Download PDF
Sportverletz Sportschaden 2023; 37(02): 67-78
DOI: 10.1055/a-1958-2730
Übersicht

Manuelle Therapietechniken an der Wirbelsäule zur Stimulation des autonomen Nervensystems - ein Scoping Review

Manual spinal therapy techniques to stimulate the autonomic nervous system: a scoping review
Slavko Rogan
1   Gesundheit, Berner Fachhochschule, Bern, SWITZERLAND (Ringgold ID: RIN128940)
,
Jan Taeymans
1   Gesundheit, Berner Fachhochschule, Bern, SWITZERLAND (Ringgold ID: RIN128940)
,
Ina Berger
2   FHG - Zentrum für Gesundheitsberuf Tirol, innsbruck, AUSTRIA
,
Heiner Baur
1   Gesundheit, Berner Fachhochschule, Bern, SWITZERLAND (Ringgold ID: RIN128940)
› Author Affiliations
› Further Information
Also available at
    Permissions and Reprints

Zusammenfassung

Hintergrund Physikalische Maßnahmen oder manualtherapeutische Techniken (MTTe) wie Mobilisationen, Manipulationen oder Weichteiltechniken führen zu einer Verbesserung des Metabolismus oder einer Senkung hypertoner Muskulatur und werden auch zur Balanceregulierung bei zentralnervösen Veränderungen des autonomen Nervensystems (ANS) eingesetzt. Bisher fehlen empirische Erkenntnisse über Wirkungsmechanismen und Reizorte von MTTe auf das ANS. Das Ziel dieses vorliegenden Scoping Reviews war es, einen Überblick zu geben über den Erkenntnisstand der Anwendung von MTTe auf diverse Niveaus der Wirbelsäule auf das ANS.

Methode Als Grundlage für die Durchführung des Scoping Reviews dienten die Datenbanken CENTRAL, Osteopathic Research Web, PEDro und PubMed. Umfang und Inhalte der Literatur wurden dokumentiert. Die Ergebnisse der einbezogenen und herangezogenen Studien wurden in narrativer Weise zusammengefasst, wobei der Fokus auf den signifikantesten klinischen Aspekten lag.

Ergebnisse Manipulationen, Mobilisationen, myofasziale Techniken und zervikale Traktionen wurden als MTTe definiert. In 27 von 35 Studien wurden gesunde Probanden therapeutisch behandelt. Zehn Studien analysierten unmittelbare Effekte an Patienten, während 2 Studien als Longitudinalstudie bei Bluthochdruckpatienten konzipiert waren. In einem Zeitraum von 4–8 Wochen betrug die Interventionshäufigkeit wöchentlich zwischen einer und 3 MTTe-Einheiten.

Schlussfolgerung Die Studienergebnisse erweisen sich als heterogen. Aus diesem Grund lassen sich keine verbindlichen, eindeutigen und allgemeingültigen Aussagen ableiten, in welcher Form, Intensität sowie in welchem Umfang MTTe angewendet werden sollen, um gezielt positive Wirkungsmechanismen am ANS in Gang zu setzen. Für zukünftige Studien sind demzufolge Longitudinalstudien mit Follow-up empfehlenswert. Darüber hinaus sollten umfassende Effekte von MTTe bei Patientengruppen mit unterschiedlichen Ausprägungen untersucht werden.

Abstract

Background Physical interventions or manual therapeutic techniques (MTTe) such as mobilisation, manipulation or soft tissue techniques not only have an influence on the target tissue with improvement of metabolism or reduction of hypertonic muscles. They are also used for balance regulation in central nervous changes of the autonomic nervous system (ANS). To date, there is a lack of empirical evidence on impact mechanisms and target locations of MTTe on the ANS. This scoping review aims to provide an overview of the evidence on the application of MTTe at diverse levels of the spine with a view to the ANS.

Method A systematic literature search was conducted on CENTRAL, Google Scholar, Osteopathic Research Web, PEDro and PubMed. The scope and content of the literature were documented. The results of the included and referenced studies were summarised in a narrative approach with the focus being on the most significant clinical aspects.

Results MTTe was described as manipulations, mobilisations, myofascial techniques and cervical traction. In 27 out of 35 studies, therapeutic treatments were carried out on healthy volunteers. Ten studies analysed immediate effects in patients, while two studies were designed as longitudinal studies in patients with hypertension. Over a period of four to eight weeks, the frequency of intervention was between one and three MTTe sessions a week.

Conclusion The study results proved to be heterogeneous. For this reason, it is not possible to draw definitive, explicit and generally valid statements regarding the type and intensity as well as the segmental level at which MTTe should be applied in order to trigger specific positive ANS response mechanisms. Consequently, longitudinal studies with follow-up are recommended for future studies. In addition, comprehensive effects of MTTe should be evaluated in groups of patients with different characteristics.

Schlüsselwörter

Manipulation - sympathisches Nervensystem - parasympathisches Nervensystem

Keywords

musculoskeletal manipulation - sympathetic nervous systems - parasympathetic nervous system


Publication History

Received: 02 July 2020

Accepted after revision: 09 October 2022

Article published online:
22 May 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • Literatur

  • 1 Birbaumer N, Schmidt RF. Autonomes Nervensystem. In: Birbaumer N, Schmidt RF. Biologische Psychologie. Berlin, Heidelberg: Springer Berlin Heidelberg; 2010: 101-115 DOI: 10.1007/978-3-540-95938-0_6
    CrossrefGoogle Scholar
  • 2 Fries E, Kirschbaum C. Chronischer Stress und stressbezogene Erkrankungen. Stress-und Schmerzursachen verstehen Gesundheitspsychologie und-soziologie in Prävention und Rehabilitation 2009; 113-125
    PubMedGoogle Scholar
  • 3 Vinik AI, Maser RE, Ziegler D. Autonomic imbalance: prophet of doom or scope for hope?. Diabetic Medicine 2011; 28: 643-651
    CrossrefPubMedGoogle Scholar
  • 4 Niemier K, Seidel W. Funktionelle Schmerztherapie des Bewegungssystems. Springer; 2009
    CrossrefGoogle Scholar
  • 5 Borges BLA, Bortolazzo GL, Neto HP. Effects of spinal manipulation and myofascial techniques on heart rate variability: a systematic review. Journal of bodywork and movement therapies 2018; 22: 203-208
    CrossrefPubMedGoogle Scholar
  • 6 Hegedus EJ, Goode A, Butler RJ. et al. The neurophysiological effects of a single session of spinal joint mobilization: does the effect last?. Journal of Manual & Manipulative Therapy 2011; 19: 143-151
    CrossrefPubMedGoogle Scholar
  • 7 Kingston L, Claydon L, Tumilty S. The effects of spinal mobilizations on the sympathetic nervous system: a systematic review. Manual therapy 2014; 19: 281-287
    CrossrefPubMedGoogle Scholar
  • 8 Schmid A, Brunner F, Wright A. et al. Paradigm shift in manual therapy? Evidence for a central nervous system component in the response to passive cervical joint mobilisation. Manual therapy 2008; 13: 387-396
    CrossrefPubMedGoogle Scholar
  • 9 Wirth B, Gassner A, De Bruin ED. et al. Neurophysiological effects of high velocity and low amplitude spinal manipulation in symptomatic and asymptomatic humans: a systematic literature review. Spine 2019; 44: E914-E926
    CrossrefPubMedGoogle Scholar
  • 10 Araujo FX, Ferreira GE, Angellos RF. et al. Autonomic Effects of Spinal Manipulative Therapy: Systematic Review of Randomized Controlled Trials. Journal of manipulative and physiological therapeutics 2019; 42: 623-634 DOI: 10.1016/j.jmpt.2018.12.005.
    CrossrefPubMedGoogle Scholar
  • 11 Mangum K, Partna L, Vavrek D. Spinal manipulation for the treatment of hypertension: a systematic qualitative literature review. Journal of manipulative and physiological therapeutics 2012; 35: 235-243
    CrossrefPubMedGoogle Scholar
  • 12 von Elm E, Schreiber G, Haupt CC. Methodische Anleitung für Scoping Reviews (JBI-Methodologie). Zeitschrift für Evidenz, Fortbildung und Qualität im Gesundheitswesen 2019; 143: 1-7
    CrossrefPubMedGoogle Scholar
  • 13 Khalil H, Peters M, Godfrey CM. et al. An evidence-based approach to scoping reviews. Worldviews on Evidence-Based Nursing 2016; 13: 118-123
    CrossrefPubMedGoogle Scholar
  • 14 Hugl U. Qualitative Inhaltsanalyse und Mind-Mapping: Ein neuer Ansatz für Datenauswertung und Organisationsdiagnose. Springer-Verlag; 2013
    Google Scholar
  • 15 Levac D, Colquhoun H, O'Brien KK. Scoping studies: advancing the methodology. Implementation science 2010; 5: 69 DOI: 10.1186/1748-5908-5-69.
    CrossrefPubMedGoogle Scholar
  • 16 Tricco AC, Lillie E, Zarin W. et al. PRISMA extension for scoping reviews (PRISMA-ScR): checklist and explanation. Annals of internal medicine 2018; 169: 467-473
    CrossrefPubMedGoogle Scholar
  • 17 Vonville H. Excel workbooks for systematic reviews. In: 2015.
    PubMedGoogle Scholar
  • 18 Tricco AC, Lillie E, Zarin W. et al. A scoping review on the conduct and reporting of scoping reviews. BMC medical research methodology 2016; 16: 15 DOI: 10.1186/s12874-016-0116-4.
    CrossrefPubMedGoogle Scholar
  • 19 Picchiottino M, Honoré M, Leboeuf-Yde C. et al. The effect of a single spinal manipulation on cardiovascular autonomic activity and the relationship to pressure pain threshold: a randomized, cross-over, sham-controlled trial. Chiropractic & Manual Therapies 2020; 28: 7 DOI: 10.1186/s12998-019-0293-4.
    CrossrefPubMedGoogle Scholar
  • 20 Bowler N, Browning P, Lascurain-Aguirrebeña I. The effects of cervical sustained natural apophyseal glides on neck range of movement and sympathetic nervous system activity. International journal of osteopathic medicine 2017; 25: 15-20
    CrossrefPubMedGoogle Scholar
  • 21 Budgell B, Polus B. The effects of thoracic manipulation on heart rate variability: a controlled crossover trial. Journal of manipulative and physiological therapeutics 2006; 29: 603-610
    CrossrefPubMedGoogle Scholar
  • 22 de Araujo FX, Schell MS, Ferreira GE. et al. Autonomic function and pressure pain threshold following thoracic mobilization in asymptomatic subjects: A randomized controlled trial. Journal of bodywork and movement therapies 2018; 22: 313-320
    CrossrefPubMedGoogle Scholar
  • 23 Giles PD, Hensel KL, Pacchia CF. et al. Suboccipital decompression enhances heart rate variability indices of cardiac control in healthy subjects. The Journal of Alternative and Complementary Medicine 2013; 19: 92-96
    CrossrefPubMedGoogle Scholar
  • 24 Henley CE, Ivins D, Mills M. et al. Osteopathic manipulative treatment and its relationship to autonomic nervous system activity as demonstrated by heart rate variability: a repeated measures study. Osteopathic Medicine and Primary Care 2008; 2: 7 DOI: 10.1186/1750-4732-2-7.
    CrossrefPubMedGoogle Scholar
  • 25 Jowsey P, Perry J. Sympathetic nervous system effects in the hands following a grade III postero-anterior rotatory mobilisation technique applied to T4: a randomised, placebo-controlled trial. Man Ther 2010; 15: 248-253 DOI: 10.1016/j.math.2009.12.008.
    CrossrefPubMedGoogle Scholar
  • 26 McGuiness J, Vicenzino B, Wright A. Influence of a cervical mobilization technique on respiratory and cardiovascular function. Manual Therapy 1997; 2: 216-220
    CrossrefPubMedGoogle Scholar
  • 27 Minarini G, Ford M, Esteves J. Immediate effect of T2, T5, T11 thoracic spine manipulation of asymptomatic patient on autonomic nervous system response: Single-blind, parallel-arm controlled-group experiment. International Journal of Osteopathic Medicine 2018; 30: 12-17
    CrossrefPubMedGoogle Scholar
  • 28 Moulson A, Watson T. A preliminary investigation into the relationship between cervical snags and sympathetic nervous system activity in the upper limbs of an asymptomatic population. Manual therapy 2006; 11: 214-224
    CrossrefPubMedGoogle Scholar
  • 29 Slater H, Vicenzino B, Wright A. 'Sympathetic Slump': The Effects of a Novel Manual Therapy. The Journal of Manual & Manipulative Therapy 1994; 2: 156-162
    CrossrefPubMedGoogle Scholar
  • 30 Vicenzino B, Cartwright T, Collins D. et al. Cardiovascular and respiratory changes produced by lateral glide mobilization of the cervical spine. Manual Therapy 1998; 3: 67-71
    CrossrefPubMedGoogle Scholar
  • 31 Vicenzino B, Collins D, Wright T. Sudomotor changes induced by neural mobilisation techniques in asymptomatic subjects. Journal of Manual & Manipulative Therapy 1994; 2: 66-74
    CrossrefPubMedGoogle Scholar
  • 32 Ward J, Coats J, Tyer K. et al. Immediate effects of anterior upper thoracic spine manipulation on cardiovascular response. J Manipulative Physiol Ther 2013; 36: 101-110 DOI: 10.1016/j.jmpt.2013.01.003.
    CrossrefPubMedGoogle Scholar
  • 33 Ward J, Tyer K, Coats J. et al. Immediate effects of atlas manipulation on cardiovascular physiology. Clinical Chiropractic 2012; 15: 147-157
    CrossrefPubMedGoogle Scholar
  • 34 Yung E, Wong M, Williams H. et al. Blood pressure and heart rate response to posteriorly directed pressure applied to the cervical spine in young, pain-free individuals: a randomized, repeated-measures, double-blind, placebo-controlled study. Journal of Orthopaedic & Sports Physical Therapy 2014; 44: 622-626
    CrossrefPubMedGoogle Scholar
  • 35 Yung EY, Oh C, Wong MS. et al. The immediate cardiovascular response to joint mobilization of the neck-a randomized, placebo-controlled trial in pain-free adults. Musculoskeletal Science and Practice 2017; 28: 71-78
    CrossrefPubMedGoogle Scholar
  • 36 Budgell B, Hirano F. Innocuous mechanical stimulation of the neck and alterations in heart-rate variability in healthy young adults. Autonomic Neuroscience 2001; 91: 96-99
    CrossrefPubMedGoogle Scholar
  • 37 Goertz CH, Grimm RH, Svendsen K. et al. Treatment of Hypertension with Alternative Therapies (THAT) Study: a randomized clinical trial. Journal of hypertension 2002; 20: 2063-2068
    CrossrefPubMedGoogle Scholar
  • 38 La Touche R, París-Alemany A, Mannheimer JS. et al. Does mobilization of the upper cervical spine affect pain sensitivity and autonomic nervous system function in patients with cervico-craniofacial pain?: A randomized-controlled trial. The Clinical journal of pain 2013; 29: 205-215
    CrossrefPubMedGoogle Scholar
  • 39 Morgan JP, Dickey JL, Hunt HH. et al. A controlled trial of spinal manipulation in the management of hypertension. The Journal of the American Osteopathic Association 1985; 85: 308-313
    CrossrefPubMedGoogle Scholar
  • 40 Moutzouri M, Perry J, Billis E. Investigation of the effects of a centrally applied lumbar sustained natural apophyseal glide mobilization on lower limb sympathetic nervous system activity in asymptomatic subjects. Journal of manipulative and physiological therapeutics 2012; 35: 286-294
    CrossrefPubMedGoogle Scholar
  • 41 Sillevis R, Cleland J. Immediate effects of the audible pop from a thoracic spine thrust manipulation on the autonomic nervous system and pain: a secondary analysis of a randomized clinical trial. Journal of manipulative and physiological therapeutics 2011; 34: 37-45
    CrossrefPubMedGoogle Scholar
  • 42 Vicenzino B, Collins D, Benson H. et al. An investigation of the interrelationship between manipulative therapy-induced hypoalgesia and sympathoexcitation. J Manipulative Physiol Ther 1998; 21: 448-453
    PubMedGoogle Scholar
  • 43 Ward J, Tyer K, Coats J. et al. Immediate effects of upper thoracic spine manipulation on hypertensive individuals. Journal of Manual & Manipulative Therapy 2015; 23: 43-50
    CrossrefPubMedGoogle Scholar
  • 44 Win NN, Jorgensen AMS, Chen YS. et al. Effects of upper and lower cervical spinal manipulative therapy on blood pressure and heart rate variability in volunteers and patients with neck pain: a randomized controlled, cross-over, preliminary study. Journal of chiropractic medicine 2015; 14: 1-9
    CrossrefPubMedGoogle Scholar
  • 45 Roy RA, Boucher JP, Comtois AS. Heart rate variability modulation after manipulation in pain-free patients vs patients in pain. Journal of manipulative and physiological therapeutics 2009; 32: 277-286
    CrossrefPubMedGoogle Scholar
  • 46 Sterling M, Jull G, Wright A. Cervical mobilisation: concurrent effects on pain, sympathetic nervous system activity and motor activity. Manual therapy 2001; 6: 72-81
    CrossrefPubMedGoogle Scholar
  • 47 Perry J, Green A, Singh S. et al. A randomised, independent groups study investigating the sympathetic nervous system responses to two manual therapy treatments in patients with LBP. Manual therapy 2015; 20: 861-867
    CrossrefPubMedGoogle Scholar
  • 48 Chiu TW, Wright A. To compare the effects of different rates of application of a cervical mobilisation technique on sympathetic outflow to the upper limb in normal subjects. Manual Therapy 1996; 1: 198-203
    CrossrefPubMedGoogle Scholar
  • 49 Petersen N, Vicenzino B, Wright A. The effects of a cervical mobilisation technique on sympathetic outflow to the upper limb in normal subjects. Physiotherapy Theory and Practice 1993; 9: 149-156
    CrossrefPubMedGoogle Scholar
  • 50 Sampath KK, Botnmark E, Mani R. et al. Neuroendocrine response following a thoracic spinal manipulation in healthy men. journal of orthopaedic & sports physical therapy 2017; 47: 617-627
    CrossrefPubMedGoogle Scholar
  • 51 Perry J, Green A. An investigation into the effects of a unilaterally applied lumbar mobilisation technique on peripheral sympathetic nervous system activity in the lower limbs. Manual Therapy 2008; 13: 492-499 DOI: 10.1016/j.math.2007.05.015.
    CrossrefPubMedGoogle Scholar
  • 52 Piekarz V, Perry J. An investigation into the effects of applying a lumbar Maitland mobilisation at different frequencies on sympathetic nervous system activity levels in the lower limb. Manual therapy 2016; 23: 83-89
    CrossrefPubMedGoogle Scholar
  • 53 Silva DRd, Osório RAL, Fernandes AB. Influence of neural mobilization in the sympathetic slump position on the behavior of the autonomic nervous system. Research on Biomedical Engineering 2018; 34: 329-336
    CrossrefPubMedGoogle Scholar
  • 54 Pan PJ, Tsai PH, Tsai CC. et al. Clinical response and autonomic modulation as seen in heart rate variability in mechanical intermittent cervical traction: a pilot study. Journal of rehabilitation medicine 2012; 44: 229-234
    CrossrefPubMedGoogle Scholar
  • 55 Navarro-Santana MJ, Gómez-Chiguano GF, Somkereki MD. et al. Effects of joint mobilisation on clinical manifestations of sympathetic nervous system activity: a systematic review and meta-analysis. Physiotherapy 2020; 107: 118-132 DOI: 10.1016/j.physio.2019.07.001.
    CrossrefPubMedGoogle Scholar
  • 56 Bialosky JE, Bishop MD, Price DD. et al. The mechanisms of manual therapy in the treatment of musculoskeletal pain: a comprehensive model. Manual therapy 2009; 14: 531-538
    CrossrefPubMedGoogle Scholar
  • 57 Rogan S, Taeymans J, Clarys P. et al. Feasibility and effectiveness of thoracic spine mobilization on sympathetic/parasympathetic balance in a healthy population-a randomized controlled double-blinded pilot study. Archives of Physiotherapy 2019; 9: 1-9
    CrossrefPubMedGoogle Scholar
  • 58 Rogan S, Taeymans J, Schürmann S. et al. Segmentale Hautdurchblutungsreaktion während und nach Stimulation im Bereich der BWS. physioscience 2016; 12: 92-99
    Article in Thieme ConnectPubMedGoogle Scholar
  • 59 Fontes MAP, Limborço Filho M, Machado NLS. et al. Asymmetric sympathetic output: The dorsomedial hypothalamus as a potential link between emotional stress and cardiac arrhythmias. Autonomic Neuroscience 2017; 207: 22-27
    CrossrefPubMedGoogle Scholar
  • 60 Fontes MAP, Xavier CH, De Menezes RCA. et al. The dorsomedial hypothalamus and the central pathways involved in the cardiovascular response to emotional stress. Neuroscience 2011; 184: 64-74
    CrossrefPubMedGoogle Scholar
  • 61 Fontes MAP, Xavier CH, Marins FR. et al. Emotional stress and sympathetic activity: contribution of dorsomedial hypothalamus to cardiac arrhythmias. Brain research 2014; 1554: 49-58
    CrossrefPubMedGoogle Scholar
  • 62 Da Jr Silva, Menezes RCA, Villela DC. et al. Excitatory amino acid receptors in the periaqueductal gray mediate the cardiovascular response evoked by activation of dorsomedial hypothalamic neurons. Neuroscience 2006; 139: 1129-1139
    CrossrefPubMedGoogle Scholar
  • 63 Moraes GCA, Mendonça MM, Mourão AA. et al. Ventromedial medullary pathway mediating cardiac responses evoked from periaqueductal gray. Autonomic Neuroscience 2020; 228: 102716 DOI: 10.1016/j.autneu.2020.102716.
    CrossrefPubMedGoogle Scholar
  • 64 Moyer CA, Rounds J, Hannum JW. A meta-analysis of massage therapy research. Psychological bulletin 2004; 130: 3 DOI: 10.1037/0033-2909.130.1.3.
    CrossrefPubMedGoogle Scholar
  • 65 Moraska A, Pollini RA, Boulanger K. et al. Physiological adjustments to stress measures following massage therapy: a review of the literature. Evidence-Based Complementary and Alternative Medicine 2010; 7: 409-418
    CrossrefPubMedGoogle Scholar
  • 66 Field T, Diego M, Hernandez-Reif M. Massage therapy research. Developmental Review 2007; 27: 75-89
    CrossrefPubMedGoogle Scholar
  • 67 Porges SW. The polyvagal theory: Phylogenetic contributions to social behavior. Physiology & behavior 2003; 79: 503-513
    CrossrefPubMedGoogle Scholar
  • 68 Takamoto K, Sakai S, Hori E. et al. Compression on trigger points in the leg muscle increases parasympathetic nervous activity based on heart rate variability. The Journal of Physiological Sciences 2009; 59: 191-197
    CrossrefPubMedGoogle Scholar
  • 69 Lastova K, Nordvall M, Walters-Edwards M. et al. Cardiac autonomic and blood pressure responses to an acute foam rolling session. The Journal of Strength & Conditioning Research 2018; 32: 2825-2830
    CrossrefPubMedGoogle Scholar
  • 70 Schleip R. Fascial plasticity–a new neurobiological explanation: Part 1. Journal of Bodywork and movement therapies 2003; 7: 11-19
    CrossrefPubMedGoogle Scholar
  • 71 Conlon K, Collins T, Kidd C. Modulation of vagal actions on heart rate produced by inhibition of nitric oxide synthase in the anaesthetized ferret. Experimental Physiology: Translation and Integration 1996; 81: 547-550
    CrossrefPubMedGoogle Scholar
  • 72 Okamoto T, Masuhara M, Ikuta K. Acute effects of self-myofascial release using a foam roller on arterial function. The Journal of Strength & Conditioning Research 2014; 28: 69-73
    CrossrefPubMedGoogle Scholar
  • 73 Cook NR, Cohen J, Hebert PR. et al. Implications of small reductions in diastolic blood pressure for primary prevention. Archives of internal medicine 1995; 155: 701-709
    CrossrefPubMedGoogle Scholar
  • 74 Haller A, Buetzberger J, Rogan S. Effects of six thoracic spine mobilization treatments on heart rate variability and heart reat ferquency – a randomized cotrolled pilot study World Congress Physical Therapy (WCPT). Geneva Switzwerland: 2019
    Google Scholar
  • 75 Anderson S, Allen P, Peckham S. et al. Asking the right questions: scoping studies in the commissioning of research on the organisation and delivery of health services. Health research policy and systems 2008; 6: 1-12
    CrossrefPubMedGoogle Scholar