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出境医 / 临床实验 / Neuroplastic Alterations of the Motor Cortex by Caffeine

Neuroplastic Alterations of the Motor Cortex by Caffeine

Study Description
Brief Summary:

Caffeine is a psychostimulant drug. It acts as a competitive antagonist at adenosine receptors, which modulate cortical excitability as well. In deep brain stimulation (DBS), the production of adenosine following the release of adenosine triphosphate (ATP) explains the reduction of tremor. Binding of adenosine to adenosine A1 receptors suppresses excitatory transmission in the thalamus and hereby reduces both tremor-and DBS-induced side effects. Also, the effect of adenosine was attenuated following the administration of the 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX) adenosine A1 receptor antagonist. Therefore, the presence of a receptor antagonist such as caffeine was suggested to reduce the effectiveness of deep brain stimulation (DBS) in treating tremor and other movement disorders.

Based on this finding, the investigators hypothesize that the antagonistic effect of caffeine can tentatively block the excitatory effects of transcranial alternating current stimulation (tACS). The plasticity effects might differ among caffeine users and non- caffeine users depending on the availability of receptor binding sites.

Apart from that, a major issue in NIBS studies including those studying motor-evoked potentials is the response variability both within and between individuals. The trial to trial variability of motor evoked potentials (MEPs) may be affected by many factors. Inherent to caffeine is its effect on vigilance. In this study, the investigator shall monitor the participant's vigilance by pupillometry to (1) better understand the factors, which might cause variability in transcranial excitability induction studies and (2) to separate the direct pharmacological effect from the indirect attentional effect of caffeine.


Condition or disease Intervention/treatment Phase
Cortical Excitability Brain Stimulation Caffeine Other: 200 mg caffeine tablet Other: Non-active tablet Not Applicable

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: 15 participants are assigned to caffeine group and another 15 are assigned to placebo group. Then, the participants who were initially in the caffeine group now be in placebo group and those who were in the placebo group were assigned to caffeine group. Finally, all participants received both placebo and caffeine
Masking: Double (Participant, Investigator)
Masking Description: A statistician prepares a randomization list. Only the pharmacist knows the medication type (caffeine or placebo) and the type of electrical stimulation. The researcher knows only the vigilance conditions (**passive or *active) . An investigator is blinded to the type of electrical stimulation and medication. In addition, all participants are naive to electrical stimulation and do not know if they receive placebo or verum drug.
Primary Purpose: Basic Science
Official Title: Neuroplastic Alterations of the Motor Cortex by Caffeine: Differences Between Caffeine and Non-caffeine Users and Influence of Vigilance During Stimulation
Actual Study Start Date : July 15, 2019
Actual Primary Completion Date : November 19, 2019
Actual Study Completion Date : November 19, 2019
Arms and Interventions
Arm Intervention/treatment
Active Comparator: Caffeine group
Participants will receive a caffeine tablet and all electrical stimulations in a random order (tACS 140 Hz at 1 mA and sham tACS). Participant's vigilance status will be monitor based on active vigilance condition or passive vigilance condition.
 Other: 200 mg caffeine tablet
  • Transcranial alternating current stimulation (140 Hz tACS) at 1 mA and active vigilance condition
  • Transcranial alternating current stimulation (140 Hz tACS) at 1 mA and passive vigilance condition
  • Transcranial alternating current stimulation (140 Hz tACS) sham and active vigilance condition
  • Transcranial alternating current stimulation (140 Hz tACS) sham and passive vigilance condition
Placebo Comparator: Placebo group
Participants will receive a placebo tablet and all electrical stimulations in a random order (tACS 140 Hz at 1 mA and sham tACS). Participant's vigilance status will be monitor based on active vigilance condition or passive vigilance condition.
 Other: Non-active tablet
  • Transcranial alternating current stimulation (140 Hz tACS) at 1 mA and active vigilance condition
  • Transcranial alternating current stimulation (140 Hz tACS) at 1 mA and passive vigilance condition
  • Transcranial alternating current stimulation (140 Hz tACS) sham and active vigilance condition
  • Transcranial alternating current stimulation (140 Hz tACS) sham and passive vigilance condition
Outcome Measures
Primary Outcome Measures :
  1. Neuroplastic changes of the cortical areas [ Time Frame: Baseline (pre-measurement), immediately after intervention, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes ]
    Motor cortex plasticity is measured from the changes in the amplitude of the motor evoked potentials (MEPs) at different time points. Transcranial magnetic stimulation (TMS) will be used to measure MEP amplitudes.

  2. The influence of vigilance during stimulation [ Time Frame: 10 minutes ]
    Participant's level of vigilance is monitored from pupil diameter and pupil unrest index (PUI) using pupillometer. This measurement is carried out during 10 minutes of transcranial alternating current stimulation (tACS)


Secondary Outcome Measures :
  1. Genetic polymorphism [ Time Frame: 1 year ]
    Brain-derived neurotrophic factor (BDNF) gene polymorphisms on cortical plasticity


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Male and female healthy participants between the ages of 18-45.
  2. Right-handed (Oldfield 1971).
  3. Free willing participation and written, informed consent of all subjects obtained prior to the start of the study.
  4. Participant's weight is above 60 kg

Exclusion Criteria:

  1. Age < 18 or > 45 years old;
  2. Left hand dominant;
  3. Evidence of a chronic disease or history with a disorder of the nervous system
  4. History of epileptic seizures;
  5. Pacemaker or deep brain stimulation;
  6. Metal implants in the head region (metal used in the head region, for example, clips after the operation of an intracerebral aneurysm (vessel sacking in the region of the brain vessels), implantation of an artificial auditory canal);
  7. Cerebral trauma with loss of consciousness in prehistory;
  8. Existence of a serious internal (internal organs) or psychiatric (mental illness)
  9. Alcohol, medication or drug addiction;
  10. Receptive or global aphasia (disturbance of speech comprehension or additionally of speech);
  11. Participation in another scientific or clinical study within the last 4 weeks;
  12. Pregnancy
  13. Breastfeeding
  14. Intolerance to caffeine or coffee products
  15. Participant who has abnormal heart activity from an electrocardiography (ECG) finding
  16. Weight is less than 60 kg
Contacts and Locations

Locations
Layout table for location information
Germany
Prof. Dr. Walter Paulus
Goettigen, Lower Saxony, Germany, 37075
Sponsors and Collaborators
University Medical Center Goettingen
Investigators
Layout table for investigator information
Principal Investigator: Walter Paulus University Medical Center Goettingen, Goettingen
Tracking Information
First Submitted Date  ICMJE May 21, 2019
First Posted Date  ICMJE July 8, 2019
Last Update Posted Date November 29, 2019
Actual Study Start Date  ICMJE July 15, 2019
Actual Primary Completion Date November 19, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 5, 2019)
  • Neuroplastic changes of the cortical areas [ Time Frame: Baseline (pre-measurement), immediately after intervention, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes ]
    Motor cortex plasticity is measured from the changes in the amplitude of the motor evoked potentials (MEPs) at different time points. Transcranial magnetic stimulation (TMS) will be used to measure MEP amplitudes.
  • The influence of vigilance during stimulation [ Time Frame: 10 minutes ]
    Participant's level of vigilance is monitored from pupil diameter and pupil unrest index (PUI) using pupillometer. This measurement is carried out during 10 minutes of transcranial alternating current stimulation (tACS)
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 5, 2019) 		Genetic polymorphism [ Time Frame: 1 year ]
Brain-derived neurotrophic factor (BDNF) gene polymorphisms on cortical plasticity
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Neuroplastic Alterations of the Motor Cortex by Caffeine
Official Title  ICMJE Neuroplastic Alterations of the Motor Cortex by Caffeine: Differences Between Caffeine and Non-caffeine Users and Influence of Vigilance During Stimulation
Brief Summary

Caffeine is a psychostimulant drug. It acts as a competitive antagonist at adenosine receptors, which modulate cortical excitability as well. In deep brain stimulation (DBS), the production of adenosine following the release of adenosine triphosphate (ATP) explains the reduction of tremor. Binding of adenosine to adenosine A1 receptors suppresses excitatory transmission in the thalamus and hereby reduces both tremor-and DBS-induced side effects. Also, the effect of adenosine was attenuated following the administration of the 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX) adenosine A1 receptor antagonist. Therefore, the presence of a receptor antagonist such as caffeine was suggested to reduce the effectiveness of deep brain stimulation (DBS) in treating tremor and other movement disorders.

Based on this finding, the investigators hypothesize that the antagonistic effect of caffeine can tentatively block the excitatory effects of transcranial alternating current stimulation (tACS). The plasticity effects might differ among caffeine users and non- caffeine users depending on the availability of receptor binding sites.

Apart from that, a major issue in NIBS studies including those studying motor-evoked potentials is the response variability both within and between individuals. The trial to trial variability of motor evoked potentials (MEPs) may be affected by many factors. Inherent to caffeine is its effect on vigilance. In this study, the investigator shall monitor the participant's vigilance by pupillometry to (1) better understand the factors, which might cause variability in transcranial excitability induction studies and (2) to separate the direct pharmacological effect from the indirect attentional effect of caffeine.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:
15 participants are assigned to caffeine group and another 15 are assigned to placebo group. Then, the participants who were initially in the caffeine group now be in placebo group and those who were in the placebo group were assigned to caffeine group. Finally, all participants received both placebo and caffeine
Masking: Double (Participant, Investigator)
Masking Description:
A statistician prepares a randomization list. Only the pharmacist knows the medication type (caffeine or placebo) and the type of electrical stimulation. The researcher knows only the vigilance conditions (**passive or *active) . An investigator is blinded to the type of electrical stimulation and medication. In addition, all participants are naive to electrical stimulation and do not know if they receive placebo or verum drug.
Primary Purpose: Basic Science
Condition  ICMJE
  • Cortical Excitability
  • Brain Stimulation
  • Caffeine
Intervention  ICMJE
  • Other: 200 mg caffeine tablet
    • Transcranial alternating current stimulation (140 Hz tACS) at 1 mA and active vigilance condition
    • Transcranial alternating current stimulation (140 Hz tACS) at 1 mA and passive vigilance condition
    • Transcranial alternating current stimulation (140 Hz tACS) sham and active vigilance condition
    • Transcranial alternating current stimulation (140 Hz tACS) sham and passive vigilance condition
  • Other: Non-active tablet
    • Transcranial alternating current stimulation (140 Hz tACS) at 1 mA and active vigilance condition
    • Transcranial alternating current stimulation (140 Hz tACS) at 1 mA and passive vigilance condition
    • Transcranial alternating current stimulation (140 Hz tACS) sham and active vigilance condition
    • Transcranial alternating current stimulation (140 Hz tACS) sham and passive vigilance condition
Study Arms  ICMJE
  • Active Comparator: Caffeine group
    Participants will receive a caffeine tablet and all electrical stimulations in a random order (tACS 140 Hz at 1 mA and sham tACS). Participant's vigilance status will be monitor based on active vigilance condition or passive vigilance condition.
    Intervention: Other: 200 mg caffeine tablet
  • Placebo Comparator: Placebo group
    Participants will receive a placebo tablet and all electrical stimulations in a random order (tACS 140 Hz at 1 mA and sham tACS). Participant's vigilance status will be monitor based on active vigilance condition or passive vigilance condition.
    Intervention: Other: Non-active tablet
Publications *
  • Antal A, Alekseichuk I, Bikson M, Brockmöller J, Brunoni AR, Chen R, Cohen LG, Dowthwaite G, Ellrich J, Flöel A, Fregni F, George MS, Hamilton R, Haueisen J, Herrmann CS, Hummel FC, Lefaucheur JP, Liebetanz D, Loo CK, McCaig CD, Miniussi C, Miranda PC, Moliadze V, Nitsche MA, Nowak R, Padberg F, Pascual-Leone A, Poppendieck W, Priori A, Rossi S, Rossini PM, Rothwell J, Rueger MA, Ruffini G, Schellhorn K, Siebner HR, Ugawa Y, Wexler A, Ziemann U, Hallett M, Paulus W. Low intensity transcranial electric stimulation: Safety, ethical, legal regulatory and application guidelines. Clin Neurophysiol. 2017 Sep;128(9):1774-1809. doi: 10.1016/j.clinph.2017.06.001. Epub 2017 Jun 19. Review.
  • Antal A, Chaieb L, Moliadze V, Monte-Silva K, Poreisz C, Thirugnanasambandam N, Nitsche MA, Shoukier M, Ludwig H, Paulus W. Brain-derived neurotrophic factor (BDNF) gene polymorphisms shape cortical plasticity in humans. Brain Stimul. 2010 Oct;3(4):230-7. doi: 10.1016/j.brs.2009.12.003. Epub 2010 Jan 14.
  • Biabani M, Farrell M, Zoghi M, Egan G, Jaberzadeh S. The minimal number of TMS trials required for the reliable assessment of corticospinal excitability, short interval intracortical inhibition, and intracortical facilitation. Neurosci Lett. 2018 May 1;674:94-100. doi: 10.1016/j.neulet.2018.03.026. Epub 2018 Mar 15.
  • Cappelletti S, Piacentino D, Sani G, Aromatario M. Caffeine: cognitive and physical performance enhancer or psychoactive drug? Curr Neuropharmacol. 2015 Jan;13(1):71-88. doi: 10.2174/1570159X13666141210215655. Review. Erratum in: Curr Neuropharmacol. 2015;13(4):554. Daria, Piacentino [corrected to Piacentino, Daria].
  • Cappelletti S, Piacentino D, Fineschi V, Frati P, Cipolloni L, Aromatario M. Caffeine-Related Deaths: Manner of Deaths and Categories at Risk. Nutrients. 2018 May 14;10(5). pii: E611. doi: 10.3390/nu10050611. Review.
  • Cavaleri R, Schabrun SM, Chipchase LS. The number of stimuli required to reliably assess corticomotor excitability and primary motor cortical representations using transcranial magnetic stimulation (TMS): a systematic review and meta-analysis. Syst Rev. 2017 Mar 6;6(1):48. doi: 10.1186/s13643-017-0440-8. Review.
  • Cuypers K, Thijs H, Meesen RL. Optimization of the transcranial magnetic stimulation protocol by defining a reliable estimate for corticospinal excitability. PLoS One. 2014 Jan 24;9(1):e86380. doi: 10.1371/journal.pone.0086380. eCollection 2014.
  • Feurra M, Paulus W, Walsh V, Kanai R. Frequency specific modulation of human somatosensory cortex. Front Psychol. 2011 Feb 2;2:13. doi: 10.3389/fpsyg.2011.00013. eCollection 2011.
  • Goldsworthy MR, Hordacre B, Ridding MC. Minimum number of trials required for within- and between-session reliability of TMS measures of corticospinal excitability. Neuroscience. 2016 Apr 21;320:205-9. doi: 10.1016/j.neuroscience.2016.02.012. Epub 2016 Feb 9.
  • Hanajima R, Tanaka N, Tsutsumi R, Shirota Y, Shimizu T, Terao Y, Ugawa Y. Effect of caffeine on long-term potentiation-like effects induced by quadripulse transcranial magnetic stimulation. Exp Brain Res. 2019 Mar;237(3):647-651. doi: 10.1007/s00221-018-5450-9. Epub 2018 Dec 10.
  • Higdon JV, Frei B. Coffee and health: a review of recent human research. Crit Rev Food Sci Nutr. 2006;46(2):101-23. Review.
  • Karabanov A, Ziemann U, Hamada M, George MS, Quartarone A, Classen J, Massimini M, Rothwell J, Siebner HR. Consensus Paper: Probing Homeostatic Plasticity of Human Cortex With Non-invasive Transcranial Brain Stimulation. Brain Stimul. 2015 May-Jun;8(3):442-54. doi: 10.1016/j.brs.2015.01.404. Epub 2015 Apr 1. Review. Corrected and republished in: Brain Stimul. 2015 Sep-Oct;8(5):993-1006.
  • Di Lazzaro V, Pellegrino G, Di Pino G, Corbetto M, Ranieri F, Brunelli N, Paolucci M, Bucossi S, Ventriglia MC, Brown P, Capone F. Val66Met BDNF gene polymorphism influences human motor cortex plasticity in acute stroke. Brain Stimul. 2015 Jan-Feb;8(1):92-6. doi: 10.1016/j.brs.2014.08.006. Epub 2014 Aug 23.
  • Lewis GN, Signal N, Taylor D. Reliability of lower limb motor evoked potentials in stroke and healthy populations: how many responses are needed? Clin Neurophysiol. 2014 Apr;125(4):748-754. doi: 10.1016/j.clinph.2013.07.029. Epub 2013 Oct 5.
  • Márquez-Ruiz J, Leal-Campanario R, Sánchez-Campusano R, Molaee-Ardekani B, Wendling F, Miranda PC, Ruffini G, Gruart A, Delgado-García JM. Transcranial direct-current stimulation modulates synaptic mechanisms involved in associative learning in behaving rabbits. Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6710-5. doi: 10.1073/pnas.1121147109. Epub 2012 Apr 9.
  • Moliadze V, Antal A, Paulus W. Boosting brain excitability by transcranial high frequency stimulation in the ripple range. J Physiol. 2010 Dec 15;588(Pt 24):4891-904. doi: 10.1113/jphysiol.2010.196998.
  • Moliadze V, Antal A, Paulus W. Electrode-distance dependent after-effects of transcranial direct and random noise stimulation with extracephalic reference electrodes. Clin Neurophysiol. 2010 Dec;121(12):2165-71. doi: 10.1016/j.clinph.2010.04.033. Epub 2010 Jun 15.
  • Moliadze V, Atalay D, Antal A, Paulus W. Close to threshold transcranial electrical stimulation preferentially activates inhibitory networks before switching to excitation with higher intensities. Brain Stimul. 2012 Oct;5(4):505-11. doi: 10.1016/j.brs.2011.11.004. Epub 2012 Feb 22.
  • Müller-Dahlhaus F, Ziemann U. Metaplasticity in human cortex. Neuroscientist. 2015 Apr;21(2):185-202. doi: 10.1177/1073858414526645. Epub 2014 Mar 11. Review.
  • Nitsche MA, Paulus W. Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. J Physiol. 2000 Sep 15;527 Pt 3:633-9.
  • Oldfield RC. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia. 1971 Mar;9(1):97-113.
  • Polanía R, Nitsche MA, Korman C, Batsikadze G, Paulus W. The importance of timing in segregated theta phase-coupling for cognitive performance. Curr Biol. 2012 Jul 24;22(14):1314-8. doi: 10.1016/j.cub.2012.05.021. Epub 2012 Jun 7.
  • Ridding MC, Ziemann U. Determinants of the induction of cortical plasticity by non-invasive brain stimulation in healthy subjects. J Physiol. 2010 Jul 1;588(Pt 13):2291-304. doi: 10.1113/jphysiol.2010.190314. Epub 2010 May 17. Review.
  • Robertson D, Wade D, Workman R, Woosley RL, Oates JA. Tolerance to the humoral and hemodynamic effects of caffeine in man. J Clin Invest. 1981 Apr;67(4):1111-7.
  • Stefan K, Kunesch E, Cohen LG, Benecke R, Classen J. Induction of plasticity in the human motor cortex by paired associative stimulation. Brain. 2000 Mar;123 Pt 3:572-84.
  • Stefan K, Kunesch E, Benecke R, Cohen LG, Classen J. Mechanisms of enhancement of human motor cortex excitability induced by interventional paired associative stimulation. J Physiol. 2002 Sep 1;543(Pt 2):699-708.
  • Zaehle T, Rach S, Herrmann CS. Transcranial alternating current stimulation enhances individual alpha activity in human EEG. PLoS One. 2010 Nov 1;5(11):e13766. doi: 10.1371/journal.pone.0013766.
  • Zulkifly MFM, Merkohitaj O, Brockmöller J, Paulus W. Confounding effects of caffeine on neuroplasticity induced by transcranial alternating current stimulation and paired associative stimulation. Clin Neurophysiol. 2021 Mar 10. pii: S1388-2457(21)00065-1. doi: 10.1016/j.clinph.2021.01.024. [Epub ahead of print]
  • Zulkifly MFM, Merkohitaj O, Paulus W, Brockmöller J. The roles of caffeine and corticosteroids in modulating cortical excitability after paired associative stimulation (PAS) and transcranial alternating current stimulation (tACS) in caffeine-naïve and caffeine-adapted subjects. Psychoneuroendocrinology. 2021 May;127:105201. doi: 10.1016/j.psyneuen.2021.105201. Epub 2021 Mar 15.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 5, 2019) 		30
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE November 19, 2019
Actual Primary Completion Date November 19, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Male and female healthy participants between the ages of 18-45.
  2. Right-handed (Oldfield 1971).
  3. Free willing participation and written, informed consent of all subjects obtained prior to the start of the study.
  4. Participant's weight is above 60 kg

Exclusion Criteria:

  1. Age < 18 or > 45 years old;
  2. Left hand dominant;
  3. Evidence of a chronic disease or history with a disorder of the nervous system
  4. History of epileptic seizures;
  5. Pacemaker or deep brain stimulation;
  6. Metal implants in the head region (metal used in the head region, for example, clips after the operation of an intracerebral aneurysm (vessel sacking in the region of the brain vessels), implantation of an artificial auditory canal);
  7. Cerebral trauma with loss of consciousness in prehistory;
  8. Existence of a serious internal (internal organs) or psychiatric (mental illness)
  9. Alcohol, medication or drug addiction;
  10. Receptive or global aphasia (disturbance of speech comprehension or additionally of speech);
  11. Participation in another scientific or clinical study within the last 4 weeks;
  12. Pregnancy
  13. Breastfeeding
  14. Intolerance to caffeine or coffee products
  15. Participant who has abnormal heart activity from an electrocardiography (ECG) finding
  16. Weight is less than 60 kg
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 45 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04011670
Other Study ID Numbers  ICMJE 33/3/19
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Prof. Dr. Walter Paulus, University Medical Center Goettingen
Study Sponsor  ICMJE University Medical Center Goettingen
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Walter Paulus University Medical Center Goettingen, Goettingen
PRS Account University Medical Center Goettingen
Verification Date November 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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