Selma Lagerlöfs Vej 249, 9260 Gistrup, Denmark
| | - Niels Ejskjaer
- Department of Clinical Medicine, Faculty of Medicine, Aalborg University, Søndre Skovvej 15, 9000 Aalborg, Denmark; Steno Diabetes Center North Denmark, Aalborg University Hospital, Mølleparkvej 4, 9000 Aalborg, Denmark; Department of Endocrinology, Aalborg University Hospital, Mølleparkvej 4, 9000 Aalborg, Denmark
| | - Jens B Frøkjær
- Department of Radiology, Aalborg University Hospital, Hobrovej 18-22, 9000 Aalborg, Denmark; Department of Clinical Medicine, Faculty of Medicine, Aalborg University, Søndre Skovvej 15, 9000 Aalborg, Denmark
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Binetti M, Tonini V. Pain in chronic pancreatitis: What can we do today? World J Methodol 2024; 14:91169. [PMID: 39310237 PMCID: PMC11230078 DOI: 10.5662/wjm.v14.i3.91169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 01/23/2024] [Accepted: 03/11/2024] [Indexed: 06/25/2024] Open
Abstract
The aim of this study is to illustrate the complexity of pain management in chronic pancreatitis (CP). In this context, pain represents the most common and debilitating symptom, and it deeply affects patient's quality of life. Multiple rating scales (unidimensional, bidimensional and multidimensional) have been proposed to quantify CP pain. However, it represents the result of complex mechanisms, involving genetic, neuropathic and neurogenic factors. Considering all these aspects, the treatment should be discussed in a multidisciplinary setting and it should be approached in a stepwise manner. First, a lifestyle change is recommended and nonsteroidal anti-inflammatory drugs represent the gold standard among medical treatments for CP patients. The second step, after medical approach, is endoscopic therapy, especially for complicated CP. In case of failure, tailored surgery represents the third step and decompressive or resection procedures can be chosen. In conclusion, CP pain's management is challenging considering all these complex aspects and the lack of international protocols.
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Affiliation(s)
- Margherita Binetti
- Department of Medical and Surgical Science, University of Bologna, Alma mater Studiorum, Bologna 40138, Italy
| | - Valeria Tonini
- Department of Medical and Surgical Science, University of Bologna, Alma mater Studiorum, Bologna 40138, Italy
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Kawka M, Lucas A, Riad AM, Hawkins D, de Madaria E, West H, Jakaityte I, Lee MJ, Kouli O, Ruanne R, Gujjuri RR, Brown S, Cambridge WA, Pandanaboyana S, Kamarajah SK, McLean KA. Quality of life instruments in acute and chronic pancreatitis: a consensus-based standards for the selection of health measurement instruments (COSMIN) approach. HPB (Oxford) 2024; 26:859-872. [PMID: 38735815 DOI: 10.1016/j.hpb.2024.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 04/07/2024] [Accepted: 04/18/2024] [Indexed: 05/14/2024]
Abstract
BACKGROUND Pancreatitis is a common surgical emergency, associated with pain and poor quality of life for patients. However, assessment of patient-reported outcome measures in these patients is unclear. This study aimed to identify and evaluate the methodological quality of the health-related quality of life instruments used for patients with acute or chronic pancreatitis. METHODS Prospective studies that evaluated health-related quality of life in acute or chronic pancreatitis were identified from systematic review of MEDLINE, EMBASE, and Web of Science until 28th June 2023 (PROSPERO: CRD42021274743). Instrument characteristics were extracted, and methodological quality assessed using COSMIN (COnsensus-based Standards for the selection of health status Measurement Instruments) guidelines and GRADE approach. Narrative synthesis was conducted, with recommendations for use based on COSMIN criteria, evaluated according to World Health Organisation (WHO) quality of life domains. RESULTS From 3850 records screened, 41 quality of life instruments were identified across 138 studies included. The majority (69.8%, n = 26) were designed to assess general health-related quality of life, whereas the remainder were abdominal-specific (n = 5) or pancreas-specific (n = 10). Only ten instruments (24.3%) demonstrated sufficient content validity, incorporating items in ≥5 WHO quality of life domains. However, only nine instruments (21.9%) incorporated public and patient involvement. Only the Gastrointestinal Quality of Life Index and PAN-PROMISE met the criteria to be recommended for use based on COSMIN methodological assessment. CONCLUSION There is significant heterogeneity in instruments used to assess quality of life after pancreatitis, with almost all instruments considered insufficient. Robust, validated, and relevant instruments are needed to better understand and determine appropriate interventions to improve quality of life for these patients.
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Walker J, Babyok OL, Saloman JL, Phillips AE. Recent advances in the understanding and management of chronic pancreatitis pain. JOURNAL OF PANCREATOLOGY 2024; 7:35-44. [PMID: 38524856 PMCID: PMC10959534 DOI: 10.1097/jp9.0000000000000163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 12/09/2023] [Indexed: 03/26/2024] Open
Abstract
Abdominal pain is the most common symptom of chronic pancreatitis (CP) and is often debilitating for patients and very difficult to treat. To date, there exists no cure for the disease. Treatment strategies focus on symptom management and on mitigation of disease progression by reducing toxin exposure and avoiding recurrent inflammatory events. Traditional treatment protocols start with medical management followed by consideration of procedural or surgical intervention on selected patients with severe and persistent pain. The incorporation of adjuvant therapies to treat comorbidities including psychiatric disorders, exocrine pancreatic insufficiency, mineral bone disease, frailty, and malnutrition, are in its early stages. Recent clinical studies and animal models have been designed to improve investigation into the pathophysiology of CP pain, as well as to improve pain management. Despite the array of tools available, many therapeutic options for the management of CP pain provide incomplete relief. There still remains much to discover about the neural regulation of pancreas-related pain. In this review, we will discuss research from the last 5 years that has provided new insights into novel methods of pain phenotyping and the pathophysiology of CP pain. These discoveries have led to improvements in patient selection for optimization of outcomes for both medical and procedural management, and identification of potential future therapies.
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Affiliation(s)
- Jessica Walker
- Department of Internal Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
| | - Olivia L. Babyok
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Jami L. Saloman
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
- Center for Pain Research, Center for Neuroscience, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Anna Evans Phillips
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
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Muthulingam JA, Olesen SS, Hansen TM, Drewes AM, Frøkjær JB. White matter brain changes in chronic pancreatitis: A 7-year longitudinal follow-up study. Pancreatology 2022; 22:871-879. [PMID: 36031507 DOI: 10.1016/j.pan.2022.08.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 08/09/2022] [Accepted: 08/12/2022] [Indexed: 12/11/2022]
Abstract
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.
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Affiliation(s)
- Janusiya Anajan Muthulingam
- Mech-Sense, Department of Radiology, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Søren Schou Olesen
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; Centre for Pancreatic Diseases, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark; Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Tine Maria Hansen
- Mech-Sense, Department of Radiology, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Asbjørn Mohr Drewes
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; Centre for Pancreatic Diseases, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Jens Brøndum Frøkjær
- Mech-Sense, Department of Radiology, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
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Mechanisms underlying paclitaxel-induced neuropathic pain: Channels, inflammation and immune regulations. Eur J Pharmacol 2022; 933:175288. [PMID: 36122757 DOI: 10.1016/j.ejphar.2022.175288] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 09/07/2022] [Accepted: 09/13/2022] [Indexed: 11/22/2022]
Abstract
Paclitaxel is a chemotherapeutic agent widely used for many types of malignancies. However, when paclitaxel is used to treat tumors, patients commonly experience severe neuropathic pain that is difficult to manage. The mechanism underlying paclitaxel-induced neuropathic pain remains unclear. Evidence demonstrates correlations between mechanisms of paclitaxel-mediated pain and associated actions of ion channels, neuroinflammation, mitochondrial damage, and other factors. This review provides a comprehensive analysis of paclitaxel-induced neuropathic pain mechanisms and suggestions for effective interventions.
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Sarkar S, Sarkar P, M R, Hazarika D, Prasanna A, Pandol SJ, Unnisa M, Jakkampudi A, Bedarkar AP, Dhagudu N, Reddy DN, Talukdar R. Pain, depression, and poor quality of life in chronic pancreatitis: Relationship with altered brain metabolites. Pancreatology 2022; 22:688-697. [PMID: 35710761 DOI: 10.1016/j.pan.2022.06.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 05/22/2022] [Accepted: 06/03/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND To evaluate if altered brain metabolites are connected to pain, depression and affective responses in CP. METHODS In this prospective study we evaluated pain characteristics, QOL (EORTC QLQc30+PAN28), depression (Beck depression inventory [BDI] II) in 558 patients with CP and 67 healthy controls. Brain metabolites were evaluated using magnetic resonance spectroscopy (MRS) in 49 patients and 5 healthy controls. We measured plasma metabolites using gas chromatography-mass spectrometry (GC-MS/MS). Relationship between metabolomic alterations, pain, depression and QOL components were assessed using statistical/bioinformatics methods. Benjamini-Hochberg FDR correction was applied for multiple testing. RESULTS 261 (46.8%) patients had depression compared to 5 (7.5%) among healthy controls [n = 67](p < 0.0001). Risk [OR (95% CI) of developing depression in the presence of pain was 1.9 (1.33-1.68); p = 0.0004. The depression scores correlated negatively with functional components and positively with symptom components of EORTC QLQ30. Significant negative correlation, though based on a small sample size, was observed between N-acetyl aspartate in the left hippocampus and choline in the left prefrontal cortex with emotional and cognitive functions. PLS-DA modelling revealed significant alteration in the plasma metabolomic profile among patients with CP who had depression. Six metabolites were significantly different between CP with depression and healthy controls, of which glycine contributed most significantly to the PLS-DA model (VIP score of 3.5). CONCLUSIONS A significant proportion of patients with CP develops depression that correlate with poor QOL functions. Pain, depression, and emotional components of QOL in patients with CP correlated with N-acetyl aspartate and choline in the left hippocampus and left prefrontal cortex of the brain.
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Affiliation(s)
- Subhaleena Sarkar
- Wellcome-DBT India Alliance Labs., Institute of Basic and Translational Research, Asian Healthcare Foundation, Asian Institute of Gastroenterology, Hyderabad, India
| | - Priyanka Sarkar
- Wellcome-DBT India Alliance Labs., Institute of Basic and Translational Research, Asian Healthcare Foundation, Asian Institute of Gastroenterology, Hyderabad, India
| | - Revanth M
- Department of Radiodiagnosis, Asian Institute of Gastroenterology, Hyderabad, India
| | - Dibyamohan Hazarika
- Department of Radiodiagnosis, Asian Institute of Gastroenterology, Hyderabad, India
| | - Ambika Prasanna
- Wellcome-DBT India Alliance Labs., Institute of Basic and Translational Research, Asian Healthcare Foundation, Asian Institute of Gastroenterology, Hyderabad, India
| | | | - Misbah Unnisa
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India
| | - Aparna Jakkampudi
- Wellcome-DBT India Alliance Labs., Institute of Basic and Translational Research, Asian Healthcare Foundation, Asian Institute of Gastroenterology, Hyderabad, India
| | | | - Naveen Dhagudu
- Division of Psychiatry, Asian Institute of Gastroenterology, Hyderabad, India
| | - D Nageshwar Reddy
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India
| | - Rupjyoti Talukdar
- Wellcome-DBT India Alliance Labs., Institute of Basic and Translational Research, Asian Healthcare Foundation, Asian Institute of Gastroenterology, Hyderabad, India; Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India.
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Kong N, Gao C, Zhang F, Zhang M, Yue J, Lv K, Zhang Q, Fan Y, Lv B, Zang Y, Xu M. Neurophysiological Effects of the Anterior Cingulate Cortex on the Exacerbation of Crohn’s Disease: A Combined fMRI-MRS Study. Front Neurosci 2022; 16:840149. [PMID: 35600612 PMCID: PMC9120361 DOI: 10.3389/fnins.2022.840149] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 03/28/2022] [Indexed: 11/13/2022] Open
Abstract
Background Crohn’s disease (CD) is characterized by repetitive phases of remission and exacerbation, the quality of life of patients with CD is strongly influenced by disease activity, as patients in the active phase experience significantly worse symptoms. To investigate the underlying mechanism of how the course of CD is exacerbated based on the bi-directionality of the brain-gut axis (BGA), we conducted a multi-modality neuroimaging study that combined resting-state functional magnetic resonance imaging (rs-fMRI) with proton magnetic resonance spectroscopy (MRS) to detect abnormalities in the anterior cingulate cortex (ACC). Materials and Methods Clinical scales including Visual Analog Scale (VAS) and Hospital Anxiety and Depression Scale (HADS) were used to evaluate the degree of abdominal pain and mood state of participants. We made a comparison between CD patients in the active phase, the remission phase and healthy controls (HCs), not only employed the innovative wavelet-transform to analyze the amplitude of low frequency fluctuation (ALFF) but also compared the sensitivity of wavelet-transform and the traditional fast Fourier transform (FFT). Brain metabolites such as glutamate (Glu), myo-inositol (mIns) and gamma-aminobutyric acid (GABA) were also detected. Then correlation analysis was made to see whether changes in the ACC correlated with CD’s clinical symptoms. Results CD patients in the active phase showed higher VAS scores (p = 0.025), the scores of anxiety and depression were also higher (all p < 0.05). Wavelet-transform is slightly more sensitive in the current research. Patients in the active phase exhibited higher ALFF in the left ACC and the left superior frontal gyrus, medial (SFGmed). Patients in the active phase showed increased Glu levels in the ACC than patients in the remission phase or HCs (p = 0.039 and 0.034 respectively) and lower levels of mIns than HCs (p = 0.036). There was a positive correlation between mWavelet-ALFF values of the ACC and HADS-depression scores in CD patients (r = 0.462, p = 0.006). Besides, concentrations of Glu positively correlated with mWavelet-ALFF in the ACC in all participants (r = 0.367, p = 0.006). Conclusion Abnormal spontaneous activity and metabolic levels in the ACC were detected in CD patients in the active phase along with severer abdominal pain and worse mood state, these may contribute to the exacerbation of CD. Therefore, the ACC might be a potential neural alternative for managing the exacerbation of CD.
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Affiliation(s)
- Ning Kong
- The First School of Clinical Medicine of Zhejiang Chinese Medical University, Hangzhou, China
- Department of Radiology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Chen Gao
- The First School of Clinical Medicine of Zhejiang Chinese Medical University, Hangzhou, China
- Department of Radiology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Fan Zhang
- The First School of Clinical Medicine of Zhejiang Chinese Medical University, Hangzhou, China
- Department of Radiology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
- Key Laboratory of Digestive Pathophysiology of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Meng Zhang
- Center for Cognition and Brain Disorders, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
- Institute of Psychological Sciences, Hangzhou Normal University, Hangzhou, China
- Zhejiang Key Laboratory for Research in Assessment of Cognitive Impairments, Hangzhou, China
| | - Juan Yue
- Center for Cognition and Brain Disorders, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
- Institute of Psychological Sciences, Hangzhou Normal University, Hangzhou, China
- Zhejiang Key Laboratory for Research in Assessment of Cognitive Impairments, Hangzhou, China
| | - Kun Lv
- Department of Radiology, Huashan Hospital, Fudan University, Shanghai, China
| | - Qi Zhang
- The First School of Clinical Medicine of Zhejiang Chinese Medical University, Hangzhou, China
- Department of Radiology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Yihong Fan
- Key Laboratory of Digestive Pathophysiology of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Bin Lv
- Key Laboratory of Digestive Pathophysiology of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Yufeng Zang
- Center for Cognition and Brain Disorders, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
- Institute of Psychological Sciences, Hangzhou Normal University, Hangzhou, China
- Zhejiang Key Laboratory for Research in Assessment of Cognitive Impairments, Hangzhou, China
| | - Maosheng Xu
- The First School of Clinical Medicine of Zhejiang Chinese Medical University, Hangzhou, China
- Department of Radiology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
- *Correspondence: Maosheng Xu,
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Yamasaki T, Okada M, Hiraishi A, Mori W, Zhang Y, Fujinaga M, Wakizaka H, Kurihara Y, Nengaki N, Zhang MR. Upregulation of Striatal Metabotropic Glutamate Receptor Subtype 1 (mGluR1) in Rats with Excessive Glutamate Release Induced by N-Acetylcysteine. Neurotox Res 2022; 40:26-35. [PMID: 34981453 DOI: 10.1007/s12640-021-00449-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 10/15/2021] [Accepted: 11/16/2021] [Indexed: 10/19/2022]
Abstract
The aim of this study is to investigate the changes in expression of metabotropic glutamate (Glu) receptor subtype 1 (mGluR1), a key molecule involved in neuroexcitetoxicity, during excessive Glu release in the brain by PET imaging. An animal model of excessive Glu release in the brain was produced by intraperitoneally implanting an Alzet osmotic pump containing N-acetylcysteine (NAC), an activator of the cysteine/Glu antiporter, into the abdomen of rats. Basal Glu concentration in the brain was measured by microdialysis, which showed that basal Glu concentration in NAC-treated rats (0.31 µM) was higher than that in saline-treated rats (0.17 µM) at day 7 after the implantation of the osmotic pump. Similarly, PET studies with [11C]ITDM, a useful radioligand for mGluR1 imaging exhibited that the striatal binding potential (BPND) of [11C]ITDM for mGluR1 in PET assessments was increased in NAC-treated animals at day 7 after implantation (2.30) compared with before implantation (1.92). The dynamic changes in striatal BPND during the experimental period were highly correlated with basal Glu concentration. In conclusion, density of mGluR1 is rapidly upregulated by increases in basal Glu concentration, suggesting that mGluR1 might to be a potential biomarker of abnormal conditions in the brain.
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Affiliation(s)
- Tomoteru Yamasaki
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, 263-8555, Japan.
| | - Maki Okada
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, 263-8555, Japan
| | - Atsuto Hiraishi
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, 263-8555, Japan
| | - Wakana Mori
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, 263-8555, Japan
| | - Yiding Zhang
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, 263-8555, Japan
| | - Masayuki Fujinaga
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, 263-8555, Japan
| | - Hidekatsu Wakizaka
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, 263-8555, Japan
| | - Yusuke Kurihara
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, 263-8555, Japan.,SHI Accelerator Service Co. Ltd, 1-17-6 Osaki, Shinagawa-ku, Tokyo, 141-0032, Japan
| | - Nobuki Nengaki
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, 263-8555, Japan.,SHI Accelerator Service Co. Ltd, 1-17-6 Osaki, Shinagawa-ku, Tokyo, 141-0032, Japan
| | - Ming-Rong Zhang
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, 263-8555, Japan
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Wang J, Chen Y, Li X, Zou X. Perineural Invasion and Associated Pain Transmission in Pancreatic Cancer. Cancers (Basel) 2021; 13:4594. [PMID: 34572820 PMCID: PMC8467801 DOI: 10.3390/cancers13184594] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 09/10/2021] [Accepted: 09/10/2021] [Indexed: 12/18/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the cancers with the highest incidence of perineural invasion (PNI), which often indicates a poor prognosis. Aggressive tumor cells invade nerves, causing neurogenic inflammation; the tumor microenvironment also induces nerves to undergo a series of structural and functional reprogramming. In turn, neurons and the surrounding glial cells promote the development of pancreatic cancer through autocrine and/or paracrine signaling. In addition, hyperalgesia in PDAC patients implies alterations of pain transmission in the peripheral and central nervous systems. Currently, the studies on this topic are relatively limited. This review will elaborate on the mechanisms of tumor-neural interactions and its possible relationship with pain from several aspects that have been focused on in recent years.
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Affiliation(s)
| | | | | | - Xiaoping Zou
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China; (J.W.); (Y.C.); (X.L.)
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Hansen TM, Frøkjaer JB, Mark EB, Drewes AM. Tapentadol and oxycodone reduce cingulate glutamate in healthy volunteers. Br J Clin Pharmacol 2021; 88:1358-1364. [PMID: 34427941 DOI: 10.1111/bcp.15050] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 06/30/2021] [Accepted: 07/03/2021] [Indexed: 12/20/2022] Open
Abstract
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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Affiliation(s)
- Tine Maria Hansen
- Mech-Sense, Department of Radiology, Aalborg University Hospital, Aalborg, Denmark.,Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Jens Brøndum Frøkjaer
- Mech-Sense, Department of Radiology, Aalborg University Hospital, Aalborg, Denmark.,Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Esben Bolvig Mark
- Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Asbjørn Mohr Drewes
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.,Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark
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Muthulingam JA, Hansen TM, Olesen SS, Drewes AM, Frøkjaer JB. Two-Week Cervical Vagus Nerve Stimulation in Chronic Pancreatitis Patients Induces Functional Connectivity Changes of Limbic Structures. Neuromodulation 2021; 25:471-478. [PMID: 35396075 DOI: 10.1111/ner.13482] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 05/05/2021] [Accepted: 05/24/2021] [Indexed: 11/26/2022]
Abstract
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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Affiliation(s)
- Janusiya Anajan Muthulingam
- Mech-Sense, Department of Radiology, Aalborg University Hospital, Aalborg, Denmark.,Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Tine Maria Hansen
- Mech-Sense, Department of Radiology, Aalborg University Hospital, Aalborg, Denmark.,Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Søren Schou Olesen
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.,Centre for Pancreatic Diseases, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Asbjørn Mohr Drewes
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.,Centre for Pancreatic Diseases, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Jens Brøndum Frøkjaer
- Mech-Sense, Department of Radiology, Aalborg University Hospital, Aalborg, Denmark.,Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
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Disrupted functional connectivity of default mode and salience networks in chronic pancreatitis patients. Clin Neurophysiol 2020; 131:1021-1029. [DOI: 10.1016/j.clinph.2020.01.016] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 12/02/2019] [Accepted: 01/07/2020] [Indexed: 12/11/2022]
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