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Pain Perception and Response: Central Nervous System Mechanisms

Published online by Cambridge University Press:  04 August 2016

Arthur J. Hudson
Arthur J. Hudson*
Affiliation:
Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada
*
Department of Clinical Neurological Sciences, London Health Sciences Centre, 339 Windermere Rd., London, Ontario, N6A 5A5
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Abstract:

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Although several decades of studies have detailed peripheral and ascending nociceptive pathways to the thalamus and cerebral cortex, pain is a symptom that has remained difficult to characterize anatomically and physiologically. Positron emission tomography (PET) and functional magnetic imaging (fMRI) have recently demonstrated a number of cerebral and brain stem loci responding to cutaneous noxious stimuli. However, intersubject variability, both in the frequency and increased or decreased intensity of the responses, has caused uncertainty as to their significance. Nevertheless, the large number of available imaging studies have shown that many areas with recognized functions are frequently affected by painful stimuli. With this evidence and recent developments in tracing central nervous system connections between areas responding to noxious stimuli, it is possible to identify nociceptive pathways that are within, or contribute to, afferent spinothalamo-cortical sensory and efferent skeletomotor and autonomic motor systems. In this study it is proposed that cortical and nuclear mechanisms for pain perception and response are hierarchically arranged with the prefrontal cortex at its highest level. Nevertheless, all components make particular contributions without which certain nociceptive failures can occur, as in pathological pain arising in some cases of nervous system injury.

Résumé:

RÉSUMÉ:

Bien que des études effectuées au cours des dernières décennies aient décrit de façon détaillée les voies nociceptives périphériques et ascendantes vers le thalamus et le cortex cérébral, la douleur est demeurée un symptôme difficile à caractériser au point de vue anatomique et physiologique. La tomographie par l'émission de positons et l'imagerie par résonance magnétique fonctionnelle ont démontré récemment l'existence d'un certain nombre de sites qui répondent à des stimuli cutanés désagréables. Cependant, la variabilité entre les sujets, tant quant à la fréquence qu'à l'augmentation ou la diminution de l'intensité de la réponse, a causé de l'incertitude sur leur signification. Toutefois, les nombreuses études d'imagerie disponibles ont montré que plusieurs zones qui ont des fonctions bien reconnues sont fréquemment touchées par les stimuli douloureux. Avec ces données et les développements récents dans la cartographie des connections entre les zones répondant aux stimuli désagréables dans le système nerveux central, il est possible d'identifier les voies nociceptives qui sont à l'intérieur ou qui contribuent au système afférent sensitif spino-thalamo-cortical et aux systèmes efférents moteurs squelettique et autonome. Dans cette étude, l'hypothèse proposée est que les mécanismes corticaux et nucléaires de la perception de la douleur et de la réponse à la douleur sont structurés de façon hiérarchique, le cortex préfrontal étant placé au plus haut niveau de la hiérarchie. Cependant, toutes les composantes fournissent une contribution particulière sans laquelle certaines défaillances nociceptives peuvent survenir comme c'est le cas dans la douleur pathologique observée dans certains cas de lésion du système nerveux.

Type
Review Article
Information
Canadian Journal of Neurological Sciences , Volume 27 , Issue 1 , February 2000 , pp. 2 - 16
Copyright
Copyright © The Canadian Journal of Neurological 2000

References

REFERENCES

1. Melzack, R, Wall, PD. Pain mechanisms: a new theory. Science 1965; 150: 971–979.Google Scholar
2. Talbot, JD, Marrett, S, Evans, AC, et al. Multiple representation of pain in human cerebral cortex. Science 1991; 251: 1355–1358.Google Scholar
3. Penfield, W, Boldrey, E. Somatic motor and sensory representation in the cerebral cortex of man as studied by electrical stimulation. Brain 1937; 60: 389–443.Google Scholar
4. Derbyshire, SWG, Jones, AKP, Gyulai, F, et al. Pain processing during three levels of noxious stimulation produces differential patterns of central activity. Pain 1997; 73: 431–445.Google Scholar
5. Leijon, G, Boivie, J, Johansson, I. Central post-stroke pain –neurological symptoms and pain characteristics. Pain 1989; 36:13–25.Google Scholar
6. Vestergaard, K, Nielsen, J, Andersen, G, et al. Sensory abnormalities in consecutive, unselected patients with central post-stroke pain. Pain 1995; 61: 177–186.Google Scholar
7. Davis, KD, Kiss, ZHT, Tasker, RR, Dostrovsky, JO. Thalamic stimulation-evoked sensations in chronic pain patients and in nonpain (movement disorder) patients. J Neurophysiol 1996; 75: 1026–1037 Google Scholar
8. Bowsher, D. Termination of the central pain pathway in man: the conscious appreciation of pain. Brain 1957; 80: 606–622.Google Scholar
9. Bentivoglio, M, Kultas-Ilinksy, K, Ilinsky, I. Limbic thalamus: structure, intrinsic organization, and connections. In: Vogt, BA, Gabriel, M, eds. Neurobiology of Cingulate Cortex and Limbic Thalamus: A Comprehensive Handbook. Boston: Birkhâuser, 1993: 71–122.Google Scholar
10. Dong, WK, Ryu, H, Wagman, IH. Nociceptive responses ofneurons in medial thalamus and their relationship to spinothalamic pathways. J Neurophysiol 1978; 41: 1592–1613.Google Scholar
11. Albe-Fessard, D, Berkley, KJ, Kruger, L, Ralston, HJ III, Willis, WD Jr. Diencephalic mechanisms of pain sensation. Brain Res Rev 1985; 9: 217–296.Google Scholar
12. Derbyshire, SWG, Jones, AKP, Devani, P, et al. Cerebral responses to pain in patients with atypical facial pain measured by positron emission tomography. J Neurol Neurosurg Psychiatry 1994;57:1166–1172.Google Scholar
13. Smith, WK. The functional significance of the rostral cingular cortex as revealed by its responses to electrical excitation. J Neurophysiol 1945; 8: 241–255.Google Scholar
14. Ward, AA Jr. The cingular gyrus: area 24. J Neurophysiol 1948;11: 13–23.CrossRefGoogle ScholarPubMed
15. Foltz, EL, White, LE Jr. Pain “relief” by frontal cingulumotomy. J Neurosurg 1962; 19: 89–100.Google Scholar
16. Meyer, A, Beck, E, McLardy, T. Prefrontal leucotomy: a neuroanatomical report. Brain 1947; 70: 18–49.Google Scholar
17. Mark, V, Ervin, FR Yakovlev, PI. Stereotactic thalmotomy. The verification of anatomical lesion sites in the human thalamus.Arch Neurol 1963; 8: 78–88.Google Scholar
18. Vogt, BA, Rosene, DL, Pandya, DN. Thalamic and cortical afferents differentiate anterior from posterior cingulate cortex in the monkey. Science 1979; 204: 205–207.Google Scholar
19. Jones, AKP, Brown, WD, Friston, KJ, Qi, LY, Frackowiak, RSJ.Cortical and subcortical localization of response to pain in man using positron emission tomography. Proc Royal Soc Lond B 1991a; 244: 39–44.Google Scholar
20. Jones, AKP, Qi, LY, Fujirawa, T, et al. In vivo distribution of opioid receptors in man in relation to the cortical projections of the medial and lateral pain systems measured with positron emission tomography. Neurosci Lett 1991b; 126: 25–28.Google Scholar
21. Rosen, SD, Paulesu, E, Frith, CD, et al. Central nervous pathways mediating angina pectoria. Lancet 1994; 344: 147–150.Google Scholar
22. Silverman, DHS, Munakata, JA, Ennes, H, et al. Regional cerebral activity in normal and pathological perception of visceral pain. Gastroenterology 1997; 112: 64–72.Google Scholar
23. Aziz, Q, Andersson, JLR, Valind, S, et al. Identification of human brain loci processing esophageal sensation using positron emission tomography. Gastroenterology 1997; 113: 50–59.Google Scholar
24. Hsieh, J-C, Hannerz, J, Ingvar, M. Right-lateralised central processing for pain of nitroglycerin-induced cluster headache. Pain 1996; 67: 59–68.Google Scholar
25. Casey, KL, Minoshima, S, Berger, KL, et al. Positron emission tomographic analysis of cerebral structures activated specifically by repetitive noxious heat stimuli. J Neurophysiol 1994; 71: 802–807.CrossRefGoogle ScholarPubMed
26. Coghill, RC, Talbot, JD, Evans, AC, et al. Distributed processing of pain and vibration by the human brain. J Neurosci 1994; 14: 4095–4108.Google Scholar
27. Craig, AD, Reiman, EM, Evans, A, Bushnell, MC. Functional imaging of an illusion of pain. Nature 1996; 384: 258–260.Google Scholar
28. Vogt, BA, Derbyshire, S, Jones, AKP. Pain processing in fourregions of human cingulate cortex localized with co-registered PET and MR imaging. Europ J Neurosci 1996; 8: 1461–1473.CrossRefGoogle ScholarPubMed
29. Hsieh, J-C, Belfrage, M, Stone-Elander, S, Hansson, P, Ingvar, M.Central representation of chronic ongoing neuropathic pain studied by positron emission tomography. Pain 1995a; 63: 225–236.Google Scholar
30. Hsieh, J-C, Stâhle-Bâckdahl, M, Hâgermark, ö, et al. Traumatic nociceptive pain activates the hypothalamus and the periaqueductal gray: a positron emission tomography study.Pain 1995b; 64: 303–314.Google Scholar
31. Weiller, C, May, A, Limmroth, V, et al. Brain stem activation in spontaneous human migraine attacks. Nature Med 1995; 1: 658–660.Google Scholar
32. Peyron, R, García-Larrea, L, Grégoire, MC, et al. Allodynia after lateral-medullary (Wallenberg) infarct: a PET study. Brain 1998; 121: 345–356.Google Scholar
33. Derbyshire, SWG, Jones, AKP. Cerebral responses to a continualtonic pain stimulus measured using positron emissiontomography. Pain 1998; 76: 127–135.Google Scholar
34. Apkarian, AV. Functional imaging of pain: new insights regarding the role of the cerebral cortex in human pain perception. Semin Neurosci. 1995; 7: 279–293.Google Scholar
35. Davis, KD, Wood, ML, Crawley, AP, Mikulis, DJ. fMRI of human somatosensory and cingulate cortex during painful electrical nerve stimulation. Neuroreport 1995; 7: 321–325.Google Scholar
36. Berman, HH, Kim, KHS, Talati, A, Hirsch, J. Representation of nociceptive stimuli in primary sensory cortex. Neuroreport 1998; 9: 4179–4187.Google Scholar
37. Davis, KD, Taylor, SJ, Crawley, AP, Wood, ML, Mikulis, DJ.Functional MRI of pain-and attention-related activations in the human cingulate cortex. J Neurophysiol 1997; 77: 3370–3380.Google Scholar
38. Davis, KD, Kwan, CL, Crawley, AP, Mikulis, DJ. Event-related fMRI of pain: entering a new era in imaging pain. Neuroreport 1998a; 9: 3019–3023.Google Scholar
39. Davis, KD, Kwan, CL, Crawley, AP, Mikulis, DJ. Functional MRI study of thalamic and cortical activations evoked by cutaneous heat, cold, and tactile stimuli. J Neurophysiol 1998b; 80: 1533–1546.Google Scholar
40. Disbrow, E, Buonocore, M, Antognini, J, Carstens, E, Rowley, HA.Somatosensory cortex: a comparison of the response to noxious thermal, mechanical, and electrical stimuli using functional magnetic resonance imaging. Human Brain Mapping 1998; 6:150–159.Google Scholar
41. Oshiro, Y, Fuijita, N, Tanaka, H, et al. Functional mapping of pain-related activation with echo-planar MRI: significance of the SII-insular region. Neuroreport 1998; 9: 2285–2289.Google Scholar
42. Porro, CA, Cettolo, V, Francescato, MP, Baraldi, P. Temporal and intensity coding of pain in human cortex. J Neurophysiol 1998; 80: 3312–3320.Google Scholar
43. Shulman, GL, Fiez, JA, Corbetta, M, et al. Common blood flow changes across visual tasks: II. Deceases in cerebral cortex. J Cog Neurosci 1997; 9: 648–663.Google Scholar
44. Jackson, JH. On the comparative study of diseases of the nervous system. Br Med J 1889; 2: 355–362.Google Scholar
45. Petrides, M, Alivisatos, B, Evans, AC, Meyer, E. Dissociation of human mid-dorsolateral from posterior dorsolateral frontal cortex in memory processing. Proc Natl Acad Sci USA,Neurobiology 1993; 90: 873–877.Google Scholar
46. Damasio, AR. The somatic marker hypothesis and the possible functions of the prefrontal cortex. Phil Trans R Soc Lond B 1996; 351: 1413–1420.Google Scholar
47. Rainer, G, Asaad, WF, Miller, EK. Selective representation of relevant information by neurons in the primate prefrontal cortex. Nature 1998; 393:577–579.Google Scholar
48. Caterina, MJ, Schumacher, MA, Tominaga, M, et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway.Nature 1997; 389: 816–824.Google Scholar
49. Willis, WD Jr. Nociceptive pathways: anatomy and physiology of nociceptive ascending pathways. Phil Trans R Soc Lond B 1985; 308: 253–268.Google Scholar
50. Cao, YQ, Mantyh, PW, Carlson, EJ, et al. Primary afferent tachykinins are required to experience moderate to intense pain. Nature 1998; 392: 390–394.CrossRefGoogle ScholarPubMed
51. Haley, JE, Sullivan, AF, Dickenson, AH. Evidence for spinal N-methyl-D-aspartate receptor involvement in prolonged chemical nociception in the rat. Brain Res 1990; 518: 218–226.Google Scholar
52. De Felipe, C, Herrero, JF, O’Brien, JA, et al. Altered nociception,analgesia and aggression in mice lacking the receptor for substance P. Nature 1998; 392: 394–397.Google Scholar
53. Iversen, L. Substance P equals pain substance? Nature 1998; 392:334–335.Google Scholar
54. Coulter, JD, Jones, EG. Differential distribution of corticospinal projections from individual cytoarchitectonic fields in the monkey. Brain Res 1977; 129: 335–340.Google Scholar
55. Cheema, SS, Rustioni, A, Whitsel, BL. Light and electron microscopic evidence for a direct corticospinal projection to superficial laminae of the dorsal horn in cats and monkeys. J Comp Neurol 1984; 225: 276–290.Google Scholar
56. Liang, F, Moret, V, Wiesendanger, M, Rouiller, EM. Corticomotoneuronal connections in the rat: evidence from double-labeling of motoneurons and corticospinal axon arborizations. J Comp Neurol 1991; 311: 356–366.Google Scholar
57. Parent, A. Carpenter’s Human Neuroanatomy. 9th Edition.Baltimore: Williams & Wilkins 1996.Google Scholar
58. Marek, P, Mogil, JS, Sternberg, WF, Panocka, I, Liebeskind, JC. N-methyl-D-aspartic acid (NMDA) receptor antagonist MK-801 blocks non-opioid stress-induced analgesia. II. Comparison across three swim-stress paradigms in selectively bred mice. Brain Res 1992; 578: 197–203.Google Scholar
59. Budai, D, Fields, HL. Endogenous opioid peptides acting at µ-opioid receptors in the dorsal horn contribute to midbrain modulation of spinal nociceptive neurons. J Neurophysiol 1998;79: 677–687.Google Scholar
60. Hardy, SGP, Leichnetz, GR. Cortical projections to the periaqueductal grey in the monkey: a retrograde and orthograde horseradish peroxidase study. Neurosci Lett 1981; 22: 97–101.Google Scholar
61. Gray, TS, Magnuson, DJ. Peptide immunoreactive neurons in the amygdala and the bed nucleus of the stria derminalis project to the midbrain central gray in the rat. Peptides 1992; 13: 451–460.Google Scholar
62. Markenson, JA. Mechanisms of chronic pain. Am J Med 1996; 101: (suppl 1A): 6S–18S.Google Scholar
63. Kiernan, JA. Barr’s Human Nervous System. An Anatomical Viewpoint. 7th edition. Philadelphia: Lippincott, Williams and Wilkins, 1998.Google Scholar
64. Iggo, A, Steedman, WM, Fleetwood-Walker, S. Spinal processing:anatomy and physiology of spinal nociceptive mechanisms. PhilTrans R Soc Lond B 1985; 308: 235–252.Google Scholar
65. Proudfit, HK. Pharmacologic evidence for the modulation of nociception by noradrenergic neurons. Prog Brain Res 1988; 77:357–370.Google Scholar
66. Hitoto, T, Tsuruoka, M, Hiruma, Y, Matsui, Y. Aô afferent fibre stimulation activates descending noradrenergic system from the locus coeruleus. Neurochem Res 1998; 23: 1461–1465.Google Scholar
67. Stanton-Hicks, M, Salamon, J. Stimulation of the central and peripheral nervous system for the control of pain. J Clin Neurophysiol 1997; 14: 46–62.Google Scholar
68. Decker, MW, Bannon, AW, Buckley, MJ, et al. Antinociceptive effects of the novel neuronal nicotinic acetylcholine receptor agonist, ABT-594, in mice. Eur J Pharm 1998; 346: 23–33.Google Scholar
69. Tyler, BM, Cusack, B, Douglas, CL, Souder, T, Richelson, E.Evidence for additional neurotensin subtypes: neurotensin analogs that distinguish between neurotensin-mediated hypothermia and antinociception. Brain Res 1998; 792: 246–252.Google Scholar
70. Iadarola, MJ, Berman, KF, Zeffiro, TA, et al. Neural activation during acute capsaicin-evoked pain and allodynia assessed with PET. Brain 1998; 121: 931–947.Google Scholar
71. May, A, Kaube, H, Büchel, C, et al. Experimental cranial painelicited by capsaicin: a PET study. Pain 1998; 74: 61–66.CrossRefGoogle Scholar
72. Giesler, GJ Jr, Katter, JT, Dado, RJ. Direct spinal pathways to the limbic system for non-nociceptive information. Trends Neurosci 1994; 17: 244–250.Google Scholar
73. Jones, EG, Pons, TP. Thalamic and brainstem contributions to large-scale plasticity of primate somatosensory cortex. Science 1998; 282: 1121–1125.Google Scholar
74. Boivie, J. An anatomical reinvestigation of the termination of the spinothalamic tract in the monkey. J Comp Neurol 1979; 186: 343–370.Google Scholar
75. Roland, P. Cortical representation of pain. Trends Neurosci 1992;15: 3–5 Google Scholar
76. Melzack, R, Casey, KL. Sensory, motivational and central control determinants of pain: a new conceptual model. In: Kenshalo, DR ed. The Skin Senses. Springfield: Ill: Charles C Thomas, 1968,423–443.Google Scholar
77. Vogt, BA, Finch, DM, Olson, CR. Functional heterogeneity incingulate cortex: the anterior executive and posterior evaluative regions. Cerebral Cortex 1992; 2: 435–443.Google Scholar
78. Bushnell, MC, Duncan, GH. Sensory and affective aspects of painperception: is medial thalamus restricted to emotional issues? Exp Brain Res 1989; 78: 415–418.Google Scholar
79. Casey, KL. Unit analysis of nociceptive mechanisms in the thalamus of the awake squirrel monkey. J Neurophysiol 1966; 29: 727–750.Google Scholar
80. Lenz, FA, Kwan, HC, Dostrovsky, JO, Tasker, RR. Characteristics of the bursting pattern of action potentials that occurs in the thalamus of patients with central pain. Brain Res 1989; 496: 357–360.Google Scholar
81. Gorecki, J, Hirayama, T, Dostrovsky, JO, Tasker, RR, Lenz, FA. Thalamic stimulation and recording in patients with deafferentation and central pain. Stereotact Funct Neurosurg 1989; 52: 219–226.Google Scholar
82. Hirayama, T, Dostrovsky, JO, Gorecki, J, Tasker, RR, Lenz, FA. Recordings of abnormal activity in patients with deafferentation and central pain. Stereotact Funct Neurosurg 1989; 52: 120–126.Google Scholar
83. Rinaldi, PC, Young, RF, Albe-Fessard, D, Chodakiewitz, J. Spontaneous neuronal hyperactivity in the medial and intralaminar thalamic nuclei of patients with deafferentation pain. J Neurosurg 1991; 74: 415–421.Google Scholar
84. Lenz, FA, Seike, M, Lin, YC, et al. Neurons in the area of human thalamic nucleus ventralis caudalis respond to painful heat stimuli. Brain Res 1993; 623: 235–240.Google Scholar
85. Lenz, FA, Gracely, RH, Rowland, LH, Dougherty, PM. A population of cells in the human thalamic principal sensory nucleus respond to painful mechanical stimuli. Neurosci Lett 1994; 180: 46–50.Google Scholar
86. Lenz, FA, Dougherty, PM. Neurons in the human thalamic somatosensory nucleus (ventralis caudalis) respond to inocuous cool and mechanical stimuli. J Neurophysiol 1998; 79: 2227–2230.Google Scholar
87. Ghosh, S, Turman, AB, Vickery, RM, Rowe, MJ. Responses of cat ventroposterolateral thalamic neurons to vibrotactile stimulation of forelimb footpads. Exp Brain Res 1992; 92: 286–298.Google Scholar
88. Brodmann, K. Vergleichende Localization lehre der Grosshirnrinde in hiren Prinzipien dargestellt auf Grund des Zellenbaues. Leipzig: J. B. Barth, 1909.Google Scholar
89. Vogt, BA, Nimchinsky, EA, Vogt, LJ, Hof, PR. Human cingulate cortex: surface features, flat maps, and cytoarchitecture. J Comp Neurol 1995; 359: 490–506.Google Scholar
90. Vogt, BA, Pandya, DN. Cingulate cortex of the Rhesus monkey: II.Cortical afferents. J Comp Neurol 1987; 262: 271–289.Google Scholar
91. Vogt, BA, Pandya, DN, Rosene, DL. Cingulate cortex of the Rhesus monkey: I. Cytoarchitecture and thalamic afferents. J Comp Neurol 1987; 262: 256–270.Google Scholar
92. Baleydier, C, Mauguiere, F. The duality of the cingulate gyrus in monkey. Neuroanatomical study and functional hypothesis. Brain 1980; 103: 525–554.Google Scholar
93. Valenstein, E, Bowers, D, Verfaellie, M, et al. Retrosplenialamnesia. Brain 1987; 110: 1631–1646.Google Scholar
94. Sikes, RW, Vogt, B, Swadlow, HA. Neuronal responses in rabbitcingulate cortex linked to quick-phase eye movements during nystagmus. J Neurophysiol 1988; 59: 922–936.Google Scholar
95. Devinsky, O, Morrell, MJ, Vogt, BA. Contributions of anterior cingulate cortex to behaviour. Brain 1995; 118: 279–306.Google Scholar
96. Rainville, P, Duncan, GH, Price, DD, Carrier, B, Bushnell, MC. Pain affect encoded in human anterior cingulate but not somatosensory cortex. Science 1997; 277: 968–971.Google Scholar
97. Cavada, C, Goldman-Rakic, P. Posterior parietal cortex in Rhesus monkey: I. Parcellation of areas based on distinctive limbic and sensory corticocortical connections. J Comp Neurol 1989; 287: 393–421.Google Scholar
98. Vaccarino, AL, Melzack, R. Temporal processes of formalin pain: differential role of the cingulum bundle, fornix pathway and medial bulboreticular formation. Pain 1992;49:257–271.Google Scholar
99. Sikes, RW, Vogt, BA. Nociceptive neurons in area 24 of rabbit cingulate cortex. J Neurophysiol 1992; 68: 1720–1732.Google Scholar
100. Hirai, T, Jones, EG. A new parcellation of the human thalamus on the basis of histochemical staining. Brain Res Rev 1989a; 14: 134.Google Scholar
101. Hirai, T, Jones, EG. Distribution of tachykinin- and enkephalin-immunoreactive fibres in the human thalamus. Brain Res Rev 1989b; 14: 35–52.Google Scholar
102. Pillay, PK, Hassenbusch, SJ. Bilateral MRI-guided stereotacticcingulotomy for intractable pain. Stereotact Funct Neurosurg 1992; 59: 33–38.Google Scholar
103. Jones, EG, Powell, TPS. An anatomical study of converging sensory pathways within the cerebral cortex of the monkey. Brain 1970; 93: 793–820.Google Scholar
104. Amaral, DG. Memory: anatomical organization of candidate brain regions. In: Plum, F. ed. Handbook of Physiology; The Nervous System. Vol 5. Higher Functions of the Brain, Part 1. Bethesda: Amer Physiol Soc, 1987: 211–294.Google Scholar
105. Friedman, DP, Murray, EA, O’Neill, JB, Mishkin, M. Cortical connections of the somatosensory fields of the lateral sulcus of macaques: evidence for a corticolimbic pathway for touch. J Comp Neurol 1986: 252; 323–347.Google Scholar
106. Schneider, RJ, Friedman, DP, Mishkin, M. A modality-specific somatosensory area within the insula of the Rhesus monkey. Brain Res 1993; 621: 116–120.Google Scholar
107. Mesulam, M.-M, Mufson, EJ. The insula of Reil in man and monkey. Architectonics, connectivity, and function. In: Peters, A, Jones, EG, eds. Cerebral Cortex. Vol 4. Association and Auditory Cortices. New York: Plenum Press, 1985: 179–226.Google Scholar
108. Hoffman, BL, Rasmussen, T. Stimulation studies of insular cortex of Macaca mulatta. J Neurophysiol 1953: 16; 343–351.Google Scholar
109. Penfield, W, and Faulk, ME Jr. The insula. Further observations on its function. Brain 1955: 78; 445–470.Google Scholar
110. Mufson, EJ, Mesulam, M.-M. Insula of the old world monkey. II: Afferent cortical input and comments on the claustrum. J Comp Neurol 1982: 212; 23–37.Google Scholar
111. Hoover, JE, Strick, PL. Multiple output channels in the basalganglia. Science 1993; 259: 819–821.Google Scholar
112. Deniau, JM, Menetrey, A, Thierry, AM. Indirectnucleus accumbens input to the prefrontal cortex via the substantia nigra pars reticulata: a combined anatomical and electrophysiological study in the rat. Neuroscience 1994; 61: 533–545.Google Scholar
113. Brown, P, Marsden, CD. What do basal ganglia do? Lancet 1998; 351: 1801–1804 Google Scholar
114. Cahill, L, Haier, RJ, Fallon, J, et al. Amygdala activity at encoding correlated with long-term, free recall of emotional information. Proc Natl Acad Sci USA 1996; 93: 8016–8021.CrossRefGoogle ScholarPubMed
115. Morris, JS, Ohman, A, Dolan, RJ. Conscious and unconscious emotional learning in the human amygdala. Nature 1998: 393; 467–470.Google Scholar
116. Galvez, R, Mesches, MH, McGaugh, JL. Norepinepherine release in the amygdala in response to footshockstimulation. Neurobiol Learning Memory 1996; 66: 253–257.Google Scholar
117. Amaral, DG, Price, JL, Pitkânen, A, Carmichael, ST. Anatomical organization of the primate amygdaloid complex. In: Aggleton, JP, ed. The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction. New York: Wiley-Liss Inc., 1992: 1–66.Google Scholar
118. Amaral, DG, Price, JL. Amygdalo-cortical projections in the monkey (Macaca fascicularis). J Comp Neurol 1984; 230: 465–496.Google Scholar
119. Van Hoesen, GW, Morecraft, RJ, Vogt, BA. Connections of the monkey cingulate cortex. In: Vogt, BA, Gabriel, M, eds. Neurobiology of Cingulate Cortex and Limbic Thalamus: A Comprehensive Handbook. Boston: Birkhâuser, 1993: 249–284.Google Scholar
120. Price, JL, Amaral, DG. An autoradiographic study of the projections of the central nucleus of the monkey amygdala. J Neurosci 1981; 1: 1242–1259.Google Scholar
121. Rolls, ET. Neurophysiology and functions of the primateamygdala. In: Aggleton, JP, ed. The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction. New York: Wiley-Liss Inc., 1992: 143–165.Google Scholar
122. Chapman, WP, Schroeder, HR, Geyer, G, et al. Physiological evidence concerning importance of the amygdaloid nuclear region in the integration of circulatory function and emotion in man. Science 1954; 120: 949–950.Google Scholar
123. Weiskrantz, L. Behavioural changes associated with ablation of the amygdaloid complex in monkeys. J Comp Physiol Psychol 1956; 49: 381–391.Google Scholar
124. Ono, T, Nishijo, H. Neurophysiological basis of the Klüver-Bucy syndrome: responses of monkey amygdaloid neurons to biologically significant objects. In: Aggleton, JP, ed. The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction. New York: Willey-Liss Inc., 1992: 167–190.Google Scholar
125. Graeff, FG, Silveira, MCL, Nogueira, RL, Audi, EA, Oliveira, RMW. Role of the amygdala and periaquedectal gray in anxiety and panic. Behav Brain Res 1993; 58: 123–131.Google Scholar
126. Nashold, BS Jr, Wilson, WP, Slaughter, G. The midbrain and pain. Adv Neurol 1974; 4: 191–196.Google Scholar
127. Bolles, RC, Fanselow, MS. A perceptual-defensive-recuperative model of fear and pain. Behav Brain Sci 1980; 3: 291–323.Google Scholar
128. Graeff, FG. Brain defense systems and anxiety. In: Burrows, GD, Roth, M, Noyes, R Jr, eds. Handbook of Anxiety. Vol. 3: The Neurobiology of Anxiety. New York: Elsevier Science Publishers, 1990: 307–354..Google Scholar
129. Fanselow, MS. The midbrain periaqueductal gray as a coordinator of action in response to fear and anxiety. In: Depaulis, A, Bandler, R, eds. The Midbrain Periaqueductal Gray Matter. New York: Plenum Press, 1991: 151–173.Google Scholar
130. Deakin, JWF, Graeff, FG. 5-HT and mechanisms of defence. J Psychopharmacol 1991; 5: 305–315.Google Scholar
131. Davis, M. The role of the amygdala in conditioned fear. In: Aggleton, JP, ed. The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction. New York: Wiley-Liss Inc., 1992: 255–305.Google Scholar
132. McGaugh, JL, Intoini-Collison, IB, Cahill, L, Kim, M, Liang, KC. Involvement of the amygdala in neuromodulatory influences on memory storage. In: Aggleton, JP, ed. The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction. New York: Wiley-Liss Inc., 1992: 431–451.Google Scholar
133. McGaugh, JL, Introini-Collison, IB, Cahill, LF, et al. Neuromodulatory systems and memory storage: role of the amygdala. Behav Brain Res 1993; 58: 81–90.Google Scholar
134. Ledoux, JE. Emotional memory systems in the brain. Behav Brain Res 1993; 58: 69–79.Google Scholar
135. Adolphs, R, Tranel, D, Damasio, H, Damasio, A. Impaired recognition of emotion in facial expressions following bilateral damage to the human amygdala. Nature 1994; 372: 669–672.Google Scholar
136. Cahill, L, Babinsky, R, Markowitsch, HJ, McGaugh, JL. The amygdala and emotional memory. Nature 1995; 377: 295–296.Google Scholar
137. Scott, SK, Young, AW, Calder, AJ, et al. Impaired auditory recognition of fear and anger following bilateral amygdalalesions. Nature 1997; 385: 254–257.Google Scholar
138. Walter, WG. The convergence and interaction of visual, auditory and tactile responses in human nonspecific cortex. Ann N Y Acad Sci 1964; 112: 320–361.Google Scholar
139. Giguere, M, Goldman-Rakic, PS. Mediodorsal nucleus: areal,laminar, and tangential distribution of afferents and efferents in the frontal lobe of Rhesus monkeys. J Comp Neurol 1988; 277: 195–213.Google Scholar
140. Fuster, JM. The Prefrontal Cortex. Anatomy, Physiology and Neuropsychology of the Frontal Lobe. Philadelphia: Lippincott-Raven, 1997.Google Scholar
141. Pandya, DN, Dye, P, Butters, N. Efferent cortico-cortical projections of the prefrontal cortex in the Rhesus monkey. Brain Res 1971; 31: 35–46.Google Scholar
142. Barbas, H, Pandya, DN. Architecture and intrinsic connections of the prefrontal cortex in the Rhesus monkey. J Comp Neurol 1989; 286: 353–375.Google Scholar
143. Pandya, DN, Van Hoesen, GW, Mesulam, M.-M. Efferent connections of the cingulate gyrus in the Rhesus monkey. Exp Brain Res 1981; 42: 319–330.Google Scholar
144. Pandya, DN, Kuypers, HGJM. Cortico-cortical connections in the Rhesus monkey. Brain Res 1969; 13: 13–36.Google Scholar
145. Goldman-Rakic, PS, Porrino, LJ. The primate mediodorsal (MD)nucleus and its projection to the frontal lobe. J Comp Neurol 1985; 242: 535–560.Google Scholar
146. Pardo, JV, Fox, PT, Raichle, ME. Localization of a human system for sustained attention by positron emission tomography. Nature 1991; 349: 61–64.Google Scholar
147. Courtney, SM, Petit, L, Maisog, JM, Ungerleider, LG, Haxby, JV. Anarea specialized for spatial working memory in human frontal cortex. Science 1998; 279: 1347–1351.Google Scholar
148. Goldman-Rakic, PS, Selemon, LD, Schwartz, ML. Dual pathways connecting the dorsolateral prefrontal cortex with the hippocampal formation and parahippocampal cortex in the Rhesus monkey. Neuroscience 1984; 12: 719–743.Google Scholar
149. Bechara, A, Damasio, H, Tranel, D, Damasio, AR. Deciding advantageously before knowing the advantageous strategy. Science 1997; 275: 1293–1295.Google Scholar
150. Vogel, G. Scientists probe feelings behind decision-making. Science 1997; 275: 1269.Google Scholar
151. Koechlin, E, Basso, G, Pietrini, P, Panzer, S, Grafman, J. The role of the anterior prefrontal cortex in human cognition. Nature 1999; 399: 148–151.Google Scholar
152. Scarff, JE. Unilateral prefrontal lobotomy for the relief of intractable pain and termination of narcotic addiction. Surg Gynec Obstet 1949; 89: 385–392.Google Scholar
153. Tucker, WI. Results of lobotomy. J Neuropsychiat 1961; 2: 153–157.Google Scholar
154. Meyer, M. A study of efferent connexions of the frontal lobe in the human brain after leucotomy. Brain 1949; 72: 265–296.Google Scholar
155. Glees, P, Cole, J, Whitty, CWM, Cairns, H. The effects of lesions in the cingular gyrus and adjacent areas in monkeys. J Neurol Neurosurg Psychiatry 1950; 13: 178–190.Google Scholar
156. Freemen, W, Watts, JW. Psychosurgery in the Treatment of Mental Disorders and Intractable Pain. Springfield Illinois: Charles C Thomas, 1950.Google Scholar
157. Picard, N, Strick, PL. Motor areas of the medial wall: a review of their location and functional activation. Cerebral Cortex 1996; 6: 342–353.Google Scholar
158. Goldman-Rakic, PS. Motor control function of the prefrontal cortex. In: Bock, G, O’Connor, M, Marsh, J, eds. Motor Areas of the Cerebral Cortex. Ciba Foundation Symposium 132, Chichester: John Wiley and Sons, 1987: 187–200.Google Scholar
159. Lu, M-T, Preston, JB, Strick, PL. Interconnections between the prefrontal cortex and the premotor areas in the frontal lobe. J Comp Neurol 1994; 341: 375–392.Google Scholar
160. Braak, H. A primitive gigantopyramidal field buried in the depth of the cingulate sulcus of the human brain. Brain Res 1976; 109: 219–233.Google Scholar
161. Selemon, LD, Goldman-Rakic, PS. Common cortical and subcortical targets of the dorsolateral prefrontal and posterior parietal cortices in the Rhesus monkey: evidence for a distributed neural network subserving spatially guided behaviour. J Neurosci 1988; 8: 4049–4068.Google Scholar
162. Morecraft, RJ, Van Hoesen, GW. Cingulate input to the primary and supplementary motor cortices in the Rhesus monkey: evidence for somatotopy in areas 24c and 23c. J Comp Neurol 1992; 322: 471–489.Google Scholar
163. Dum, RP, Strick, PL. Cingulate motor areas. In: Vogt, BA, Gabriel, M, eds. Neurobiology of Cingulate Cortex and Limbic Thalamus: A Comprehensive Handbook. Boston: Birkhâuser, 1993: 415–441.Google Scholar
164. Neafsey, EJ, Terreberry, RR, Hurley, KM, Ruit, KG, Frysztak, RJ. Anterior cingulate cortex in rodents: connections, visceral control functions, and implications for emotion. In: Vogt, BA, Gabriel, M, eds. Neurobiology of Cingulate Cortex and Limbic Thalamus: A Comprehensive Handbook. Boston: Birkhâuser, 1993: 206–223.Google Scholar
165. Vogt, BA. Structural organization of cingulate cortex: areas,neurons, and somatodendritic transmitter receptors. In: Vogt, BA, Gabriel, M, eds. Neurobiology of Cingulate Cortex and Limbic Thalamus: A Comprehensive Handbook. Boston: Birkhâuser, 1993: 19–70.Google Scholar
166. Avendaño, C, Price, JL, Amaral, DG. Evidence for an amygdaloid projection to premotor cortex but not to motor cortex in the monkey. Brain Res 1983; 264: 111–117.Google Scholar
167. Coderre, TJ, Katz, J, Vaccarino, AL, Melzack, R. Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence. Pain 1993; 52: 259–285.Google Scholar
168. Ploghaus, A, Tracey, I, Gati, JS, et al. Dissociating pain from its anticipation in the human brain. Science 1999; 284: 1979–1981.Google Scholar
169. MacLean, PD. The limbic system (“visceral brain”) and emotional behaviour. Arch Neurol Psychiatry 1955; 73: 130–134.Google Scholar
170. Freeman, JH Jr, Cuppernell, C, Flannery, K, Gabriel, M. Limbic thalamic, cingulate cortical and hippocampal neuronal correlates of discriminative approach learning in rabbits. Behav Brain Res 1996; 80: 123–136.Google Scholar