Advertisement

Acta Diabetologica

, Volume 56, Issue 2, pp 135–144 | Cite as

Brain functional imaging in obese and diabetic patients

  • Maria Angela GuzzardiEmail author
  • Patricia Iozzo
Review Article
  • 282 Downloads

Abstract

Obesity and type 2 diabetes are associated with greater risk of brain damage. Over the last decade, functional imaging techniques (functional magnetic resonance imaging, fMRI, positron emission tomography, PET, electroencephalography, magnetoencephalography, near infrared spectroscopy) have been exploited to better characterize behavioral and cognitive processes, by addressing cerebral reactions to a variety of stimuli or tasks, including hormones and substrates (e.g., glucose, insulin, gut peptides), environmental cues (e.g., presentation of sensory stimuli), and cognitive tasks. Among these techniques, fMRI and PET are most commonly used, and this review focuses on results obtained with these techniques in relation to brain substrate metabolism, appetite control and food intake, and cognitive decline in obesity and type 2 diabetes. The available knowledge indicates that there are a series of cerebral abnormalities associating with, or preceding obesity and type 2 diabetes, including impaired substrate handling, insulin resistance, disruption of inter-organ cross-talk and of resting state networking. Some of these abnormalities are reversed by metabolic interventions, suggesting that they are partly a consequence rather than cause of disease. Therefore, causal implications and mechanisms remain to be determined.

Keywords

Brain substrate metabolism Appetite control Cognitive processes Functional magnetic resonance imaging Positron emission tomography 

Notes

Compliance with ethical standards

Conflict of interest

The author(s) declare that they have no competing interests.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

References

  1. 1.
    Amaro E Jr, Barker GJ (2006) Study design in fMRI: basic principles. Brain Cogn 60(3):220–232.  https://doi.org/10.1016/j.bandc.2005.11.009 CrossRefGoogle Scholar
  2. 2.
    Iozzo P, Guiducci L, Guzzardi MA, Pagotto U (2012) Brain PET imaging in obesity and food addiction: current evidence and hypothesis. Obes Facts 5(2):155–164.  https://doi.org/10.1159/000338328 CrossRefGoogle Scholar
  3. 3.
    Hirvonen J, Virtanen KA, Nummenmaa L et al (2011) Effects of insulin on brain glucose metabolism in impaired glucose tolerance. Diabetes 60(2):443–447.  https://doi.org/10.2337/db10-0940 CrossRefGoogle Scholar
  4. 4.
    Liistro T, Guiducci L, Burchielli S et al (2010) Brain glucose overexposure and lack of acute metabolic flexibility in obesity and type 2 diabetes: a PET-[18F]FDG study in Zucker and ZDF rats. J Cereb Blood Flow Metab 30(5):895–899.  https://doi.org/10.1038/jcbfm.2010.27 CrossRefGoogle Scholar
  5. 5.
    Ferrannini E, Bjorkman O, Reichard GA Jr et al (1985) The disposal of an oral glucose load in healthy subjects. A quantitative study. Diabetes 34(6):580–588CrossRefGoogle Scholar
  6. 6.
    Eastman RC, Carson RE, Gordon MR et al (1990) Brain glucose metabolism in noninsulin-dependent diabetes mellitus: a study in Pima Indians using positron emission tomography during hyperinsulinemia with euglycemic glucose clamp. J Clin Endocrinol Metab 71(6):1602–1610.  https://doi.org/10.1210/jcem-71-6-1602 CrossRefGoogle Scholar
  7. 7.
    Tuulari JJ, Karlsson HK, Hirvonen J et al (2013) Weight loss after bariatric surgery reverses insulin-induced increases in brain glucose metabolism of the morbidly obese. Diabetes 62(8):2747–2751.  https://doi.org/10.2337/db12-1460 CrossRefGoogle Scholar
  8. 8.
    Rebelos E, Bucci M, Immonen H et al (2017) Endogenous glucose production is independently associated to brain glucose uptake in morbidly obese subjects. Diabetologia 60:(S80–81)Google Scholar
  9. 9.
    Bingham EM, Hopkins D, Smith D et al (2002) The role of insulin in human brain glucose metabolism: an 18fluoro-deoxyglucose positron emission tomography study. Diabetes 51(12):3384–3390CrossRefGoogle Scholar
  10. 10.
    Honkala SM, Johansson J, Motiani KK et al (2017) Short-term interval training alters brain glucose metabolism in subjects with insulin resistance. J Cereb Blood Flow Metab.  https://doi.org/10.1177/0271678X17734998 Google Scholar
  11. 11.
    Guzzardi MA, Sanguinetti E, Bartoli A et al (2017) Elevated glycemia and brain glucose utilization predict BDNF lowering since early life. J Cereb Blood Flow Metab.  https://doi.org/10.1177/0271678X17697338 Google Scholar
  12. 12.
    Sanguinetti E, Liistro T, Mainardi M et al (2016) Maternal high-fat feeding leads to alterations of brain glucose metabolism in the offspring: positron emission tomography study in a porcine model. Diabetologia 59(4):813–821.  https://doi.org/10.1007/s00125-015-3848-5 CrossRefGoogle Scholar
  13. 13.
    Heni M, Wagner R, Kullmann S et al (2017) Hypothalamic and striatal insulin action suppresses endogenous glucose production and may stimulate glucose uptake during hyperinsulinemia in lean but not in overweight men. Diabetes 66(7):1797–1806.  https://doi.org/10.2337/db16-1380 CrossRefGoogle Scholar
  14. 14.
    Sanguinetti E, Guzzardi MA, Ditaranto F et al (2017) Maternal high-fat feeding and/or overweight and the early programming of metabolic and cognitive risk in the offspring: a study in mice and human infants. Obes Facts 10(suppl 1):82Google Scholar
  15. 15.
    Karmi A, Iozzo P, Viljanen A et al (2010) Increased brain fatty acid uptake in metabolic syndrome. Diabetes 59(9):2171–2177.  https://doi.org/10.2337/db09-0138 CrossRefGoogle Scholar
  16. 16.
    Berthoud HR, Munzberg H, Morrison CD (2017) Blaming the brain for obesity: integration of hedonic and homeostatic mechanisms. Gastroenterology 152(7):1728–1738.  https://doi.org/10.1053/j.gastro.2016.12.050 CrossRefGoogle Scholar
  17. 17.
    Matsuda M, Liu Y, Mahankali S et al (1999) Altered hypothalamic function in response to glucose ingestion in obese humans. Diabetes 48(9):1801–1806CrossRefGoogle Scholar
  18. 18.
    Vidarsdottir S, Smeets PA, Eichelsheim DL et al (2007) Glucose ingestion fails to inhibit hypothalamic neuronal activity in patients with type 2 diabetes. Diabetes 56(10):2547–2550.  https://doi.org/10.2337/db07-0193 CrossRefGoogle Scholar
  19. 19.
    Stice E, Spoor S, Bohon C, Veldhuizen MG, Small DM (2008) Relation of reward from food intake and anticipated food intake to obesity: a functional magnetic resonance imaging study. J Abnorm Psychol 117(4):924–935.  https://doi.org/10.1037/a0013600 CrossRefGoogle Scholar
  20. 20.
    Stoeckel LE, Weller RE, Cook EW III, Twieg DB, Knowlton RC, Cox JE (2008) Widespread reward-system activation in obese women in response to pictures of high-calorie foods. Neuroimage 41(2):636–647.  https://doi.org/10.1016/j.neuroimage.2008.02.031 CrossRefGoogle Scholar
  21. 21.
    Scharmuller W, Ubel S, Ebner F, Schienle A (2012) Appetite regulation during food cue exposure: a comparison of normal-weight and obese women. Neurosci Lett 518(2):106–110.  https://doi.org/10.1016/j.neulet.2012.04.063 CrossRefGoogle Scholar
  22. 22.
    Killgore WD, Young AD, Femia LA et al (2003) Cortical and limbic activation during viewing of high- versus low-calorie foods. Neuroimage 19(4):1381–1394CrossRefGoogle Scholar
  23. 23.
    Wang GJ, Volkow ND, Telang F et al (2004) Exposure to appetitive food stimuli markedly activates the human brain. Neuroimage 21(4):1790–1797.  https://doi.org/10.1016/j.neuroimage.2003.11.026 CrossRefGoogle Scholar
  24. 24.
    Fuhrer D, Zysset S, Stumvoll M (2008) Brain activity in hunger and satiety: an exploratory visually stimulated FMRI study. Obesity (Silver Spring) 16(5):945–950.  https://doi.org/10.1038/oby.2008.33 CrossRefGoogle Scholar
  25. 25.
    O’Doherty JP, Deichmann R, Critchley HD, Dolan RJ (2002) Neural responses during anticipation of a primary taste reward. Neuron 33(5):815–826CrossRefGoogle Scholar
  26. 26.
    Burger KS, Stice E (2014) Greater striatopallidal adaptive coding during cue-reward learning and food reward habituation predict future weight gain. Neuroimage 99:122–128.  https://doi.org/10.1016/j.neuroimage.2014.05.066 CrossRefGoogle Scholar
  27. 27.
    Wang GJ, Volkow ND, Felder C et al (2002) Enhanced resting activity of the oral somatosensory cortex in obese subjects. Neuroreport 13(9):1151–1155CrossRefGoogle Scholar
  28. 28.
    Volkow ND, Wang GJ, Fowler JS, Telang F (2008) Overlapping neuronal circuits in addiction and obesity: evidence of systems pathology. Philos Trans R Soc Lond B Biol Sci 363(1507):3191–3200.  https://doi.org/10.1098/rstb.2008.0107 CrossRefGoogle Scholar
  29. 29.
    DelParigi A, Chen K, Salbe AD, Reiman EM, Tataranni PA (2005) Sensory experience of food and obesity: a positron emission tomography study of the brain regions affected by tasting a liquid meal after a prolonged fast. Neuroimage 24(2):436–443.  https://doi.org/10.1016/j.neuroimage.2004.08.035 CrossRefGoogle Scholar
  30. 30.
    Wang GJ, Volkow ND, Logan J et al (2001) Brain dopamine and obesity. Lancet 357(9253):354–357CrossRefGoogle Scholar
  31. 31.
    Volkow ND, Wang GJ, Telang F et al (2008) Low dopamine striatal D2 receptors are associated with prefrontal metabolism in obese subjects: possible contributing factors. Neuroimage 42(4):1537–1543.  https://doi.org/10.1016/j.neuroimage.2008.06.002 CrossRefGoogle Scholar
  32. 32.
    Ziauddeen H, Fletcher PC (2013) Is food addiction a valid and useful concept? Obes Rev 14(1):19–28.  https://doi.org/10.1111/j.1467-789X.2012.01046.x CrossRefGoogle Scholar
  33. 33.
    Lindgren E, Gray K, Miller G et al (2018) Food addiction: a common neurobiological mechanism with drug abuse. Front Biosci (Landmark Ed) 23:811–836CrossRefGoogle Scholar
  34. 34.
    Berthoud HR (2008) Vagal and hormonal gut–brain communication: from satiation to satisfaction. Neurogastroenterol Motil 20(Suppl 1):64–72.  https://doi.org/10.1111/j.1365-2982.2008.01104.x CrossRefGoogle Scholar
  35. 35.
    Goldstone AP, Prechtl CG, Scholtz S et al (2014) Ghrelin mimics fasting to enhance human hedonic, orbitofrontal cortex, and hippocampal responses to food. Am J Clin Nutr 99(6):1319–1330.  https://doi.org/10.3945/ajcn.113.075291 CrossRefGoogle Scholar
  36. 36.
    Malik S, McGlone F, Bedrossian D, Dagher A (2008) Ghrelin modulates brain activity in areas that control appetitive behavior. Cell Metab 7(5):400–409.  https://doi.org/10.1016/j.cmet.2008.03.007 CrossRefGoogle Scholar
  37. 37.
    Jones RB, McKie S, Astbury N et al (2012) Functional neuroimaging demonstrates that ghrelin inhibits the central nervous system response to ingested lipid. Gut 61(11):1543–1551.  https://doi.org/10.1136/gutjnl-2011-301323 CrossRefGoogle Scholar
  38. 38.
    Jastreboff AM, Sinha R, Arora J et al (2016) Altered brain response to drinking glucose and fructose in obese adolescents. Diabetes 65(7):1929–1939.  https://doi.org/10.2337/db15-1216 CrossRefGoogle Scholar
  39. 39.
    Savage SW, Zald DH, Cowan RL et al (2014) Regulation of novelty seeking by midbrain dopamine D2/D3 signaling and ghrelin is altered in obesity. Obesity (Silver Spring) 22(6):1452–1457.  https://doi.org/10.1002/oby.20690 CrossRefGoogle Scholar
  40. 40.
    Batterham RL, Ffytche DH, Rosenthal JM et al (2007) PYY modulation of cortical and hypothalamic brain areas predicts feeding behaviour in humans. Nature 450(7166):106–109.  https://doi.org/10.1038/nature06212 CrossRefGoogle Scholar
  41. 41.
    De Silva A, Salem V, Long CJ et al (2011) The gut hormones PYY 3–36 and GLP-1 7–36 amide reduce food intake and modulate brain activity in appetite centers in humans. Cell Metab 14(5):700–706.  https://doi.org/10.1016/j.cmet.2011.09.010 CrossRefGoogle Scholar
  42. 42.
    le Roux CW, Batterham RL, Aylwin SJ et al (2006) Attenuated peptide YY release in obese subjects is associated with reduced satiety. Endocrinology 147(1):3–8.  https://doi.org/10.1210/en.2005-0972 CrossRefGoogle Scholar
  43. 43.
    van Bloemendaal L, RG IJerman, Ten Kulve JS et al (2014) GLP-1 receptor activation modulates appetite- and reward-related brain areas in humans. Diabetes 63(12):4186–4196.  https://doi.org/10.2337/db14-0849 CrossRefGoogle Scholar
  44. 44.
    Farr OM, Sofopoulos M, Tsoukas MA et al (2016) GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: a crossover, randomised, placebo-controlled trial. Diabetologia 59(5):954–965.  https://doi.org/10.1007/s00125-016-3874-y CrossRefGoogle Scholar
  45. 45.
    Ten Kulve JS, Veltman DJ, van Bloemendaal L et al (2016) Endogenous GLP1 and GLP1 analogue alter CNS responses to palatable food consumption. J Endocrinol 229(1):1–12.  https://doi.org/10.1530/JOE-15-0461 CrossRefGoogle Scholar
  46. 46.
    Daniele G, Iozzo P, Molina-Carrion M et al (2015) Exenatide regulates cerebral glucose metabolism in brain areas associated with glucose homeostasis and reward system. Diabetes 64(10):3406–3412.  https://doi.org/10.2337/db14-1718 CrossRefGoogle Scholar
  47. 47.
    Farooqi IS, Bullmore E, Keogh J, Gillard J, O’Rahilly S, Fletcher PC (2007) Leptin regulates striatal regions and human eating behavior. Science 317(5843):1355.  https://doi.org/10.1126/science.1144599 CrossRefGoogle Scholar
  48. 48.
    Baicy K, London ED, Monterosso J et al (2007) Leptin replacement alters brain response to food cues in genetically leptin-deficient adults. Proc Natl Acad Sci USA 104(46):18276–18279.  https://doi.org/10.1073/pnas.0706481104 CrossRefGoogle Scholar
  49. 49.
    Rosenbaum M, Sy M, Pavlovich K, Leibel RL, Hirsch J (2008) Leptin reverses weight loss-induced changes in regional neural activity responses to visual food stimuli. J Clin Investig 118(7):2583–2591.  https://doi.org/10.1172/JCI35055 Google Scholar
  50. 50.
    Hinkle W, Cordell M, Leibel R, Rosenbaum M, Hirsch J (2013) Effects of reduced weight maintenance and leptin repletion on functional connectivity of the hypothalamus in obese humans. PLoS One 8(3):e59114.  https://doi.org/10.1371/journal.pone.0059114 CrossRefGoogle Scholar
  51. 51.
    Frost G, Sleeth ML, Sahuri-Arisoylu M et al (2014) The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nat Commun 5:3611.  https://doi.org/10.1038/ncomms4611 CrossRefGoogle Scholar
  52. 52.
    Byrne CS, Chambers ES, Alhabeeb H et al (2016) Increased colonic propionate reduces anticipatory reward responses in the human striatum to high-energy foods. Am J Clin Nutr 104(1):5–14.  https://doi.org/10.3945/ajcn.115.126706 CrossRefGoogle Scholar
  53. 53.
    Wang GJ, Zhao J, Tomasi D et al (2018) Effect of combined naltrexone and bupropion therapy on the brain’s functional connectivity. Int J Obes (Lond).  https://doi.org/10.1038/s41366-018-0040-2 Google Scholar
  54. 54.
    Scholtz S, Miras AD, Chhina N et al (2014) Obese patients after gastric bypass surgery have lower brain-hedonic responses to food than after gastric banding. Gut 63(6):891–902.  https://doi.org/10.1136/gutjnl-2013-305008 CrossRefGoogle Scholar
  55. 55.
    van de Sande-Lee S, Pereira FR, Cintra DE et al (2011) Partial reversibility of hypothalamic dysfunction and changes in brain activity after body mass reduction in obese subjects. Diabetes 60(6):1699–1704.  https://doi.org/10.2337/db10-1614 CrossRefGoogle Scholar
  56. 56.
    Ochner CN, Kwok Y, Conceicao E et al (2011) Selective reduction in neural responses to high calorie foods following gastric bypass surgery. Ann Surg 253(3):502–507.  https://doi.org/10.1097/SLA.0b013e318203a289 CrossRefGoogle Scholar
  57. 57.
    Goldstone AP, Miras AD, Scholtz S et al (2016) Link between increased satiety gut hormones and reduced food reward after gastric bypass surgery for obesity. J Clin Endocrinol Metab 101(2):599–609.  https://doi.org/10.1210/jc.2015-2665 CrossRefGoogle Scholar
  58. 58.
    Hunt KF, Dunn JT, le Roux CW et al (2016) Differences in regional brain responses to food ingestion after Roux-en-Y gastric bypass and the role of gut peptides: a neuroimaging study. Diabetes Care 39(10):1787–1795.  https://doi.org/10.2337/dc15-2721 CrossRefGoogle Scholar
  59. 59.
    Musen G, Jacobson AM, Bolo NR et al (2012) Resting-state brain functional connectivity is altered in type 2 diabetes. Diabetes 61(9):2375–2379.  https://doi.org/10.2337/db11-1669 CrossRefGoogle Scholar
  60. 60.
    Cheke LG, Bonnici HM, Clayton NS, Simons JS (2017) Obesity and insulin resistance are associated with reduced activity in core memory regions of the brain. Neuropsychologia 96:137–149.  https://doi.org/10.1016/j.neuropsychologia.2017.01.013 CrossRefGoogle Scholar
  61. 61.
    Marder TJ, Flores VL, Bolo NR et al (2014) Task-induced brain activity patterns in type 2 diabetes: a potential biomarker for cognitive decline. Diabetes 63(9):3112–3119.  https://doi.org/10.2337/db13-1783 CrossRefGoogle Scholar
  62. 62.
    Manschot SM, Brands AM, van der Grond J et al (2006) Brain magnetic resonance imaging correlates of impaired cognition in patients with type 2 diabetes. Diabetes 55(4):1106–1113CrossRefGoogle Scholar
  63. 63.
    Tiehuis AM, van der Graaf Y, Visseren FL et al (2008) Diabetes increases atrophy and vascular lesions on brain MRI in patients with symptomatic arterial disease. Stroke 39(5):1600–1603.  https://doi.org/10.1161/STROKEAHA.107.506089 CrossRefGoogle Scholar
  64. 64.
    Debette S, Seshadri S, Beiser A et al (2011) Midlife vascular risk factor exposure accelerates structural brain aging and cognitive decline. Neurology 77(5):461–468.  https://doi.org/10.1212/WNL.0b013e318227b227 CrossRefGoogle Scholar
  65. 65.
    Moran C, Phan TG, Chen J et al (2013) Brain atrophy in type 2 diabetes: regional distribution and influence on cognition. Diabetes Care 36(12):4036–4042.  https://doi.org/10.2337/dc13-0143 CrossRefGoogle Scholar
  66. 66.
    Willette AA, Xu G, Johnson SC et al (2013) Insulin resistance, brain atrophy, and cognitive performance in late middle-aged adults. Diabetes Care 36(2):443–449.  https://doi.org/10.2337/dc12-0922 CrossRefGoogle Scholar
  67. 67.
    Bauer CC, Moreno B, Gonzalez-Santos L, Concha L, Barquera S, Barrios FA (2015) Child overweight and obesity are associated with reduced executive cognitive performance and brain alterations: a magnetic resonance imaging study in Mexican children. Pediatr Obes 10(3):196–204.  https://doi.org/10.1111/ijpo.241 CrossRefGoogle Scholar
  68. 68.
    Yau PL, Kang EH, Javier DC, Convit A (2014) Preliminary evidence of cognitive and brain abnormalities in uncomplicated adolescent obesity. Obesity (Silver Spring) 22(8):1865–1871.  https://doi.org/10.1002/oby.20801 CrossRefGoogle Scholar
  69. 69.
    Thompson PM, Hayashi KM, de Zubicaray G et al (2003) Dynamics of gray matter loss in Alzheimer’s disease. J Neurosci 23(3):994–1005CrossRefGoogle Scholar
  70. 70.
    Murray AM, Hsu FC, Williamson JD et al (2017) ACCORDION MIND: results of the observational extension of the ACCORD MIND randomised trial. Diabetologia 60(1):69–80.  https://doi.org/10.1007/s00125-016-4118-x CrossRefGoogle Scholar
  71. 71.
    Dickerson BC, Sperling RA (2008) Functional abnormalities of the medial temporal lobe memory system in mild cognitive impairment and Alzheimer’s disease: insights from functional MRI studies. Neuropsychologia 46(6):1624–1635.  https://doi.org/10.1016/j.neuropsychologia.2007.11.030 CrossRefGoogle Scholar
  72. 72.
    Zhou H, Lu W, Shi Y et al (2010) Impairments in cognition and resting-state connectivity of the hippocampus in elderly subjects with type 2 diabetes. Neurosci Lett 473(1):5–10.  https://doi.org/10.1016/j.neulet.2009.12.057 CrossRefGoogle Scholar
  73. 73.
    Cui Y, Jiao Y, Chen YC et al (2014) Altered spontaneous brain activity in type 2 diabetes: a resting-state functional MRI study. Diabetes 63(2):749–760.  https://doi.org/10.2337/db13-0519 CrossRefGoogle Scholar
  74. 74.
    Xia W, Wang S, Sun Z et al (2013) Altered baseline brain activity in type 2 diabetes: a resting-state fMRI study. Psychoneuroendocrinology 38(11):2493–2501.  https://doi.org/10.1016/j.psyneuen.2013.05.012 CrossRefGoogle Scholar
  75. 75.
    Cui Y, Li SF, Gu H et al (2016) Disrupted brain connectivity patterns in patients with type 2 diabetes. AJNR Am J Neuroradiol.  https://doi.org/10.3174/ajnr.A4858 Google Scholar
  76. 76.
    Hoth KF, Gonzales MM, Tarumi T, Miles SC, Tanaka H, Haley AP (2011) Functional MR imaging evidence of altered functional activation in metabolic syndrome. AJNR Am J Neuroradiol 32(3):541–547.  https://doi.org/10.3174/ajnr.A2315 CrossRefGoogle Scholar
  77. 77.
    Kuczynski B, Jagust W, Chui HC, Reed B (2009) An inverse association of cardiovascular risk and frontal lobe glucose metabolism. Neurology 72(8):738–743.  https://doi.org/10.1212/01.wnl.0000343005.35498.e5 CrossRefGoogle Scholar
  78. 78.
    Willette AA, Bendlin BB, Starks EJ et al (2015) Association of insulin resistance with cerebral glucose uptake in late middle-aged adults at risk for Alzheimer disease. JAMA Neurol 72(9):1013–1020.  https://doi.org/10.1001/jamaneurol.2015.0613 CrossRefGoogle Scholar
  79. 79.
    Baker LD, Cross DJ, Minoshima S, Belongia D, Watson GS, Craft S (2011) Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. Arch Neurol 68(1):51–57.  https://doi.org/10.1001/archneurol.2010.225 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia S.r.l., part of Springer Nature 2018

Authors and Affiliations

  1. 1.Institute of Clinical PhysiologyNational Research Council (CNR)PisaItaly

Personalised recommendations