Impaired cerebellar-dependent eyeblink conditioning in first-degree relatives of individuals with schizophrenia

Schizophrenia Bulletin

Volumn 40, Issue 5, 2014, Pages 1001-1010

  Bolbecker, Amanda R ^a,b,c   Kent, Jerillyn S ^a   Petersen, Isaac T ^a   Klaunig, Mallory J ^c   Forsyth, Jennifer K ^c   Howell, Josselyn M ^c   Westfall, Daniel R ^c   O'Donnell, Brian F ^a,b,c   Hetrick, William P ^a,b,c  

^a INDIANA UNIVERSITY   (United States)

^b INDIANA UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c Larue D Carter Memorial Hospital   (United States)

Author keywords

Associative learning; Cerebellum; Cognition; Conditioned response; Eyeblink conditioning; Psychosis; Reflex conditioning; Relatives; Schizophrenia

Indexed keywords

ADULT; ARTICLE; CEREBELLAR DEPENDENT DELAY EYEBLINK CONDITIONING DEFICIT; CEREBELLUM DISEASE; CLINICAL ARTICLE; CONDITIONED REFLEX; CONTROLLED STUDY; DISEASE MARKER; ELECTROMYOGRAPHY; EYELID REFLEX; FEMALE; FIRST DEGREE RELATIVE; GROWTH CURVE; HUMAN; LEARNING DISORDER; MALE; NERVE CELL NETWORK; PRIORITY JOURNAL; RISK FACTOR; SCHIZOPHRENIA; STATE DEPENDENT LEARNING; STIMULUS RESPONSE; BLINKING; CEREBELLUM; CONDITIONING; GENETICS; LEARNING; MIDDLE AGED; NUCLEAR FAMILY; PATHOPHYSIOLOGY; PHYSIOLOGY; PSYCHOSIS;

ADULT; ASSOCIATION LEARNING; BLINKING; CEREBELLUM; CONDITIONING, EYELID; ELECTROMYOGRAPHY; FEMALE; HUMANS; MALE; MIDDLE AGED; NUCLEAR FAMILY; PSYCHOTIC DISORDERS; SCHIZOPHRENIA;

EID: 84907312289     PISSN: 05867614     EISSN: 17451701     Source Type: Journal    
DOI: 10.1093/schbul/sbt112     Document Type: Article

References (95)

1. Kraepelin E. Dementia Praecox and Paraphrenia. Edinburgh: Living-stone; 1919.
2. Ivry RB, Keele SW. Timing of functions of the cerebellum. J Cogn Neurosci. 1989;1: 136-162.
3. Katz DB, Steinmetz JE. Psychological functions of the cerebellum. Behav Cogn Neurosci Rev. 2002;1: 229-241.
4. Leiner HC, Leiner AL, Dow RS. Cognitive and language functions of the human cerebellum. Trends Neurosci. 1993;16: 444-447.
5. Schmahmann JD. Disorders of the cerebellum: ataxia, dysmetria of thought, and the cerebellar cognitive affective syndrome. J Neuropsychiatry Clin Neurosci. 2004;16: 367-378.
6. Schmahmann JD, Sherman JC. Cerebellar cognitive affective syndrome. Int Rev Neurobiol. 1997;41: 433-440.
7. Schmahmann JD, Sherman JC. The cerebellar cognitive affective syndrome. Brain. 1998;121(Pt 4): 561-579.
8. Loeber RT, Sherwood AR, Renshaw PF, Cohen BM, Yurgelun-Todd DA. Differences in cerebellar blood volume in schizophrenia and bipolar disorder. Schizophr Res. 1999;37: 81-89.
9. Molina V, Martín C, Ballesteros A, de Herrera AG, Hernández-Tamames JA. Optimized voxel brain morphometry: association between brain volumes and the response to atypical antipsychotics. Eur Arch Psychiatry Clin Neurosci. 2011;261: 407-416.
10. Nopoulos PC, Ceilley JW, Gailis EA, Andreasen NC. An MRI study of cerebellar vermis morphology in patients with schizophrenia: evidence in support of the cognitive dysmetria concept. Biol Psychiatry. 1999;46: 703-711.
11. Volz H, Gaser C, Sauer H. Supporting evidence for the model of cognitive dysmetria in schizophrenia-A structural magnetic resonance imaging study using deformation-based morphometry. Schizophr Res. 2000;46: 45-56.
12. Ichimiya T, Okubo Y, Suhara T, Sudo Y. Reduced volume of the cerebellar vermis in neuroleptic-naive schizophrenia. Biol Psychiatry. 2001;49: 20-27.
13. Henze R, Brunner R, Thiemann U, et al. Gray matter alterations in first-admission adolescents with schizophrenia. J Neuroimaging. 2011;21: 241-246.
14. Bottmer C, Bachmann S, Pantel J, et al. Reduced cerebellar volume and neurological soft signs in first-episode schizophrenia. Psychiatry Res. 2005;140: 239-250.
15. Kaspárek T, Marecek R, Schwarz D, et al. Source-based morphometry of gray matter volume in men with first-episode schizophrenia. Hum Brain Mapp. 2010;31: 300-310.
16. Rasser PE, Schall U, Peck G, et al. Cerebellar grey matter deficits in first-episode schizophrenia mapped using cortical pattern matching. Neuroimage. 2010;53: 1175-1180.
17. Jacobsen LK, Giedd JN, Berquin PC, et al. Quantitative morphology of the cerebellum and fourth ventricle in childhood-onset schizophrenia. Am J Psychiatry. 1997;154: 1663-1669.
18. Cahn W, Hulshoff Pol HE, Bongers M, et al. Brain morphology in antipsychotic-naïve schizophrenia: a study of multiple brain structures. Br J Psychiatry Suppl. 2002;43: s66-s72.
19. Levitt JJ, McCarley RW, Nestor PG, et al. Quantitative volumetric MRI study of the cerebellum and vermis in schizophrenia: clinical and cognitive correlates. Am J Psychiatry. 1999;156: 1105-1107.
20. Maloku E, Covelo IR, Hanbauer I, et al. Lower number of cerebellar Purkinje neurons in psychosis is associated with reduced reelin expression. Proc Natl Acad Sci U S A. 2010;107: 4407-4411.
21. Reyes MG, Gordon A. Cerebellar vermis in schizophrenia. Lancet. 1981;2: 700-701.
22. Tran KD, Smutzer GS, Doty RL, Arnold SE. Reduced Purkinje cell size in the cerebellar vermis of elderly patients with schizophrenia. Am J Psychiatry. 1998;155: 1288-1290.
23. Steinberg JL, Devous MD Sr, Moeller FG, Paulman RG, Raese JD, Gregory RR. Cerebellar blood flow in schizophrenic patients and normal control subjects. Psychiatry Res. 1995;61: 15-31.
24. Volkow ND, Levy A, Brodie JD, et al. Low cerebellar metabolism in medicated patients with chronic schizophrenia. Am J Psychiatry. 1992;149: 686-688.
25. Andreasen NC, O'Leary DS, Cizadlo T, et al. Schizophrenia and cognitive dysmetria: a positron-emission tomography study of dysfunctional prefrontal-thalamic-cerebellar circuitry. Proc Natl Acad Sci U S A. 1996;93: 9985-9990.
26. Crespo-Facorro B, Paradiso S, Andreasen NC, et al. Recalling word lists reveals "cognitive dysmetria" in schizophrenia: a positron emission tomography study. Am J Psychiatry. 1999;156: 386-392.
27. Kim JJ, Mohamed S, Andreasen NC, et al. Regional neural dysfunctions in chronic schizophrenia studied with positron emission tomography. Am J Psychiatry. 2000;157: 542-548.
28. Ho BC, Mola C, Andreasen NC. Cerebellar dysfunction in neuroleptic naive schizophrenia patients: clinical, cognitive, and neuroanatomic correlates of cerebellar neurologic signs. Biol Psychiatry. 2004;55: 1146-1153.
29. Potkin SG, Alva G, Fleming K, et al. A PET study of the pathophysiology of negative symptoms in schizophrenia. Positron emission tomography. Am J Psychiatry. 2002;159: 227-237.
30. Wassink TH, Andreasen NC, Nopoulos P, Flaum M. Cerebellar morphology as a predictor of symptom and psychosocial outcome in schizophrenia. Biol Psychiatry. 1999;45: 41-48.
31. Segarra N, Bernardo M, Valdes M, et al. Cerebellar deficits in schizophrenia are associated with executive dysfunction. Neuroreport. 2008;19: 1513-1517.
32. Park KM, Kim JJ, Seok JH, Chun JW, Park HJ, Lee JD. Anhedonia and ambivalence in schizophrenic patients with fronto-cerebellar metabolic abnormalities: a fluoro-d-glucose positron emission tomography study. Psychiatry Investig. 2009;6: 72-77.
33. Repovs G, Csernansky JG, Barch DM. Brain network connectivity in individuals with schizophrenia and their siblings. Biol Psychiatry. 2011;69: 967-973.
34. Carroll CA, Boggs J, O'Donnell BF, Shekhar A, Hetrick WP. Temporal processing dysfunction in schizophrenia. Brain Cogn. 2008;67: 150-161.
35. Carroll CA, O'Donnell BF, Shekhar A, Hetrick WP. Timing dysfunctions in schizophrenia span from millisecond to several- second durations. Brain Cogn. 2009;70: 181-190.
36. Carroll CA, O'Donnell BF, Shekhar A, Hetrick WP. Timing dysfunctions in schizophrenia as measured by a repetitive finger tapping task. Brain Cogn. 2009;71: 345-353.
37. Bolbecker AR, Mehta CS, Edwards CR, Steinmetz JE, O'Donnell BF, Hetrick WP. Eye-blink conditioning deficits indicate temporal processing abnormalities in schizophrenia. Schizophr Res. 2009;111: 182-191.
38. Bolbecker AR, Steinmetz AB, Mehta CS, et al. Exploration of cerebellar-dependent associative learning in schizophrenia: effects of varying and shifting interstimulus interval on eyeblink conditioning. Behav Neurosci. 2011;125: 687-698.
39. Brown SM, Kieffaber PD, Carroll CA, et al. Eyeblink conditioning deficits indicate timing and cerebellar abnormalities in schizophrenia. Brain Cogn. 2005;58: 94-108.
40. Forsyth JK, Bolbecker AR, Mehta CS, et al. Cerebellardependent eyeblink conditioning deficits in schizophrenia spectrum disorders. Schizophr Bull. 2012;38: 751-759.
41. Marcelis M, Suckling J, Woodruff P, Hofman P, Bullmore E, van Os J. Searching for a structural endophenotype in psychosis using computational morphometry. Psychiatry Res. 2003;122: 153-167.
42. Greenstein D, Lenroot R, Clausen L, et al. Cerebellar development in childhood onset schizophrenia and non-psychotic siblings. Psychiatry Res. 2011;193: 131-137.
43. Collin G, Hulshoff Pol HE, Haijma SV, Cahn W, Kahn RS, van den Heuvel MP. Impaired cerebellar functional connectivity in schizophrenia patients and their healthy siblings. Front Psychiatry. 2011;2: 73.
44. Kim JJ, Thompson RF. Cerebellar circuits and synaptic mechanisms involved in classical eyeblink conditioning. Trends Neurosci. 1997;20: 177-181.
45. Steinmetz JE. Brain substrates of classical eyeblink conditioning: a highly localized but also distributed system. Behav Brain Res. 2000;110: 13-24.
46. Christian KM, Thompson RF. Neural substrates of eyeblink conditioning: acquisition and retention. Learn Mem. 2003;10: 427-455.
47. Fanselow MS, Poulos AM. The neuroscience of mammalian associative learning. Annu Rev Psychol. 2005;56: 207-234.
48. Maxwell ME. Manual for the Family Interview for Genetic Studies (FIGS). Bethesda, MD: National Institute of Mental Health; 1992.
49. First MB, Spitzer, RL, Gibbon M, and Williams JBW. Structured Clinical Interview for DSM- IV-TR Axis I Disorders, Research Version, Patient Edition (SCID-I/P). New York, NY: Biometrics Research, New York State Psychiatric Institute; 2002.
50. First MB, Gibbon, M, Spitzer, RL, Williams JBW, Benjamin LS. SCID-II Personality Questionnaire. Washington, DC: American Psychiatric Press; 1997.
51. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured Clinical Interview for DSM-IV Axis I disorders-Nonpatient Version 2.0. New York: New York State Psychiatric Institute; 1995.
52. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13: 261-276.
53. Leucht S, Kane JM, Kissling W, Hamann J, Etschel E, Engel RR. What does the PANSS mean? Schizophr Res. 2005;79: 231-238.
54. Lang PJ, Greenwald MK. The International Affective Picture System Standardization Procedure and Initial Group Results for Affective Judgements: Technical Reports 1A and 1B. Gainseville, FL: Center for Research in Psychophysiology, University of Florida; 1988.
55. Bolbecker AR, Hetrick WP, Johannesen JK, O'Donnell BF, Steinmetz JE, Shekhar AS. Secretin effects on cerebellardependent motor learning in schizophrenia. Am J Psychiatry. 2009;166: 460-466.
56. Bolbecker AR, Mehta C, Johannesen JK, et al. Eyeblink conditioning anomalies in bipolar disorder suggest cerebellar dysfunction. Bipolar Disord. 2009;11: 19-32.
57. Steinmetz AB, Edwards CR, Steinmetz JE, Hetrick WP. Comparison of auditory and visual conditioning stimuli in delay eyeblink conditioning in healthy young adults. Learn Behav. 2009;37: 349-356.
58. Steinmetz AB, Skosnik PD, Edwards CR, Bolbecker AR, Steinmetz JE, Hetrick WP. Evaluation of bidirectional interstimulus interval (ISI) shift in auditory delay eye-blink conditioning in healthy humans. Learn Behav. 2011;39: 358-370.
59. Bryk AS, Raudenbush SW. Heterogeneity of variance in experimental studies: A challenge to conventional interpretations. Psychol Bull. 1988;104: 396-404.
60. Pinheiro J, Bates D, DebRoy S, Sarkar D; Team Rc. NLME: Linear and Nonlinear Mixed Effects Models; R Package Version 3; 2009.
61. Singer JD, Willett JB. Applied Longitudinal Data Analysis: Modeling Change and Event Occurrence. New York, NY: Oxford; 2003.
62. Lavond DG. Role of the nuclei in eyeblink conditioning. Ann N Y Acad Sci. 2002;978: 93-105.
63. Steinmetz JE, Logue SF, Steinmetz SS. Rabbit classically conditioned eyelid responses do not reappear after interpositus nucleus lesion and extensive post-lesion training. Behav Brain Res. 1992;51: 103-114.
64. Yeo CH, Hardiman MJ, Glickstein M. Classical conditioning of the nictitating membrane response of the rabbit. I. Lesions of the cerebellar nuclei. Exp Brain Res. 1985;60: 87-98.
65. Garcia KS, Mauk MD. Pharmacological analysis of cerebellar contributions to the timing and expression of conditioned eyelid responses. Neuropharmacology. 1998;37: 471-480.
66. Steinmetz JE, Kim J, Thompson RF. Biological models of associative learning. In: Gallagher M, Nelson R, eds. Handbook of Psychology, Volume 3 Biological Psychology. New York: Wiley; 2002.
67. Garcia KS, Steele PM, Mauk MD. Cerebellar cortex lesions prevent acquisition of conditioned eyelid responses. J Neurosci. 1999;19: 10940-10947.
68. Perrett SP, Ruiz BP, Mauk MD. Cerebellar cortex lesions disrupt learning-dependent timing of conditioned eyelid responses. J Neurosci. 1993;13: 1708-1718.
69. Edwards CR, Newman S, Bismark A, et al. Cerebellum volume and eyeblink conditioning in schizophrenia. Psychiatry Res. 2008;162: 185-194.
70. Gerwig M, Hajjar K, Dimitrova A, et al. Timing of conditioned eyeblink responses is impaired in cerebellar patients. J Neurosci. 2005;25: 3919-3931.
71. Guidotti A, Auta J, Davis JM, et al. Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. Arch Gen Psychiatry. 2000;57: 1061-1069.
72. Sheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini- International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59(suppl 20): 22-33; quiz 34-57.
73. Fatemi SH, Hossein Fatemi S, et al. GABAergic dysfunction in schizophrenia and mood disorders as reflected by decreased levels of glutamic acid decarboxylase 65 and 67 kDa and Reelin proteins in cerebellum. Schizophr Res. 2005;72: 109-122.
74. Siever LJ, Davis KL. The pathophysiology of schizophrenia disorders: perspectives from the spectrum. Am J Psychiatry. 2004;161: 398-413.
75. Kendler KS, Gardner CO. The risk for psychiatric disorders in relatives of schizophrenic and control probands: a comparison of three independent studies. Psychol Med. 1997;27: 411-419.
76. McGue M, Gottesman II, Rao DC. The transmission of schizophrenia under a multifactorial threshold model. Am J Hum Genet. 1983;35: 1161-1178.
77. Zerbin-Rüdin E. [What are the implications of the current findings in twins for schizophrenia research?]. Dtsch Med Wochenschr. 1967;92: 2121-2122.
78. Hofer E, Doby D, Anderer P, Dantendorfer K. Impaired conditional discrimination learning in schizophrenia. Schizophr Res. 2001;51: 127-136.
79. Lubow RE. Classical eyeblink conditioning and schizophrenia: a short review. Behav Brain Res. 2009;202: 1-4.
80. Wray NR, Gottesman II. Using summary data from the danish national registers to estimate heritabilities for schizophrenia, bipolar disorder, and major depressive disorder. Front Genet. 2012;3: 118.
81. Andreasen NC, Pierson R. The role of the cerebellum in schizophrenia. Biol Psychiatry. 2008;64: 81-88.
82. Fusar-Poli P, Perez J, Broome M, et al. Neurofunctional correlates of vulnerability to psychosis: a systematic review and meta-analysis. Neurosci Biobehav Rev. 2007;31: 465-484.
83. MacDonald AW 3rd, Thermenos HW, Barch DM, Seidman LJ. Imaging genetic liability to schizophrenia: systematic review of fMRI studies of patients' nonpsychotic relatives. Schizophr Bull. 2009;35: 1142-1162.
84. Frangou S, Chitins X, Williams SC. Mapping IQ and gray matter density in healthy young people. Neuroimage. 2004;23: 800-805.
85. Paradiso S, Andreasen NC, O'Leary DS, Arndt S, Robinson RG. Cerebellar size and cognition: correlations with IQ, verbal memory and motor dexterity. Neuropsychiatry Neuropsychol Behav Neurol. 1997;10: 1-8.
86. Taki Y, Hashizume H, Sassa Y, et al. Correlation among body height, intelligence, and brain gray matter volume in healthy children. Neuroimage. 2012;59: 1023-1027.
87. Bolbecker AR, Mehta CS, Edwards CR, Steinmetz JE, O'Donnell BF, Hetrick WP. Eye-blink conditioning deficits indicate temporal processing abnormalities in schizophrenia. Schizophr Res. 2009;111: 182-191.
88. Tamminga CA, Buchanan RW, Gold JM. The role of negative symptoms and cognitive dysfunction in schizophrenia outcome. Int Clin Psychopharmacol. 1998;13(suppl 3): S21-S26.
89. Faraone SV, Seidman LJ, Kremen WS, Toomey R, Pepple JR, Tsuang MT. Neuropsychologic functioning among the nonpsychotic relatives of schizophrenic patients: the effect of genetic loading. Biol Psychiatry. 2000;48: 120-126.
90. Mittal VA, Neumann C, Saczawa M, Walker EF. Longitudinal progression of movement abnormalities in relation to psychotic symptoms in adolescents at high risk of schizophrenia. Arch Gen Psychiatry. 2008;65: 165-171.
91. Mittal VA, Walker EF. Movement abnormalities predict conversion to Axis I psychosis among prodromal adolescents. J Abnorm Psychol. 2007;116: 796-803.
92. Mittal VA, Walker EF, Bearden CE, et al. Markers of basal ganglia dysfunction and conversion to psychosis: neurocognitive deficits and dyskinesias in the prodromal period. Biol Psychiatry. 2010;68: 93-99.
93. Ridler K, Veijola JM, Tanskanen P, et al. Fronto-cerebellar systems are associated with infant motor and adult executive functions in healthy adults but not in schizophrenia. Proc Natl Acad Sci U S A. 2006;103: 15651-15656.
94. Sanches M, Roberts RL, Sassi RB, et al. Developmental abnormalities in striatum in young bipolar patients: a preliminary study. Bipolar Disord. 2005;7: 153-158.
95. Demirtas-Tatlidede A, Freitas C, Cromer JR, et al. Safety and proof of principle study of cerebellar vermal theta burst stimulation in refractory schizophrenia. Schizophr Res. 2010;124: 91-100.