nach oben

Current Neurology and Neuroscience Reports

Erschienen in:

01.12.2019 | Behavior (H. S. Kirshner, Section Editor)

Can Salient Stimuli Enhance Responses in Disorders of Consciousness? A Systematic Review

verfasst von: Alfonso Magliacano, Francesco De Bellis, Alejandro Galvao-Carmona, Anna Estraneo, Luigi Trojano

Erschienen in: Current Neurology and Neuroscience Reports | Ausgabe 12/2019

Einloggen, um Zugang zu erhalten

Abstract

Purpose of Review

Diagnostic classification of patients with disorders of consciousness (DoC) is based on clinician’s observation of volitional behaviours. However, patients’ caregivers often report higher levels of responsiveness with respect to those observed during the clinical assessment. Thus, increasing efforts have been aimed at comprehending the effects of self-referential and emotional stimuli on patients’ responsiveness. Here we systematically reviewed the original experimental studies that compared behavioural and electrophysiological responses with salient vs. neutral material in patients in vegetative state/unresponsive wakefulness syndrome or in minimally conscious state.

Recent Findings

Most of the reviewed studies showed that salient stimuli (i.e. patient’s own or familiar faces, patient’s own name, and familiar voices) seem to elicit a higher amount of behavioural or electrophysiological responses with respect to neutral pictures or sounds. Importantly, a quite high percentage of patients seem to respond to salient stimuli only.

Summary

The present review could foster use of personally salient stimuli in assessing DoC. However, the low overall quality of evidence and some limitations in the general reviewing process might induce caution in transferring these suggestions into clinical practice.

Nur mit Berechtigung zugänglich

•• Giacino JT, Katz DI, Schiff ND, Whyte J, Ashman EJ, Ashwal S, et al. Practice guideline update recommendations summary: disorders of consciousness: report of the Guideline Development, Dissemination, and Implementation. Arch Phys Med Rehabil. 2018;99(9):1699–709. https://doi.org/10.1016/j.apmr.2018.07.001 This paper provides the most recent practice recommendations for improving diagnostic and prognostic accuracy in patients with prolonged DoC. CrossRef

Multi-Society Task Force on PVS. Medical aspects of the persistent vegetative state. New Engl J Med. 1994;330(21):1499–508. https://doi.org/10.1056/nejm199507133330216.CrossRef

Laureys S, Celesia GG, Cohadon F, Lavrijsen J, León-Carrión J, Sannita WG, et al. Unresponsive wakefulness syndrome: a new name for the vegetative state or apallic syndrome. BMC Med. 2010;8(1):68. https://doi.org/10.1186/1741-7015-8-68.CrossRefPubMedPubMedCentral

Giacino JT, Ashwal S, Childs N, Cranford R, Jennett B, Katz DI, et al. The minimally conscious state: definition and diagnostic criteria. Neurology. 2002;58(3):349–53. https://doi.org/10.1212/wnl.58.3.349.CrossRefPubMed

Giacino JT, Kalmar K. The vegetative and minimally conscious states: a comparison of clinical features and functional outcome. J Head Trauma Rehabil. 1997;12(4):36–51.CrossRef

Bernat JL. Chronic disorders of consciousness. Lancet. 2006;367(9517):1181–92. https://doi.org/10.1016/S0140-6736(06)68508-5.CrossRefPubMed

Estraneo A, Trojano L. Prognosis in disorders of consciousness. In: Schnakers C, Laureys S, editors. Coma and disorders of consciousness. Cham: Springer; 2018. p. 17–36.CrossRef

Schnakers C, Vanhaudenhuyse A, Giacino J, Ventura M, Boly M, Majerus S, et al. Diagnostic accuracy of the vegetative and minimally conscious state: clinical consensus versus standardized neurobehavioral assessment. BMC Neurol. 2009;9(1):35. https://doi.org/10.1186/1471-2377-9-35.CrossRefPubMedPubMedCentral

Majerus S, Gill-Thwaites H, Andrews K, Laureys S. Behavioral evaluation of consciousness in severe brain damage. Prog Brain Res. 2005;150:397–413. https://doi.org/10.1016/S0079-6123(05)50028-1.CrossRefPubMed

10.

Giacino JT, Kalmar K, Whyte J. The JFK Coma Recovery Scale-Revised: measurement characteristics and diagnostic utility. Arch Phys Med Rehabil. 2004;85(12):2020–9. https://doi.org/10.1016/j.apmr.2004.02.033.CrossRefPubMed

11.

Formisano R, Giustini M, Aloisi M, Contrada M, Schnakers C, Zasler N, et al. An International survey on diagnostic and prognostic protocols in patients with disorder of consciousness. Brain Inj. 2019:1–11. https://doi.org/10.1080/02699052.2019.1622785.CrossRef

12.

Estraneo A, Moretta P, Cardinale V, De Tanti A, Gatta G, Giacino JT, et al. A multicentre study of intentional behavioural responses measured using the Coma Recovery Scale–Revised in patients with minimally conscious state. Clin Rehabil. 2015;29(8):803–8. https://doi.org/10.1177/0269215514556002.CrossRefPubMed

13.

Estraneo A, Loreto V, Guarino I, Boemia V, Paone G, Moretta P, et al. Standard EEG in diagnostic process of prolonged disorders of consciousness. Neurophysiology. 2016;127(6):2379–85. https://doi.org/10.1016/j.clinph.2016.03.021.CrossRef

14.

Faugeras F, Rohaut B, Weiss N, Bekinschtein TA, Galanaud D, Puybasset L, et al. Probing consciousness with event-related potentials in the vegetative state. Neurology. 2011;77(3):264–8. https://doi.org/10.1212/WNL.0b013e3182217ee8.CrossRefPubMedPubMedCentral

15.

Faugeras F, Rohaut B, Weiss N, Bekinschtein T, Galanaud D, Puybasset L, et al. Event related potentials elicited by violations of auditory regularities in patients with impaired consciousness. Neuropsychologia. 2012;50(3):403–18. https://doi.org/10.1016/j.neuropsychologia.2011.12.015.CrossRefPubMed

16.

Trojano L, Moretta P, Loreto V, Cozzolino A, Santoro L, Estraneo A. Quantitative assessment of visual behavior in disorders of consciousness. J Neurol. 2012;259(9):1888–95. https://doi.org/10.1007/s00415-012-6435-4.CrossRefPubMed

17.

Giacino JT. The vegetative and minimally conscious states: consensus-based criteria for establishing diagnosis and prognosis. Neurorehabilitation. 2004;19(4):293–8.PubMed

18.

Estraneo A, Moretta P, De Tanti A, Gatta G, Giacino JT, Trojano L. An Italian multicentre validation study of the coma recovery scale-revised. Eur J Phys Rehabil Med. 2015;51(5):627–34.PubMed

19.

Jox RJ, Kuehlmeyer K, Klein AM, Herzog J, Schaupp M, Nowak DA, et al. Diagnosis and decision making for patients with disorders of consciousness: a survey among family members. Arch Phys Med Rehabil. 2015;96(2):323–30. https://doi.org/10.1016/j.apmr.2014.09.030.CrossRefPubMed

20.

Moretta P, Trojano L, Masotta O, Cardinale V, Loreto V, Estraneo A. Family caregivers’ opinions about interaction with the environment in consciousness disorders. Rehabil Psychol. 2017;62(2):208. https://doi.org/10.1037/rep0000144.CrossRefPubMed

21.

Mack A, Pappas Z, Silverman M, Gay R. What we see: inattention and the capture of attention by meaning. Conscious Cogn. 2002;11(4):488–506.CrossRef

22.

Vanhaudenhuyse A, Schnakers C, Brédart S, Laureys S. Assessment of visual pursuit in post-comatose states: use a mirror. J Neurol Neurosurg Psychiatry. 2008;79(2):223–3. https://doi.org/10.1136/jnnp.2007.121624.CrossRef

23.

• Di H, Nie Y, Hu X, Tong Y, Heine L, Wannez S, et al. Assessment of visual fixation in vegetative and minimally conscious states. BMC Neurol. 2014;14(1):147. https://doi.org/10.1186/1471-2377-14-147 The authors investigated the effect of using a mirror, compared with an object or a flashing light, to elicit visual fixation, and turned out to be the study with higher methodological accuracy, as assessed by the GRADE system, in the present review. CrossRefPubMedPubMedCentral

24.

Perrin F, Schnakers C, Schabus M, Degueldre C, Goldman S, Brédart S, et al. Brain response to one’s own name in vegetative state, minimally conscious state, and locked-in syndrome. Arch Neurol. 2006;63(4):562–9. https://doi.org/10.1001/archneur.63.4.562.CrossRefPubMed

25.

Schnakers C, Perrin F, Schabus M, Majerus S, Ledoux D, Damas P, et al. Voluntary brain processing in disorders of consciousness. Neurology. 2008;71(20):1614–20. https://doi.org/10.1212/01.wnl.0000334754.15330.69.CrossRefPubMed

26.

Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151(4):264–9. https://doi.org/10.1016/j.ijsu.2010.02.007.CrossRefPubMed

27.

Schünemann H. The GRADE handbook. Cochrane Collaboration; 2013.

28.

Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction—GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64(4):383–94. https://doi.org/10.1016/j.jclinepi.2010.04.026.CrossRefPubMed

29.

Formisano R, D’Ippolito M, Risetti M, Riccio A, Caravasso CF, Catani S, et al. Vegetative state, minimally conscious state, akinetic mutism and Parkinsonism as a continuum of recovery from disorders of consciousness: an exploratory and preliminary study. Funct Neurol. 2011;26(1):15.PubMedPubMedCentral

30.

Di Stefano C, Cortesi A, Masotti S, Simoncini L, Piperno R. Increased behavioural responsiveness with complex stimulation in VS and MCS: preliminary results. Brain Inj. 2012;26(10):1250–6. https://doi.org/10.3109/02699052.2012.667588.CrossRefPubMed

31.

Cheng L, Gosseries O, Ying L, Hu X, Yu D, Gao H, et al. Assessment of localisation to auditory stimulation in post-comatose states: use the patient’s own name. BMC Neurol. 2013;13(1):27. https://doi.org/10.1186/1471-2377-13-27.CrossRefPubMedPubMedCentral

32.

Trojano L, Moretta P, Loreto V, Santoro L, Estraneo A. Affective saliency modifies visual tracking behavior in disorders of consciousness: a quantitative analysis. J Neurol. 2013;260(1):306–8. https://doi.org/10.1007/s00415-012-6717-x.CrossRefPubMed

33.

Trojano L, Moretta P, Masotta O, Loreto V, Estraneo A. Visual pursuit of one’s own face in disorders of consciousness: a quantitative analysis. Brain Inj. 2018;32(12):1549–55. https://doi.org/10.1080/02699052.2018.1504117.CrossRefPubMed

34.

• Thonnard M, Wannez S, Keen S, Brédart S, Brun MA, Gosseries O, et al. Detection of visual pursuit in patients in minimally conscious state: a matter of stimuli and visual plane? Brain Inj. 2014;28(9):1164–70. https://doi.org/10.3109/02699052.2014.920521 The authors demonstrated on a very large sample of patients with DoC the importance of using a mirror, compared with an object or a moving person, when clinically evaluating visual pursuit, a critical marker discriminating VS/UWS and MCS. CrossRefPubMed

35.

Cavinato M, Volpato C, Silvoni S, Sacchetto M, Merico A, Piccione F. Event-related brain potential modulation in patients with severe brain damage. Clin Neurophysiol. 2011;122(4):719–24. https://doi.org/10.1016/j.clinph.2010.08.024.CrossRefPubMed

36.

Del Giudice R, Blume C, Wislowska M, Lechinger J, Heib DP, Pichler G, et al. Can self-relevant stimuli help assessing patients with disorders of consciousness? Conscious Cogn. 2016;44:51–60. https://doi.org/10.1016/j.concog.2016.06.013.CrossRefPubMed

37.

Bates D. The vegetative state: guidance on diagnosis and management-a report of a working party of the Royal College of Physicians. Clin Med. 2003;3(3):249–54. https://doi.org/10.7861/clinmedicine.3-3-249.

38.

Shiel A, Horn SA, Wilson BA, Watson MJ, Campbell MJ, McLellan DL. The Wessex Head Injury Matrix (WHIM) main scale: a preliminary report on a scale to assess and monitor patient recovery after severe head injury. Clin Rehabil. 2000;14(4):408–16. https://doi.org/10.1191/0269215500cr326oa.CrossRefPubMed

39.

Formisano R, Vinicola V, Carlesimo GA, Sabbadini M, Penta F. Assessment scale for patients with prolonged disturbances of consciousness (postcoma scale). Proceedings of the Fifth Conference of the International Association for the study of Traumatic Brain Injury and 20th Conference of the Australian Society for the Study of Brain Impairment. Melbourne: Australian Academic Press. 1996. p. 15-18.

40.

Brédart S, Delchambre M, Laureys S. One’s own face is hard to ignore. Q J Exp Psychol. 2006;59(1):46–52. https://doi.org/10.1080/17470210500343678.CrossRef

41.

Devue C, Brédart S. Attention to self-referential stimuli: can I ignore my own face? Acta Psychol (Amst). 2008;128(2):290–7. https://doi.org/10.1016/j.actpsy.2008.02.004.CrossRefPubMed

42.

Tacikowski P, Nowicka A. Allocation of attention to self-name and self-face: an ERP study. Biol Psychol. 2010;84(2):318–24. https://doi.org/10.1016/j.biopsycho.2010.03.009.CrossRefPubMed

43.

Tong F, Nakayama K. Robust representations for faces: evidence from visual search. J Exp Psychol Hum Percept Perform. 1999;25(4):1016. https://doi.org/10.1037//0096-1523.25.4.1016.CrossRefPubMed

44.

Bruno MA, Vanhaudenhuyse A, Thibaut A, Moonen G, Laureys S. From unresponsive wakefulness to minimally conscious PLUS and functional locked-in syndromes: recent advances in our understanding of disorders of consciousness. J Neurol. 2011;258(7):1373–84. https://doi.org/10.1007/s00415-011-6114-x.CrossRefPubMed

45.

Menon DK, Owen AM, Boniface SJ, Pickard JD. Cortical processing in persistent vegetative state. Lancet. 1998;352(9134):1148–9. https://doi.org/10.1016/s0140-6736(05)77805-3.CrossRef

46.

Owen AM, Menon DK, Johnsrude IS, Bor D, Scott SK, Manly T, et al. Detecting residual cognitive function in persistent vegetative state. Neurocase. 2002;8(5):394–403. https://doi.org/10.1076/neur.8.4.394.16184.CrossRefPubMed

47.

Sharon H, Pasternak Y, Simon EB, Gruberger M, Giladi N, Krimchanski BZ, et al. Emotional processing of personally familiar faces in the vegetative state. PLoS One. 2013;8(9):e74711. https://doi.org/10.1371/journal.pone.0074711.CrossRefPubMedPubMedCentral

48.

Grill-Spector K, Knouf N, Kanwisher N. The fusiform face area subserves face perception, not generic within-category identification. Nat Neurosci. 2004;7(5):555. https://doi.org/10.1038/nn1224.CrossRefPubMed

49.

Kanwisher N, Yovel G. The fusiform face area: a cortical region specialized for the perception of faces. Philos Trans R Soc Lond B Biol Sci. 2006;361(1476):2109–28. https://doi.org/10.1098/rstb.2006.1934.CrossRefPubMedPubMedCentral

50.

Menon V, Uddin LQ. Saliency, switching, attention and control: a network model of insula function. Brain Struct Funct. 2010;214(5-6):655–67. https://doi.org/10.1007/s00429-010-0262-0.CrossRefPubMedPubMedCentral

51.

Pessoa L, Adolphs R. Emotion processing and the amygdala: from a ‘low road’ to ‘many roads’ of evaluating biological significance. Nat Rev Neurosci. 2010;11(11):773. https://doi.org/10.1038/nrn2920.CrossRefPubMedPubMedCentral

52.

Zhu J, Wu X, Gao L, Mao Y, Zhong P, Tang W, et al. Cortical activity after emotional visual stimulation in minimally conscious state patients. J Neurotrauma. 2009;26(5):677–88. https://doi.org/10.1089/neu.2008.0691.CrossRef

53.

Wannez S, Vanhaudenhuyse A, Laureys S, Brédart S. Mirror efficiency in the assessment of visual pursuit in patients in minimally conscious state. Brain Inj. 2017;31(11):1429–35. https://doi.org/10.1080/02699052.2017.1376755.CrossRefPubMed

54.

Xiao NG, Perrotta S, Quinn PC, Wang Z, Sun YHP, Lee K. On the facilitative effects of face motion on face recognition and its development. Front Psychol. 2014;5:633. https://doi.org/10.3389/fpsyg.2014.00633.CrossRefPubMedPubMedCentral

55.

Cherry EC. Some experiments on the recognition of speech, with one and with two ears. J Acoust Soc Am. 1953;25(5):975–9.CrossRef

56.

Oswald I, Taylor AM, Treisman M. Discriminative responses to stimulation during human sleep. Brain. 1960;80:440–53. https://doi.org/10.1093/brain/83.3.440.CrossRef

57.

Kurtz D, Trapp C, Kieny MT, Wassmer JM, Mugnaioni MD, Pack A, et al. Study of recovery and the post-anaesthetic period (author’s transl). Rev Electroencephalogr Neurophysiol Clin. 1977;7(1):62–9.

58.

Staffen W, Kronbichler M, Aichhorn M, Mair A, Ladurner G. Selective brain activity in response to one’s own name in the persistent vegetative state. J Neurol Neurosurg Psychiatry. 2006;77(12):1383–4. https://doi.org/10.1136/jnnp.2006.095166.CrossRefPubMedPubMedCentral

59.

Bick AS, Leker RR, Ben-Hur T, Levin N. Implementing novel imaging methods for improved diagnosis of disorder of consciousness patients. J Neurol Sci. 2013;334(1-2):130–8. https://doi.org/10.1016/j.jns.2013.08.009.CrossRefPubMed

60.

Nicholas CR, McLaren DG, Gawrysiak MJ, Rogers BP, Dougherty JH, Nash MR. Functional neuroimaging of personally-relevant stimuli in a paediatric case of impaired awareness. Brain Inj. 2014;28(8):1135–8. https://doi.org/10.3109/02699052.2014.890745.CrossRefPubMed

61.

Bekinschtein T, Niklison J, Sigman L, Manes FRLJA, Leiguarda R, Armony J, et al. Emotion processing in the minimally conscious state. J Neurol Neurosurg Psychiatry. 2004;75(5):788–8. https://doi.org/10.1136/jnnp.2003.034876.CrossRef

62.

Kotchoubey B, Merz S, Lang S, Markl A, Mülle F, Yu T, et al. Global functional connectivity reveals highly significant differences between the vegetative and the minimally conscious state. J Neurol. 2013;260(4):975–83. https://doi.org/10.1007/s00415-012-6734-9.CrossRef

63.

Yu T, Lang S, Vogel D, Markl A, Müller F, Kotchoubey B. Patients with unresponsive wakefulness syndrome respond to the pain cries of other people. Neurology. 2013;80(4):345–52. https://doi.org/10.1212/WNL.0b013e31827f0846.CrossRefPubMed

64.

Harris CR, Pashler H. Attention and the processing of emotional words and names: not so special after all. Psychol Sci. 2004;15(3):171–8. https://doi.org/10.1111/j.0956-7976.2004.01503005.x.CrossRefPubMed

65.

Laureys S, Perrin F, Brédart S. Self-consciousness in non-communicative patients. Conscious Cogn. 2007;16(3):722–41. https://doi.org/10.1016/j.concog.2007.04.004.CrossRefPubMed

66.

Seel RT, Sherer M, Whyte J, Katz DI, Giacino JT, Rosenbaum AM, et al. Assessment scales for disorders of consciousness: evidence-based recommendations for clinical practice and research. Arch Phys Med Rehabil. 2010;91(12):1795–813. https://doi.org/10.1016/j.apmr.2010.07.218.CrossRefPubMed

67.

Laureys S, Perrin F, Faymonville ME, Schnakers C, Boly M, Bartsch V, et al. Cerebral processing in the minimally conscious state. Neurology. 2004;63(5):916–8. https://doi.org/10.1212/01.wnl.0000137421.30792.9b.CrossRefPubMed

68.

De Salvo S, Caminiti F, Bonanno L, De Cola MC, Corallo F, Caizzone A, et al. Neurophysiological assessment for evaluating residual cognition in vegetative and minimally conscious state patients: a pilot study. Funct Neurol. 2015;30(4):237.PubMed

69.

Wang XY, Wu HY, Lu HT, Huang TT, Zhang H, Zhang T. Assessment of mismatch negativity and P300 response in patients with disorders of consciousness. Eur Rev Med Pharmacol Sci. 2017;21(21):4896–906.PubMed

70.

Castro M, Tillmann B, Luauté J, Corneyllie A, Dailler F, André-Obadia N, et al. Boosting cognition with music in patients with disorders of consciousness. Neurorehab Neural Repair. 2015;29(8):734–42. https://doi.org/10.1177/1545968314565464.CrossRef

71.

Riganello F, Candelieri A, Quintieri M, Conforti D, Dolce G. Heart rate variability: an index of brain processing in vegetative state? An artificial intelligence, data mining study. Clin Neurophysiol. 2010;121(12):2024–34. https://doi.org/10.1016/j.clinph.2010.05.010.CrossRefPubMed

Titel: Can Salient Stimuli Enhance Responses in Disorders of Consciousness? A Systematic Review
verfasst von: Alfonso Magliacano
Francesco De Bellis
Alejandro Galvao-Carmona
Anna Estraneo
Luigi Trojano
Publikationsdatum: 01.12.2019
Verlag: Springer US
Erschienen in: Current Neurology and Neuroscience Reports / Ausgabe 12/2019
Print ISSN: 1528-4042
Elektronische ISSN: 1534-6293
DOI: https://doi.org/10.1007/s11910-019-1018-8

Leitlinien kompakt für die Neurologie

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Neurologie

Demenzkranke durch Antipsychotika vielfach gefährdet

Demenz Nachrichten

Der Einsatz von Antipsychotika gegen psychische und Verhaltenssymptome in Zusammenhang mit Demenzerkrankungen erfordert eine sorgfältige Nutzen-Risiken-Abwägung. Neuen Erkenntnissen zufolge sind auf der Risikoseite weitere schwerwiegende Ereignisse zu berücksichtigen.

Nicht Creutzfeldt Jakob, sondern Abführtee-Vergiftung

29.05.2024 Hyponatriämie Nachrichten

Eine ältere Frau trinkt regelmäßig Sennesblättertee gegen ihre Verstopfung. Der scheint plötzlich gut zu wirken. Auf Durchfall und Erbrechen folgt allerdings eine Hyponatriämie. Nach deren Korrektur kommt es plötzlich zu progredienten Kognitions- und Verhaltensstörungen.

Schutz der Synapsen bei Alzheimer

29.05.2024 Morbus Alzheimer Nachrichten

Mit einem Neurotrophin-Rezeptor-Modulator lässt sich möglicherweise eine bestehende Alzheimerdemenz etwas abschwächen: Erste Phase-2-Daten deuten auf einen verbesserten Synapsenschutz.

Sozialer Aufstieg verringert Demenzgefahr

24.05.2024 Demenz Nachrichten

Ein hohes soziales Niveau ist mit die beste Versicherung gegen eine Demenz. Noch geringer ist das Demenzrisiko für Menschen, die sozial aufsteigen: Sie gewinnen fast zwei demenzfreie Lebensjahre. Umgekehrt steigt die Demenzgefahr beim sozialen Abstieg.

Update Neurologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Abstract

Purpose of Review

Recent Findings

Summary

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 12/2019

Neurological Complications in Patients with Systemic Lupus Erythematosus

Links Between the C9orf72 Repeat Expansion and Psychiatric Symptoms

Current Diagnosis and Treatment of Painful Small Fiber Neuropathy

Neurological Manifestations of Achondroplasia

Atypical Pediatric Demyelinating Diseases of the Central Nervous System