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Cited by 102Memory and Neural MechanismsDementia and Cognitive Impairment ResearchAlzheimer's disease research and treatments

Fear conditioning in frontotemporal lobar degeneration and Alzheimer's disease

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Hoefer, M., Allison, S. C., Schauer, G. F., Neuhaus, J. M., Hall, J., Dang, J. N., Weiner, M. W., Miller, B. L. +1 more·2008·Brain
DOI 10.1093/brain/awn082PMC PMC2544622
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Abstract

Emotional blunting and abnormal processing of rewards and punishments represent early features of frontotemporal lobar degeneration (FTLD). Better understanding of the physiological underpinnings of these emotional changes can be facilitated by the use of classical psychology approaches. Fear conditioning (FC) is an extensively used paradigm for studying emotional processing that has rarely been applied to the study of dementia. We studied FC in controls (n = 25), Alzheimer's disease (n = 25) and FTLD (n = 25). A neutral stimulus (coloured square on a computer screen) was repeatedly paired with a 1 s burst of 100 db white noise. Change in skin conductance response to the neutral stimulus was used to measure conditioning. Physiological-anatomical correlations were examined using voxel-based morphometry (VBM). Both patient groups showed impaired acquisition of conditioned responses. However, the basis for this deficit appeared to differ between groups. In Alzheimer's disease, impaired FC occurred despite normal electrodermal responses to the aversive stimulus. In contrast, FTLD patients showed reduced skin conductance responses to the aversive stimulus, which contributed significantly to their FC deficit. VBM identified correlations with physiological reactivity in the amygdala, anterior cingulate cortex, orbitofrontal cortex and insula. These data indicate that Alzheimer's disease and FTLD both show abnormalities in emotional learning, but they suggest that in FTLD this is associated with a deficit in basic electrodermal response to aversive stimuli, consistent with the emotional blunting described with this disorder. Deficits in responses to aversive stimuli could contribute to both the behavioural and cognitive features of FTLD and Alzheimer's disease. Further study of FC in humans and animal models of dementia could provide a valuable window into these symptoms.

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  • Context-associated memory deficit is typical in AD patients and manifested as dysfunction of fear conditioning involving neural circuits of the amygdala, hippocampus, and prefrontal cortex.

    “Context-associated memory: This deficit is typical in AD patients [128][129][130] and manifested as dysfunction of fear conditioning 82 involving neural circuits of the amygdala, hippocampus, and prefrontal cortex 131,132 .”

    From NAD+ hydrolase Sarm1 is a key driver of synapse degeneration and memory loss in Alzheimer’s disease (2025) · cites this paper as [128]

    The Discussion reports impaired fear conditioning in Alzheimer’s disease, and the Introduction identifies the amygdala and ventromedial prefrontal cortex as regions involved in fear conditioning. However, the paper does not identify the hippocampus as part of the fear-conditioning circuitry studied or establish that this impairment manifests a context-associated memory deficit in Alzheimer’s disease. (LLM, conf=0.84)

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Research works printed but not linked: 60

  1. Amaral DG, Price JL. Amygdalo-cortical projections in the monkey (Macaca fascicularis). J Comp Neurol 1984; 230: 465-96.
  2. Ashburner J, Friston KJ. Voxel-based morphometry-the methods. Neuroimage 2000; 11: 805-21.
  3. Barnes J, Whitwell JL, Frost C, Josephs KA, Rossor M, Fox NC. Measurements of the amygdala and hippocampus in pathologically confirmed Alzheimer disease and frontotemporal lobar degeneration. Arch Neurol 2006; 63: 1434-9.
  4. Basso M, Yang J, Warren L, MacAvoy MG, Varma P, Bronen RA, et al. Volumetry of amygdala and hippocampus and memory performance in Alzheimer's disease. Psychiatry Res 2006; 146: 251-61.
  5. Bechara A, Damasio H, Damasio AR. Emotion, decision making and the orbitofrontal cortex. Cereb Cortex 2000; 10: 295-307.
  6. Bechara A, Tranel D, Damasio H, Adolphs R, Rockland C, Damasio AR. Double dissociation of conditioning and declarative knowledge relative to the amygdala and hippocampus in humans. Science 1995; 269: 1115-8.
  7. Boccardi M, Sabattoli F, Laakso MP, Testa C, Rossi R, Beltramello A, et al. Frontotemporal dementia as a neural system disease. Neurobiol Aging 2005; 26: 37-44.
  8. Bozeat S, Gregory CA, Ralph MA, Hodges JR. Which neuropsychiatric and behavioural features distinguish frontal and temporal variants of frontotemporal dementia from Alzheimer's disease? J Neurol Neurosurg Psychiatry 2000; 69: 178-86.
  9. Brignell CM, Curran HV. Drugs, sweat, and fears: a comparison of the effects of diazepam and methylphenidate on fear conditioning. Psychopharmacology (Berl) 2006; 186: 504-16.
  10. Buchel C, Dolan RJ. Classical fear conditioning in functional neuroima- ging. Curr Opin Neurobiol 2000; 10: 219-23.
  11. Cahill L, McGaugh JL. Mechanisms of emotional arousal and lasting declarative memory. Trends Neurosci 1998; 21: 294-9.
  12. Chan D, Fox NC, Scahill RI, Crum WR, Whitwell JL, Leschziner G, et al. Patterns of temporal lobe atrophy in semantic dementia and Alzheimer's disease. Ann Neurol 2001; 49: 433-42.
  13. Critchley HD, Elliott R, Mathias CJ, Dolan RJ. Neural activity relating to generation and representation of galvanic skin conductance responses: a functional magnetic resonance imaging study. J Neurosci 2000; 20: 3033-40.
  14. Cummings JL. The Neuropsychiatric Inventory: assessing psychopathology in dementia patients. Neurology 1997; 48: S10-6.
  15. Diehl J, Grimmer T, Drzezga A, Riemenschneider M, Forstl H, Kurz A. Cerebral metabolic patterns at early stages of frontotemporal dementia and semantic dementia. A PET study. Neurobiol Aging 2004; 25: 1051-6.
  16. Evans AC, Kamber M, Collins DL, Macdonald D. An MRI-based probabilistic atlas of neuroanatomy. In: Shorvon S, Fish D, Andermann F, Bydder GM, Stefan H, editors. Magnetic resonance scanning and epilepsy. Vol. 264. Plenum Press; 1994. p. 263-74.
  17. Folstein MF, Folstein SE, McHugh PR. 'Mini-mental state'. A practical method for grading the mental state of patients for the clinician. J Psychiatr Res 1975; 12: 189-98.
  18. Fryer JD, Lukas RJ. Antidepressants noncompetitively inhibit nicotinic acetylcholine receptor function. J Neurochem 1999; 72: 1117-24.
  19. Good CD, Johnsrude IS, Ashburner J, Henson RN, Friston KJ, Frackowiak RS. A voxel-based morphometric study of ageing in 465 normal adult human brains. Neuroimage 2001; 14: 21-36.
  20. Good CD, Scahill RI, Fox NC, Ashburner J, Friston KJ, Chan D, et al. Automatic differentiation of anatomical patterns in the human brain: validation with studies of degenerative dementias. Neuroimage 2002; 17: 29-46.
  21. Grillon C, Cordova J, Morgan CA, Charney DS, Davis M. Effects of the beta-blocker propranolol on cued and contextual fear conditioning in humans. Psychopharmacology (Berl) 2004; 175: 342-52.
  22. Hamann S, Monarch ES, Goldstein FC. Impaired fear conditioning in Alzheimer's disease. Neuropsychologia 2002; 40: 1187-95.
  23. Hamann SB, Monarch ES, Goldstein FC. Memory enhancement for emotional stimuli is impaired in early Alzheimer's disease. Neuropsychology 2000; 14: 82-92.
  24. Ibach B, Poljansky S, Marienhagen J, Sommer M, Manner P, Hajak G. Contrasting metabolic impairment in frontotemporal degeneration and early onset Alzheimer's disease. Neuroimage 2004; 23: 739-43.
  25. King AB, Menon RS, Hachinski V, Cechetto DF. Human forebrain activation by visceral stimuli. J Comp Neurol 1999; 413: 572-82.
  26. Labar KS, Cook CA, Torpey DC, Welsh-Bohmer KA. Impact of healthy aging on awareness and fear conditioning. Behav Neurosci 2004; 118: 905-15.
  27. LaBar KS, Gatenby JC, Gore JC, LeDoux JE, Phelps EA. Human amygdala activation during conditioned fear acquisition and extinction: a mixed- trial fMRI study. Neuron 1998; 20: 937-45.
  28. LaBar KS, LeDoux JE, Spencer DD, Phelps EA. Impaired fear conditioning following unilateral temporal lobectomy in humans. J Neurosci 1995; 15: 6846-55.
  29. Leaton RN, Cassella JV, Borszcz GS. Short-term and long-term habituation of the acoustic startle response in chronic decerebrate rats. Behav Neurosci 1985; 99: 901-12.
  30. LeDoux JE. Brain mechanisms of emotion and emotional learning. Curr Opin Neurobiol 1992; 2: 191-7.
  31. Liu W, Miller BL, Kramer JH, Rankin K, Wyss-Coray C, Gearhart R, et al. Behavioral disorders in the frontal and temporal variants of fronto- temporal dementia. Neurology 2004; 62: 742-8.
  32. Maldjian JA, Laurienti PJ, Kraft RA, Burdette JH. An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. Neuroimage 2003; 19: 1233-9.
  33. Markesbery WR, Schmitt FA, Kryscio RJ, Davis DG, Smith CD, Wekstein DR. Neuropathologic substrate of mild cognitive impairment. Arch Neurol 2006; 63: 38-46.
  34. McCulloch CE, Searle SR. Generalized, linear, and mixed models. New York: John Wiley and Sons; 2001.
  35. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS- ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer's disease. Neurology 1984; 34: 939-44.
  36. McKhann GM, Albert MS, Grossman M, Miller B, Dickson D, Trojanowski JQ. Clinical and pathological diagnosis of frontotemporal dementia: report of the work group on frontotemporal dementia and Pick's disease. Arch Neurol 2001; 58: 1803-9.
  37. Mesulam MM, Mufson EJ. Insula of the old world monkey. I. Architectonics in the insulo-orbito-temporal component of the para- limbic brain. J Comp Neurol 1982a; 212: 1-22.
  38. Mesulam MM, Mufson EJ. Insula of the old world monkey. III: efferent cortical output and comments on function. J Comp Neurol 1982b; 212: 38-52.
  39. Milad MR, Quinn BT, Pitman RK, Orr SP, Fischl B, Rauch SL. Thickness of ventromedial prefrontal cortex in humans is correlated with extinction memory. Proc Natl Acad Sci USA 2005; 102: 10706-11.
  40. Miller RG. Simultaneous statistical inference. New York: Springer-Verlag; 1981.
  41. Morris JC. Clinical dementia rating: a reliable and valid diagnostic and staging measure for dementia of the Alzheimer type. Int Psychogeriatr 1997; 9: 173-6discussion 177-8.
  42. Mueck-Weymann M, Acker J, Agelink MW. Autonomic responses of blood vessels and sweat glands in patients with schizophrenia treated with olanzapine or clozapine. Psychopharmacology (Berl) 2001; 157: 368-72.
  43. Mufson EJ, Mesulam MM. Insula of the old world monkey. II: afferent cortical input and comments on the claustrum. J Comp Neurol 1982; 212: 23-37.
  44. Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998; 51: 1546-54.
  45. Ohman A, Hamm A, Hugdahl K. Cognition and the autonomic nervous system: orienting, anticipation, and conditioning. In: Cacioppo JT, Tassinary LG, Berntson GG, editors. Handbook of psychophysiology. New York: Cambridge University Press; 2000.
  46. Phillips ML, Drevets WC, Rauch SL, Lane R. Neurobiology of emotion perception I: the neural basis of normal emotion perception. Biol Psychiatry 2003a; 54: 504-14.
  47. Phillips ML, Drevets WC, Rauch SL, Lane R. Neurobiology of emotion perception II: implications for major psychiatric disorders. Biol Psychiatry 2003b; 54: 515-28.
  48. Praharaj SK, Arora M. Paroxetine useful for palmar-plantar hyperhidrosis. Ann Pharmacother 2006; 40: 1884-6.
  49. Reitan RM. Validity of the Trailmaking Test as an indication of organic brain damage. Percept Mot Skills 1958; 8: 271-6.
  50. Rosen HJ, Allison SC, Ogar JM, Amici S, Rose K, Dronkers N, et al. Behavioral features in semantic dementia vs other forms of progressive aphasias. Neurology 2006; 67: 1752-6.
  51. Rosen HJ, Allison SC, Schauer GF, Gorno-Tempini ML, Weiner MW, Miller BL. Neuroanatomical correlates of behavioural disorders in dementia. Brain 2005; 128: 2612-25.
  52. Rosen HJ, Gorno-Tempini ML, Goldman WP, Perry RJ, Schuff N, Weiner M, et al. Patterns of brain atrophy in frontotemporal dementia and semantic dementia. Neurology 2002; 58: 198-208.
  53. Shi C, Davis M. Pain pathways involved in fear conditioning measured with fear-potentiated startle: lesion studies. J Neurosci 1999; 19: 420-30.
  54. Siepmann M, Kirch W, Krause S, Joraschky P, Mueck-Weymann M. The effects of St. John's wort extract and amitriptyline on autonomic responses of blood vessels and sweat glands in healthy volunteers. J Clin Psychopharmacol 2004; 24: 79-82.
  55. Snowden JS, Bathgate D, Varma A, Blackshaw A, Gibbons ZC, Neary D. Distinct behavioural profiles in frontotemporal dementia and semantic dementia. J Neurol Neurosurg Psychiatry 2001; 70: 323-32.
  56. Sturm VE, Rosen HJ, Allison S, Miller BL, Levenson RW. Self-conscious emotion deficits in frontotemporal lobar degeneration. Brain 2006; 129: 2508-16.
  57. Testa C, Laakso MP, Sabattoli F, Rossi R, Beltramello A, Soininen H, et al. A comparison between the accuracy of voxel-based morphometry and hippocampal volumetry in Alzheimer's disease. J Magn Reson Imaging 2004; 19: 274-82.
  58. Tranel D, Damasio H. Neuroanatomical correlates of electrodermal skin conductance responses. Psychophysiology 1994; 31: 427-38.
  59. Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Crivello F, Etard O, Delcroix N, et al. Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single- subject brain. Neuroimage 2002; 15: 273-89.
  60. Yesavage JA, Brink TL, Rolse TL, Lum O, Huang V, Adey M, et al. Development and validity of a Geriatric Depression Scale: a preliminary report. J Psychiatr Res 1983; 17: 37-49.

Cited by

Sorted by citations

Authors
Hoefer, M., Allison, S. C., Schauer, G. F., Neuhaus, J. M., Hall, J., Dang, J. N., Weiner, M. W., Miller, B. L., & Rosen, H. J.
Affiliations
  • University of California, San Francisco (US)
  • San Francisco VA Medical Center (US)
ORCID
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2008-01-29
Volume
131
Issue
6
Pages
1646-1657
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awn082
PMC
PMC2544622
OpenAlex
W2136228456
Cited by
102
References
11
Citations by year
2026: 2 · 2025: 3 · 2024: 2 · 2023: 5 · 2022: 4 · 2021: 8 · 2020: 5 · 2019: 3 · 2018: 6 · 2017: 7 · 2016: 5 · 2015: 7 · 2014: 14 · 2013: 10 · 2012: 12
FWCI
1.56
Type
journal article
Language
en
Open access
Locations
  • Brain (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Canadian Centre for Applied Research in Cancer Control
  • National Institutes of Health (5m01rr000079-42, 1k08ag020760-01, AG05142, AG10129, NS050915)
  • University of California, San Francisco
  • National Institute on Aging (P30AG010129, 1K08AG020760-01, K08 AG020760, AG 05142, P50AG016570, AG 16570, P50-AG05142, AG-10129, P50AG005142, P01AG019724)
  • National Institute of Neurological Disorders and Stroke (RF1NS050915, R56NS050915, R01NS050915, NS050915)
  • National Center for Research Resources (M01-RR000079, M01 RR-00079)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
fear conditioning, frontotemporal lobar degeneration, Alzheimer's disease, emotional blunting, emotional learning, skin conductance response, electrodermal response, amygdala, anterior cingulate cortex, orbitofrontal cortex, insula, voxel-based morphometry, dementia
MeSH terms
Acoustic Stimulation, Aged, Aged, 80 and over, Alzheimer Disease, Conditioning, Psychological, Dementia, Fear, Female, Galvanic Skin Response, Humans, Male, Middle Aged, Neuropsychological Tests, Photic Stimulation, Random Allocation, Multivariate Analysis, Case-Control Studies

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