Acta Neurochirurgica

, Volume 158, Issue 11, pp 2163–2171 | Cite as

Pathological changes of the hippocampus and cognitive dysfunction following frontal lobe surgery in a rat model

  • Santiago Hem
  • Romina Albite
  • Monica Loresi
  • Jorge Rasmussen
  • Pablo Ajler
  • Claudio Yampolsky
  • Joseph D. Chabot
  • Peter C. Gerszten
  • Ezequiel Goldschmidt
Experimental Research - Brain Injury

Abstract

Background

Postoperative cognitive dysfunction (POCD) is a known complication after intracranial surgery. Impaired hippocampal neurogenesis has been associated with cognitive dysfunction in animal models.

Methods

In order to assess hippocampal changes after brain surgery, a frontal lobe corticectomy was performed in ten adult Wistar rats (group 4). Three different control groups (n = 10 each) included no treatment (G1), general anesthesia alone (G2), and craniectomy without dural opening (G3). Twenty-four hours after surgery, half of the animals were killed, and the mRNA levels for IL-6, TNF-α, and brain-derived growth factor (BDNF) in the contralateral hippocampus were assessed by qPCR. Seven days later, the remaining animals underwent anxiety and memory testing. Afterwards, the number of immature neurons in the hippocampal cortex was measured by doublecortin (DCX) staining.

Results

Twenty-four hours after surgery, mRNA levels of IL-6 and TNF-α increased and BDNF decreased in both surgical groups G3 and G4 (p = 0.012). Cognitive tests demonstrated an increase in anxiety levels and memory impairment in surgical groups compared with non-surgical animals. These changes correlated with an inhibition of hippocampal neurogenesis evidenced by a decreased number of new neurons (mean ± SD for G1-4: 66.4 ± 24; 57.6 ± 22.2; 21.3 ± 3.78; 5.7 ± 1.05, p < 0.001, non-parametric ANOVA).

Conclusions

Intracranial surgery was demonstrated to induce an inflammatory reaction within the hippocampus that compromised neurogenesis and impaired normal cognitive processing. Corticectomy had a greater effect than craniotomy alone, indicating a central trigger for hippocampal inflammatory changes. POCD after craniotomy may originate from a central inflammatory response resulting from surgical trauma to the brain parenchyma.

Keywords

Cerebral surgery Hippocampus Inflammation Postoperative cognitive dysfunction 

References

  1. 1.
    Abildstrom H, Rasmussen LS, Rentowl P, Hanning CD, Rasmussen H, Kristensen PA, Moller JT (2000) Cognitive dysfunction 1–2 years after non-cardiac surgery in the elderly. ISPOCD group. International Study of Post-Operative Cognitive Dysfunction. Acta Anaesthesiol Scand 44(10):1246–1251CrossRefPubMedGoogle Scholar
  2. 2.
    Bekinschtein P, Cammarota M, Medina JH (2014) BDNF and memory processing. Neuropharmacology 76:677–683CrossRefPubMedGoogle Scholar
  3. 3.
    Biedler A, Juckenhöfel S, Larsen R, Radtke F, Stotz A, Warmann J, Braune E, Dyttkowitz A, Henning F, Strickmann B, Lauven PM (1999) Postoperative cognition disorders in elderly patients. the results of the “International Study of Postoperative Cognitive Dysfunction” ISPOCD 1). Anaesthesist 48(12):884–895CrossRefPubMedGoogle Scholar
  4. 4.
    Binder DK, Scharfman HE (2004) Brain-derived neurotrophic factor. Growth Factors 22(3):123–131CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Bramham CR (2007) Control of synaptic consolidation in the dentate gyrus: mechanisms, functions, and therapeutic implications. Prog Brain Res 163:453–471CrossRefPubMedGoogle Scholar
  6. 6.
    Canet J, Raeder J, Rasmussen LS, Enlund M, Kuipers HM, Hanning CD, Jolles J, Korttila K, Siersma VD, Dodds C, Abildstrom H, Sneyd JR, Vila P, Johnson T, Munoz Corsini L, Silverstein JH, Nielsen IK, Moller JT (2003) Cognitive dysfunction after minor surgery in the elderly. Acta Anaesthesiol Scand 47(10):1204–1210CrossRefPubMedGoogle Scholar
  7. 7.
    Cao X-Z, Ma H, Wang J-K, Liu F, Wu B-Y, Tian A-Y, Wang L-L, Tan W-F (2010) Postoperative cognitive deficits and neuroinflammation in the hippocampus triggered by surgical trauma are exacerbated in aged rats. Prog Neuropsychopharmacol Biol Psychiatry 34(8):1426–1432CrossRefPubMedGoogle Scholar
  8. 8.
    Caza N, Taha R, Qi Y, Blaise G (2008) The effects of surgery and anesthesia on memory and cognition. Prog Brain Res 169:409–422CrossRefPubMedGoogle Scholar
  9. 9.
    Chen K, Wei P, Zheng Q, Zhou J, Li J (2015) Neuroprotective effects of intravenous lidocaine on early postoperative cognitive dysfunction in elderly patients following spine surgery. Med Sci Monit 21:1402–1407CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Chida K, Ogasawara K, Suga Y, Saito H, Kobayashi M, Yoshida K, Otawara Y, Ogawa A (2009) Postoperative cortical neural loss associated with cerebral hyperperfusion and cognitive impairment after carotid endarterectomy 123I-iomazenil SPECT study. Stroke. doi:10.1161/STROKEAHA.108.515775 Google Scholar
  11. 11.
    Cibelli M, Fidalgo AR, Terrando N, Ma D, Monaco C, Feldmann M, Takata M, Lever IJ, Nanchahal J, Fanselow MS, Maze M (2010) Role of interleukin-1beta in postoperative cognitive dysfunction. Ann Neurol 68(3):360–368CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Deng W, Aimone JB, Gage FH (2010) New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat Rev Neurosci 11(5):339–350CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    DiPatri AJ, Pham M, Muro K (2009) Late effects of neurosurgery. Cancer Treat. Res, 7–22Google Scholar
  14. 14.
    Failla MD, Juengst SB, Arenth PM, Wagner AK (2015) Preliminary associations between brain-derived neurotrophic factor, memory impairment, functional cognition, and depressive symptoms following severe TBI. Neurorehabil Neural Repair. doi:10.1177/1545968315600525 Google Scholar
  15. 15.
    Griesbach GS, Hovda DA, Molteni R, Gomez-Pinilla F (2002) Alterations in BDNF and synapsin I within the occipital cortex and hippocampus after mild traumatic brain injury in the developing rat: reflections of injury-induced neuroplasticity. J Neurotrauma 19(7):803–814CrossRefPubMedGoogle Scholar
  16. 16.
    Hillis AE, Anderson N, Sampath P, Rigamonti D (2000) Cognitive impairments after surgical repair of ruptured and unruptured aneurysms. J Neurol Neurosurg Psychiatry 69(5):608–615CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Hong JH, Chiang CS, Campbell IL, Sun JR, Withers HR, McBride WH (1995) Induction of acute phase gene expression by brain irradiation. Int J Radiat Oncol Biol Phys 33(3):619–626CrossRefPubMedGoogle Scholar
  18. 18.
    Ji R-R, Xu Z-Z, Gao Y-J (2014) Emerging targets in neuroinflammation-driven chronic pain. Nat Rev Drug Discov 13(7):533–548CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Jin K, Sun Y, Xie L, Peel A, Mao XO, Batteur S, Greenberg DA (2003) Directed migration of neuronal precursors into the ischemic cerebral cortex and striatum. Mol Cell Neurosci 24(1):171–189CrossRefPubMedGoogle Scholar
  20. 20.
    Leal G, Afonso PM, Salazar IL, Duarte CB (2014) Regulation of hippocampal synaptic plasticity by BDNF. Brain Res. doi:10.1016/j.brainres.2014.10.019 PubMedGoogle Scholar
  21. 21.
    Lee WH, Sonntag WE, Mitschelen M, Yan H, Lee YW (2010) Irradiation induces regionally specific alterations in pro-inflammatory environments in rat brain. Int J Radiat Biol 86(2):132–144CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Lin G-X, Wang T, Chen M-H, Hu Z-H, Ouyang W (2014) Serum high-mobility group box 1 protein correlates with cognitive decline after gastrointestinal surgery. Acta Anaesthesiol Scand 58(6):668–674CrossRefPubMedGoogle Scholar
  23. 23.
    Lin S-Y, Yin Z-L, Gao J, Zhou L-J, Chen X (2014) Effect of acupuncture-anesthetic composite anesthesia on the incidence of POCD and TNF-alpha, IL-1beta, IL-6 in elderly patients. Zhongguo Zhong Xi Yi Jie He Za Zhi 34(7):795–799PubMedGoogle Scholar
  24. 24.
    Lunn S, Crawley F, Harrison MJG, Brown MM, Newman SP (1999) Impact of carotid endarterectomy upon cognitive functioning. Cerebrovasc Dis 9(2):74–81CrossRefPubMedGoogle Scholar
  25. 25.
    Ma Y, Cheng Q, Wang E, Li L, Zhang X (2015) Inhibiting tumor necrosis factor-α signaling attenuates postoperative cognitive dysfunction in aged rats. Mol Med Rep 12(2):3095–3100PubMedGoogle Scholar
  26. 26.
    Moller JT, Cluitmans P, Rasmussen LS, Houx P, Rasmussen H, Canet J, Rabbitt P, Jolles J, Larsen K, Hanning CD, Langeron O, Johnson T, Lauven PM, Kristensen PA, Biedler A, Van Beem H, Fraidakis O, Silverstein JH, Beneken JEW, Gravenstein JS (1998) Long-term postoperative cognitive dysfunction in the elderly: ISPOCD1 study. Lancet 351(9106):857–861CrossRefPubMedGoogle Scholar
  27. 27.
    Mumby DG, Gaskin S, Glenn MJ, Schramek TE, Lehmann H (2002) Hippocampal damage and exploratory preferences in rats: memory for objects, places, and contexts. Learn Mem 9(2):49–57CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Oomen CA, Bekinschtein P, Kent BA, Saksida LM, Bussey TJ (2014) Adult hippocampal neurogenesis and its role in cognition. Wiley Interdiscip Rev Cogn Sci 5(5):573–587CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Otawara Y, Ogasawara K, Ogawa A, Yamadate K (2005) Cognitive function before and after surgery in patients with unruptured intracranial aneurysm. Stroke 36(1):142–143CrossRefPubMedGoogle Scholar
  30. 30.
    Parihar VK, Acharya MM, Roa DE, Bosch O, Christie L-A, Limoli CL (2014) Defining functional changes in the brain caused by targeted stereotaxic radiosurgery. Transl Cancer Res 3(2):124–137PubMedPubMedCentralGoogle Scholar
  31. 31.
    Peng L, Xu L, Ouyang W (2013) Role of peripheral inflammatory markers in postoperative cognitive dysfunction (POCD): a meta-analysis. PLoS One 8(11):e79624CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Radtke FM, Franck M, Herbig TS, Papkalla N, Kleinwaechter R, Kork F, Brockhaus WR, Wernecke K-D, Spies CD (2012) Incidence and risk factors for cognitive dysfunction in patients with severe systemic disease. J Int Med Res 40(2):612–620CrossRefPubMedGoogle Scholar
  33. 33.
    Rasmussen LS, Johnson T, Kuipers HM, Kristensen D, Siersma VD, Vila P, Jolles J, Papaioannou A, Abildstrom H, Silverstein JH, Bonal JA, Raeder J, Nielsen IK, Korttila K, Munoz L, Dodds C, Hanning CD, Moller JT (2003) Does anaesthesia cause postoperative cognitive dysfunction? A randomised study of regional versus general anaesthesia in 438 elderly patients. Acta Anaesthesiol Scand 47(3):260–266CrossRefPubMedGoogle Scholar
  34. 34.
    Riazi K, Galic MA, Kentner AC, Reid AY, Sharkey KA, Pittman QJ (2015) Microglia-dependent alteration of glutamatergic synaptic transmission and plasticity in the hippocampus during peripheral inflammation. J Neurosci 35(12):4942–4952CrossRefPubMedGoogle Scholar
  35. 35.
    Richardson JTE (1991) Cognitive performance following rupture and repair of intracranial aneurysm. Acta Neurol Scand 83(2):110–122CrossRefPubMedGoogle Scholar
  36. 36.
    Schober ME, Block B, Requena DF, Hale MA, Lane RH (2012) Developmental traumatic brain injury decreased brain-derived neurotrophic factor expression late after injury. Metab Brain Dis 27(2):167–173CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Seo JS, Park SW, Lee YS, Chung C, Kim YB (2014) Risk factors for delirium after spine surgery in elderly patients. J Korean Neurosurg Soc 56(1):28–33CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Shi C, Yang C, Gao R, Yuan W (2015) Risk factors for delirium after spinal surgery: a meta-analysis. World Neurosurg. doi:10.1016/j.wneu.2015.05.057 Google Scholar
  39. 39.
    Steinmetz J, Christensen KB, Lund T, Lohse N, Rasmussen LS (2009) Long-term consequences of postoperative cognitive dysfunction. Anesthesiology 110(3):548–555CrossRefPubMedGoogle Scholar
  40. 40.
    Strøm C, Rasmussen LS (2014) Challenges in anaesthesia for elderly. Singapore Dent J 35C:23–29CrossRefPubMedGoogle Scholar
  41. 41.
    Vacas S, Degos V, Feng X, Maze M (2013) The neuroinflammatory response of postoperative cognitive decline. Br Med Bull 106:161–178CrossRefPubMedGoogle Scholar
  42. 42.
    Vezzani A, Viviani B (2015) Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability. Neuropharmacology 96(Pt A):70–82CrossRefPubMedGoogle Scholar
  43. 43.
    Walf AA, Frye CA (2007) The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc 2(2):322–328CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Walker AK, Kavelaars A, Heijnen CJ, Dantzer R (2014) Neuroinflammation and comorbidity of pain and depression. Pharmacol Rev 66(1):80–101CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Wang F (2014) Postoperative cognitive dysfunction: current developments in mechanism and prevention. Med Sci Monit 20:1908–1912CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Wang L, Chang X, She L, Xu D, Huang W, Poo M (2015) Autocrine action of BDNF on dendrite development of adult-born hippocampal neurons. J Neurosci 35(22):8384–8393CrossRefPubMedGoogle Scholar
  47. 47.
    Weber CF, Friedl H, Hueppe M, Hintereder G, Schmitz-Rixen T, Zwissler B, Meininger D (2009) Impact of general versus local anesthesia on early postoperative cognitive dysfunction following carotid endarterectomy: GALA Study Subgroup Analysis. World J Surg 33(7):1526–1532CrossRefPubMedGoogle Scholar
  48. 48.
    Zheng XU, Ma Z, Gu X (2015) Plasma levels of tumor necrosis factor-α in adolescent idiopathic scoliosis patients serve as a predictor for the incidence of early postoperative cognitive dysfunction following orthopedic surgery. Exp Ther Med 9(4):1443–1447PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Wien 2016

Authors and Affiliations

  • Santiago Hem
    • 1
  • Romina Albite
    • 2
  • Monica Loresi
    • 2
  • Jorge Rasmussen
    • 1
  • Pablo Ajler
    • 1
  • Claudio Yampolsky
    • 1
  • Joseph D. Chabot
    • 3
  • Peter C. Gerszten
    • 3
  • Ezequiel Goldschmidt
    • 1
    • 2
    • 3
  1. 1.Department of NeurosurgeryHospital Italiano de Buenos AiresBuenos AiresArgentina
  2. 2.Institute of Basic Sciences and Experimental MedicineHospital Italiano de Buenos AiresBuenos AiresArgentina
  3. 3.Department of NeurosurgeryUniversity of Pittsburgh Medical CenterPittsburghUSA

Personalised recommendations