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Classical eyeblink conditioning and schizophrenia: A short review
Behavioural Brain Research 202 (2009) 1–4
Contents lists available at ScienceDirect
Behavioural Brain Research journal homepage: www.elsevier.com/locate/bbr
Review
Classical eyeblink conditioning and schizophrenia: A short review R.E. Lubow Department of Psychology, Tel Aviv University, Ramat Aviv 69978, Israel
a r t i c l e
i n f o
Article history: Received 23 February 2009 Accepted 4 March 2009 Available online 19 March 2009 Keywords: Eyeblink responses Schizophrenia Cerebellar structures Conditioning
a b s t r a c t There is considerable evidence for the involvement of cerebellar structures and circuits in classical conditioning of eyeblink responses (EBC) and in the pathophyiology of schizophrenia, leading to the expectation that schizophrenia patients should exhibit impaired EBC. A review of the literature indicates that such a position is not supported. Of the nine published studies, three reported poorer EBS in patients compared to controls, three reported better EBC, and three reported no significant EBC differences between the groups. Overall, medicated schizophrenia patients showed poorer EBC, and non-medicated patients exhibited better or normal EBC, relative to healthy control groups. In the light of those results and the fact that no experiment explicitly compared medicated and non-medicated patients, one cannot assume that the EBC deficits in patient groups are attributable to anything other than an effect from medication. © 2009 Elsevier B.V. All rights reserved.
Contents 1. 2. 3.
Classical eyeblink conditioning and schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Basic EBC procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Eyeblink conditioning in patients with schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Classical eyeblink conditioning and schizophrenia Early research on classical conditioning and psychopathology focused on learning deficits in patient populations while implicitly acknowledging that the pathology was not caused by a disruption of classical conditioning per se. More recently, evidence of cerebellar involvement in schizophrenia and in eyeblink conditioning (EBC) has suggested that purported EBC anomalies in schizophrenia may cast light on an underlying impairment in timing that can account for a variety of their symptoms. Indeed, the case for a correlation between cerebellar structure/function and the schizophrenia disorders is compelling, as is the one for cerebellar involvement in EBC (see below). On the other hand, the link between schizophrenia and EBC is less clear. The purpose of the present paper is simply to review the evidence for a linkage between EBC and schizophrenia. 2. Basic EBC procedures In EBC experiments, the temporal relationship between the CS (usually a tone) and US (almost always an air-puff to the eye) can be
E-mail address: [email protected]. 0166-4328/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2009.03.006
1 1 1 3
such that the presentations of the CS and US overlap in time, with the CS preceding the US, but both terminating together (delay conditioning). On the other hand, the US can be presented some short period of time after the CS has terminated (trace conditioning). The two types of EBCs are subserved by different neural pathways. The acquisition of a delay-conditioned eyeblink response is largely dependent on cerebellum and brainstem areas, but may be modulated by forebrain areas, including the hippocampus. In contrast, trace conditioning appears to rely on hippocampal circuitry, at least with long CS–US trace intervals (for reviews, see Refs. [1–3]). In this regard, it should be noted that most EBC studies with schizophrenic patients have used the delay conditioning protocol, usually with a single cue in the acquisition session (see Table 1). 3. Eyeblink conditioning in patients with schizophrenia The EBC protocol is considered by many to be an important tool for studying information processing deficits in schizophrenia because the neural structures, neurotransmitters, and circuitry of EBC are well defined and they overlap with those implicated in schizophrenia (for recent review, see Ref. [4]). Specifically, delay-EBC is an associative motor learning task that is essentially controlled by circuits within the cerebellum that are involved with the timing of the CR and the US-induced blink response (for reviews,
2
R.E. Lubow / Behavioural Brain Research 202 (2009) 1–4
Table 1 Experiments using eyelid conditioning with healthy and schizophrenic subjects. Experimenta
Conditioning type
CS
Healthy M/F
Schizophrenic M/F
Brown et al. [8] Edwards et al. [13] Hofer et al. [10]
Delay Delay Delay/disc
Tone Tone Tone
7/6 6b 17/3
Marenco et al. [7]
Delay Trace
Tone Tone
O’Connor and Rawnsley [15]
Delay
Sears et al. [9] Spain [16] Stevens et al. [11] Taylor and Spence [17]g a b c d e f g h i
Subjects
Schiz.-Med.
Results
7/6 5/4 21/3
Medicated Medicated Medicated
Sz impaired CR; more timing variability Sz impaired CR Sz-poorer conditioning; no disc
10 9
10 10
Medicated Medicated
Sz longer onset and peak latency CRs Both groups—no conditioning
Tone
20/0
40/0
Non-medicated
No differences between normals, and chronic paranoids and non-paranoidsc
Delay Delay
Tone Light/toned
15 12/12
15 32/22e
Non-medicated Non-medicated
Delay/disc Delay
Tone Light
13/12 74h
28/22 42i
Medicatedf Non-medicated
Sz more CRs Sz more CRs; correlated with GSR. Group × modality interaction Rapid cond; no diff between groups Psychotics gave more CRs than neurotics (p < .10)
King and Landis [14] is omitted. The “psychiatric patient” group consisted of “five women and three men, [only] two of whom were diagnosed as schizophrenic . . .” No breakdown; “matched”? Absence of differences may be due to a floor effect. 18 CS-alone trials were interspersed with 30 CS–US trials. Within-subject design. Numbers in the text do not correspond to the numbers in the tables. 25 subjects on classical neuroleptics (e.g., haloperidol) and 25 on olanzipine, each with 13/12 sex ratio. The data from some of the subjects in this study were reported by Spence and Taylor [37]. Non-psychotic subjects with a variety of diagnoses, mostly “neurotic”. 31 of 42 subjects diagnosed as some category of schizophrenia.
see Refs. [1,5]). Since the cerebellum is also involved in schizophrenia (for review, see Ref. [6]), differences between patients and controls should be detected in conditioning performance. Indeed, a number of researchers have accepted such a relationship. For example, Gerwig et al. ([2], p. 41) write, “. . . impaired acquisition of eyeblink conditioning in essential tremor and various neuropsychiatric diseases (autism, schizophrenia, dyslexia, attention-deficit hyperactivity disorder) have been interpreted in favor of a cerebellar role in the pathogenesis of these disorders” for which they cite a single empirical article by Marenco et al. [7]. However, in this latter report, which used both delay and trace procedures, neither the schizophrenia patient group nor the healthy group provided any evidence of conditioning with either protocol, although the patients exhibited longer onset and peak latencies of CRs. Although Picard et al. [4] accept the inconsistency of the EBC–schizophrenia data, they nevertheless write of “impaired eyeblink conditioning” in schizophrenia patients. This, in spite of the fact that of the four studies that they list in their Table 1, two are credited with supporting cerebellar involvement [8,9] and two not [10,11]. Indeed, Brown et al. [8] did report poorer conditioning and more timing variability for schizophrenia patients than for healthy controls. Sears et al. [9], however, found better conditioning in patients as compared to controls. The discrepancy may well be due to the fact that the former study had medicated patients and the latter, non-medicated patients (see below). Although Picard et al. [4] credited the Hofer et al. [10] and Stevens et al. [11] studies as failing to support cerebellar involvement in schizophrenia, in fact the former did find poorer conditioning in patients (medicated) than in controls, while the latter found no differences between patients (medicated) and controls. Interestingly, a general review of clinical models and applications of classical eyeblink conditioning by Steinmetz et al. [12] refers to autism, fetal alcohol syndrome and obsessive-compulsive disorder, with no mention of schizophrenia. Thus, in spite of claims for a relationship between eyelid conditioning performance and schizophrenia, the data are, at best, ambiguous. In an attempt to clarify the situation, I have reviewed all of the published articles that have used EBC with schizophrenic patients. These papers are summarized in Table 1, where it can
be seen that some studies have reported poorer conditioning in schizophrenic patients compared to controls [8,10,13], or no difference [7,11,14,15], while other studies have obtained better conditioning in patients than controls [9,16,17]. An inspection of Table 1 strongly suggests that the differences in EBC performance between schizophrenic and healthy groups are largely due to medication status. Thus, non-medicated patients consistently display better conditioning scores than healthy controls [9,16,17], while medicated schizophrenia patients exhibit either poorer conditioning than controls [8,10,13] or no difference [7,11,15]. This pattern of findings indicates that the results from EBC studies with schizophrenic patients may not reflect processes involved with schizophrenia, but rather with the effects of antipsychotic drugs. In particular, although the cerebellar involvement in the pathogenesis of schizophrenia has been linked theoretically (e.g., Refs. [6,18]) and empirically (e.g., Ref. [19]; but see Picard et al. [4], who cite the absence of such an association when considering clinical, cognitive, and functional data), and delay-EBC is largely under control of cerebellar structures, attempts to reinforce this connection with EBC data would seem to be quite premature, both in regard to the general proposition concerning the relation between cerebellar activity and schizophrenia, as well as to the proposal that some schizophrenia symptoms may be the outcome of a basic dysfunction in the temporal coordination of information (e.g., Refs. [8,13]). In support of caution in accepting the EBC–schizophrenia link, it should be noted that the anti-psychotic medication administered to the schizophrenia patients in these experiments appears to act in the opposite direction from what one would normally expect. As described above, non-medicated patients either show better conditioning than controls or no differences, while poorer conditioning by schizophrenics compared to controls has only been observed with medicated patients. Thus, neuroleptic medication impairs EBC in these patients rather than normalizing it. However, this same effect might have been observed if the drugs were also administered to the healthy control groups, as has been found in animal EBC preparations [20–23]. It is still possible that the EBC effects in patients might be due to a neuroleptic × pathology interaction.
R.E. Lubow / Behavioural Brain Research 202 (2009) 1–4
Indeed, a study by Schmajuk, Cox and Christiansen [24] found that haloperidol, a powerful dopamine antagonist and neuroleptic, has no effect on EBC in sham-lesioned rats, but that it impairs EBC in cortically lesioned rats (see their Fig. 4), as well as restoring latent inhibition in rats with hippocampal formation lesions. Unfortunately, research on EBC with schizophrenia patients has often been challenged by methodological problems. Of particular concern, many of these studies did not take into account possible differences in spontaneous blink rates between patient and control groups. This is especially important since spontaneous blink rate, a measure of central dopaminergic activity, is elevated in patients with schizophrenia (e.g., Refs. [25–29]) and often normalized by neuroleptic treatment [30–32] (but see Ref. [33]). In short, the relatively high spontaneous blink rate of unmedicated schizophrenia patients may be a source of exaggerated CR scores. On the other hand, common neuroleptics, which are dopamine antagonists, may have the reverse effect. Similar concerns can be raised for eyeblink startle responses (alpha responses). If these short latency responses are not omitted from the analysis, they too would artificially inflate the number of CRs attributed to the unmedicated patient group, and perhaps underestimate the number of CRs in the medicated patient group compared to the control group. There are several other sources of potential confounding, at least to the extent that one wants to attribute between-group differences in CRs to conditioning per se, i.e. the basic ability to form an association between the CS and US. For example, habituation of the UR to the US may be more rapid for schizophrenia patients than for controls, as has often been reported for habituation of the orienting response (OR) component of the electrodermal response (e.g., Ref. [34]). Related considerations may also have an impact on the CS, as in latent inhibition, albeit in opposite directions for schizophrenia patients with positive and negative symptoms [35,36]. In other words, patients and controls may differ in the way that they process/encode the CS and/or the US, the results of which would affect relative numbers of CRs, but would say nothing about intrinsic associability, the latter of which is presumably of importance in building the case for using EBC data to explicate the cerebellar involvement in schizophrenia. Nevertheless, since it is still the case that delay-EBC is largely governed by cerebellar circuitry and that the cerebellum is implicated in schizophrenia, some reliable relationship between the two might have been expected. The failure to convincingly demonstrate such a connection, assuming that it exists, may have a number of sources, including the possibility that the cerebellar circuitry involved in EBC is different from that impaired in schizophrenia. Equally likely, the inconsistency of results may be related to the heterogeneity of behaviors that are subsumed under the schizophrenia diagnosis. A review of the publications listed in Table 1 indicates that classification of patients in the older articles was primarily based on reviews of case files [15–17], while the more recent ones used DSM-IV [7,9–11,13] or SCID-1 [8]. Although many of the reports, new and old, do not provide sub-classifications for schizophrenia, the ones that do point to the large differences amongst subjects across studies: paranoid and residual [10]; schizophrenic and depressed schizoaffective [7]; chronic paranoid and chronic non-paranoid [15], and a group composed of simple, paranoid, hebephrenic and mixed types [17]. The inconsistency of the EBC data that might be attributed to the heterogeneity of the subjects is exacerbated even further by small sample sizes and disproportionate numbers of males in the patient groups as compared to their control groups. In summary, medicated schizophrenia patients show poorer EBC, and non-medicated patients exhibit better or normal EBC, relative to healthy control groups. However, since no single experiment explicitly compared medicated and non-medicated patients, one cannot assume that the EBC deficits in patient groups are
3
attributable to anything other than an effect from medication. If true, then the role of EBC data for understanding cerebellar activity in schizophrenia should be re-evaluated. In the meantime, until the appropriate experiments are conducted, it still would be prudent to recall that absence of evidence is not evidence of absence. References [1] Christian KM, Thompson RF. Neural substrates of eyeblink conditioning: acquisition and retention. Learn Mem 2003;10:427–55. [2] Gerwig M, Kolb FP, Timmann D. The involvement of the human cerebellum in eyeblink conditioning. Cerebellum 2007;6:38–57. [3] Thompson RF, Bao SW, Chen L, Cipriano BD, Grethe JS, Kim JJ, et al. Associative learning. Cerebellum Cogn 1997;41:151–89. [4] Picard H, Amado I, Mouchet-Mages S, Olie J-P, Krebs M-O. The role of the cerebellum in schizophrenia: an update of clinical, cognitive, and functional evidences. Schizophr Bull 2008;34:155–72. [5] Villarreal RP, Steinmetz JE. Neuroscience and learning: lessons from studying the involvement of a region of cerebellar cortex in eyeblink classical conditioning. J Exp Anal Behav 2005;84:631–52. [6] Andreasen NC, Pierson R. The role of the cerebellum in schizophrenia. Biol Psychiatry 2008;64:81–8. [7] Marenco S, Weinberger DR, Schreurs BG. Single-cue delay and trace classical conditioning in schizophrenia. Biol Psychiatry 2003;53:390–402. [8] Brown SM, Kieffaber PD, Carroll CA, Vohs JL, Tracy JA, Shekhar A, et al. Eyeblink conditioning deficits indicate timing and cerebellar abnormalities in schizophrenia. Brain Cogn 2005;58:94–108. [9] Sears LL, Andreasen NC, O’Leary DS. Cerebellar functional abnormalities in schizophrenia are suggested by classical eyeblink conditioning. Biol Psychiatry 2000;48:204–9. [10] Hofer E, Doby D, Anderer P, Dantendorfer K. Impaired conditional discrimination learning in schizophrenia. Schizophr Res 2001;51:127–36. [11] Stevens A, Schwarz J, Schwarz B, Ruf I, Kolter T, Czekalla J. Implicit and explicit learning in schizophrenics treated with olanzapine and with classic neuroleptics. Psychopharmacology 2002;160:299–306. [12] Steinmetz JE, Tracy JA, Green JT. Classical eyeblink conditioning: clinical models and applications. Integr Physiol Behav Sci 2001;36:220–38. [13] Edwards CR, Newman S, Bismark A, Skosnik PD, O’Donnell BF, Shekhar A, et al. Cerebellum volume and eyeblink conditioning in schizophrenia. Psychiatry Res: Neuroimaging 2008;162:185–94. [14] King HE, Landis CA. comparison of eyelid responses conditioned with reflex and voluntary reinforcement in normal individuals and in psychiatric patients. J Exp Psychol 1943;33:210–20. [15] O’Connor N, Rawnsley K. Two types of conditioning in psychotics and normals. J Abnorm Soc Psychol 1959;58:157–61. [16] Spain B. Eyelid conditioning and arousal in schizophrenic and normal subjects. J Abnorm Psychol 1966;71:260–6. [17] Taylor J, Spence KW. Conditioning level in the behavior disorders. J Abnorm Soc Psychol 1954;49:497–502. [18] Andreasen NC. A unitary model of schizophrenia—Bleuler’s “fragmented phrene” as schizencephaly. Arch Gen Psychiatry 1999;56:781–7. [19] Keller A, Castellanos FX, Vaituzis AC, Jeffries NO, Giedd JN, Rapoport JL. Progressive loss of cerebellar volume in childhood-onset schizophrenia. Am J Psychiatry 2003;160:128–33. [20] Harvey JA, Gormezano I. Effects of haloperidol and pimozide on classical conditioning of the rabbit nictitating membrane response. J Pharmacol Exp Therap 1981;218:712–9. [21] Sears LL, Steinmetz JE. Haloperidol impairs classically conditioned nictitating membrane responses and conditioning-related cerebellar interpositus nucleus activity in rabbits. Pharmacol Biochem Behav 1990;36:821–9. [22] Sears LL, Steinmetz JE. Effects of haloperidol on sensory processing in the hippocampus during classical eyeblink conditioning. Psychopharmacology 1997;130:254–60. [23] White IM, Miller DP, White W, Dike GL, Rebec GV, Steinmetz JE. Neuronal activity in rabbit neostriatum during classical eyelid conditioning. Exp Brain Res 1994;99:179–90. [24] Schmajuk NA, Cox L, Christiansen BA. Haloperidol reinstates latent inhibition impaired by hippocampal lesions: data and theory. Behav Neurosci 2000;114:659–70. [25] Chan KCK, Chen EYH. Blink rate does matter: a study of blink rate, sustained attention, and neurological signs in schizophrenia. J Nerv Ment Dis 2004;192:781–3. [26] Chen EYH, Lam LCW, Chen RYL, Nguyen DGH. Blink rate, neurocognitive impairments, and symptoms in schizophrenia. Biol Psychiatry 1996;40:597–603. [27] Karson CN, Goldberg TE, Leleszi JP. Increased blink rate in adolescent patients with psychosis. Psychiatry Res 1986;17:195–8. [28] Stevens JR. Disturbances of ocular movements and blinking in schizophrenia. J Neurol Neurosurg Psychiatry 1978;41:1024–30. [29] Swarztrauber K, Fujikawa DG. An electroencephalographic study comparing maximum blink rates in schizophrenic and nonschizophrenic psychiatric patients and nonpsychiatric control subjects. Biol Psychiatry 1998;43: 282–7. [30] Karson CN. Spontaneous eye-blink rates and dopaminergic systems. Brain 1983;106:643–53.
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[31] Mackert A, Flechtner KM, Woyth C, Frick K. Increased blink rates in schizophrenics—influences of neuroleptics and psychopathology. Schizophr Res 1991;4:41–4. [32] Mackert A, Woyth C, Flechtner KM, Volz HP. Increased blink rate in drug-naïve acute schizophrenic patients. Biol Psychiatry 1990;27:1197–202. [33] Jacobsen LK, Hommer DW, Hong WL, Castellanos FX, Frazier JA, Giedd JN, et al. Blink rate in childhood-onset schizophrenia: comparison with normal and attention-deficit hyperactivity disorder controls. Biol Psychiatry 1996;40:1222–9. [34] Bernstein AS, Frith CD, Gruzelier JH, Patterson T, Straube E, Venables PH, et al. An analysis of the skin conductance orienting response in samples of American, British, and German schizophrenics. Biol Psychol 1982;14:155–211.
[35] Lubow RE. Latent inhibition and schizophrenia: the ins and outs of context. In: Lubow RE, Weiner I, editors. Latent inhibition: data, theories, and applications to schizophrenia. New York: Cambridge University Press, in press. [36] Weiner I, Arad M. The pharmacology of latent inhibition: modeling domains of pathology in schizophrenia and their treatment. In: Lubow RE, Weiner I, editors. Latent inhibition: data, theories, and applications to schizophrenia. New York: Cambridge University Press, in press. [37] Spence KW, Taylor JA. The relation of conditioned response strength to anxiety in normal, neurotic, and psychotic subjects. J Exp Psychol 1953;45: 265–72.
Contents lists available at ScienceDirect
Behavioural Brain Research journal homepage: www.elsevier.com/locate/bbr
Review
Classical eyeblink conditioning and schizophrenia: A short review R.E. Lubow Department of Psychology, Tel Aviv University, Ramat Aviv 69978, Israel
a r t i c l e
i n f o
Article history: Received 23 February 2009 Accepted 4 March 2009 Available online 19 March 2009 Keywords: Eyeblink responses Schizophrenia Cerebellar structures Conditioning
a b s t r a c t There is considerable evidence for the involvement of cerebellar structures and circuits in classical conditioning of eyeblink responses (EBC) and in the pathophyiology of schizophrenia, leading to the expectation that schizophrenia patients should exhibit impaired EBC. A review of the literature indicates that such a position is not supported. Of the nine published studies, three reported poorer EBS in patients compared to controls, three reported better EBC, and three reported no significant EBC differences between the groups. Overall, medicated schizophrenia patients showed poorer EBC, and non-medicated patients exhibited better or normal EBC, relative to healthy control groups. In the light of those results and the fact that no experiment explicitly compared medicated and non-medicated patients, one cannot assume that the EBC deficits in patient groups are attributable to anything other than an effect from medication. © 2009 Elsevier B.V. All rights reserved.
Contents 1. 2. 3.
Classical eyeblink conditioning and schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Basic EBC procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Eyeblink conditioning in patients with schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Classical eyeblink conditioning and schizophrenia Early research on classical conditioning and psychopathology focused on learning deficits in patient populations while implicitly acknowledging that the pathology was not caused by a disruption of classical conditioning per se. More recently, evidence of cerebellar involvement in schizophrenia and in eyeblink conditioning (EBC) has suggested that purported EBC anomalies in schizophrenia may cast light on an underlying impairment in timing that can account for a variety of their symptoms. Indeed, the case for a correlation between cerebellar structure/function and the schizophrenia disorders is compelling, as is the one for cerebellar involvement in EBC (see below). On the other hand, the link between schizophrenia and EBC is less clear. The purpose of the present paper is simply to review the evidence for a linkage between EBC and schizophrenia. 2. Basic EBC procedures In EBC experiments, the temporal relationship between the CS (usually a tone) and US (almost always an air-puff to the eye) can be
E-mail address: [email protected]. 0166-4328/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2009.03.006
1 1 1 3
such that the presentations of the CS and US overlap in time, with the CS preceding the US, but both terminating together (delay conditioning). On the other hand, the US can be presented some short period of time after the CS has terminated (trace conditioning). The two types of EBCs are subserved by different neural pathways. The acquisition of a delay-conditioned eyeblink response is largely dependent on cerebellum and brainstem areas, but may be modulated by forebrain areas, including the hippocampus. In contrast, trace conditioning appears to rely on hippocampal circuitry, at least with long CS–US trace intervals (for reviews, see Refs. [1–3]). In this regard, it should be noted that most EBC studies with schizophrenic patients have used the delay conditioning protocol, usually with a single cue in the acquisition session (see Table 1). 3. Eyeblink conditioning in patients with schizophrenia The EBC protocol is considered by many to be an important tool for studying information processing deficits in schizophrenia because the neural structures, neurotransmitters, and circuitry of EBC are well defined and they overlap with those implicated in schizophrenia (for recent review, see Ref. [4]). Specifically, delay-EBC is an associative motor learning task that is essentially controlled by circuits within the cerebellum that are involved with the timing of the CR and the US-induced blink response (for reviews,
2
R.E. Lubow / Behavioural Brain Research 202 (2009) 1–4
Table 1 Experiments using eyelid conditioning with healthy and schizophrenic subjects. Experimenta
Conditioning type
CS
Healthy M/F
Schizophrenic M/F
Brown et al. [8] Edwards et al. [13] Hofer et al. [10]
Delay Delay Delay/disc
Tone Tone Tone
7/6 6b 17/3
Marenco et al. [7]
Delay Trace
Tone Tone
O’Connor and Rawnsley [15]
Delay
Sears et al. [9] Spain [16] Stevens et al. [11] Taylor and Spence [17]g a b c d e f g h i
Subjects
Schiz.-Med.
Results
7/6 5/4 21/3
Medicated Medicated Medicated
Sz impaired CR; more timing variability Sz impaired CR Sz-poorer conditioning; no disc
10 9
10 10
Medicated Medicated
Sz longer onset and peak latency CRs Both groups—no conditioning
Tone
20/0
40/0
Non-medicated
No differences between normals, and chronic paranoids and non-paranoidsc
Delay Delay
Tone Light/toned
15 12/12
15 32/22e
Non-medicated Non-medicated
Delay/disc Delay
Tone Light
13/12 74h
28/22 42i
Medicatedf Non-medicated
Sz more CRs Sz more CRs; correlated with GSR. Group × modality interaction Rapid cond; no diff between groups Psychotics gave more CRs than neurotics (p < .10)
King and Landis [14] is omitted. The “psychiatric patient” group consisted of “five women and three men, [only] two of whom were diagnosed as schizophrenic . . .” No breakdown; “matched”? Absence of differences may be due to a floor effect. 18 CS-alone trials were interspersed with 30 CS–US trials. Within-subject design. Numbers in the text do not correspond to the numbers in the tables. 25 subjects on classical neuroleptics (e.g., haloperidol) and 25 on olanzipine, each with 13/12 sex ratio. The data from some of the subjects in this study were reported by Spence and Taylor [37]. Non-psychotic subjects with a variety of diagnoses, mostly “neurotic”. 31 of 42 subjects diagnosed as some category of schizophrenia.
see Refs. [1,5]). Since the cerebellum is also involved in schizophrenia (for review, see Ref. [6]), differences between patients and controls should be detected in conditioning performance. Indeed, a number of researchers have accepted such a relationship. For example, Gerwig et al. ([2], p. 41) write, “. . . impaired acquisition of eyeblink conditioning in essential tremor and various neuropsychiatric diseases (autism, schizophrenia, dyslexia, attention-deficit hyperactivity disorder) have been interpreted in favor of a cerebellar role in the pathogenesis of these disorders” for which they cite a single empirical article by Marenco et al. [7]. However, in this latter report, which used both delay and trace procedures, neither the schizophrenia patient group nor the healthy group provided any evidence of conditioning with either protocol, although the patients exhibited longer onset and peak latencies of CRs. Although Picard et al. [4] accept the inconsistency of the EBC–schizophrenia data, they nevertheless write of “impaired eyeblink conditioning” in schizophrenia patients. This, in spite of the fact that of the four studies that they list in their Table 1, two are credited with supporting cerebellar involvement [8,9] and two not [10,11]. Indeed, Brown et al. [8] did report poorer conditioning and more timing variability for schizophrenia patients than for healthy controls. Sears et al. [9], however, found better conditioning in patients as compared to controls. The discrepancy may well be due to the fact that the former study had medicated patients and the latter, non-medicated patients (see below). Although Picard et al. [4] credited the Hofer et al. [10] and Stevens et al. [11] studies as failing to support cerebellar involvement in schizophrenia, in fact the former did find poorer conditioning in patients (medicated) than in controls, while the latter found no differences between patients (medicated) and controls. Interestingly, a general review of clinical models and applications of classical eyeblink conditioning by Steinmetz et al. [12] refers to autism, fetal alcohol syndrome and obsessive-compulsive disorder, with no mention of schizophrenia. Thus, in spite of claims for a relationship between eyelid conditioning performance and schizophrenia, the data are, at best, ambiguous. In an attempt to clarify the situation, I have reviewed all of the published articles that have used EBC with schizophrenic patients. These papers are summarized in Table 1, where it can
be seen that some studies have reported poorer conditioning in schizophrenic patients compared to controls [8,10,13], or no difference [7,11,14,15], while other studies have obtained better conditioning in patients than controls [9,16,17]. An inspection of Table 1 strongly suggests that the differences in EBC performance between schizophrenic and healthy groups are largely due to medication status. Thus, non-medicated patients consistently display better conditioning scores than healthy controls [9,16,17], while medicated schizophrenia patients exhibit either poorer conditioning than controls [8,10,13] or no difference [7,11,15]. This pattern of findings indicates that the results from EBC studies with schizophrenic patients may not reflect processes involved with schizophrenia, but rather with the effects of antipsychotic drugs. In particular, although the cerebellar involvement in the pathogenesis of schizophrenia has been linked theoretically (e.g., Refs. [6,18]) and empirically (e.g., Ref. [19]; but see Picard et al. [4], who cite the absence of such an association when considering clinical, cognitive, and functional data), and delay-EBC is largely under control of cerebellar structures, attempts to reinforce this connection with EBC data would seem to be quite premature, both in regard to the general proposition concerning the relation between cerebellar activity and schizophrenia, as well as to the proposal that some schizophrenia symptoms may be the outcome of a basic dysfunction in the temporal coordination of information (e.g., Refs. [8,13]). In support of caution in accepting the EBC–schizophrenia link, it should be noted that the anti-psychotic medication administered to the schizophrenia patients in these experiments appears to act in the opposite direction from what one would normally expect. As described above, non-medicated patients either show better conditioning than controls or no differences, while poorer conditioning by schizophrenics compared to controls has only been observed with medicated patients. Thus, neuroleptic medication impairs EBC in these patients rather than normalizing it. However, this same effect might have been observed if the drugs were also administered to the healthy control groups, as has been found in animal EBC preparations [20–23]. It is still possible that the EBC effects in patients might be due to a neuroleptic × pathology interaction.
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Indeed, a study by Schmajuk, Cox and Christiansen [24] found that haloperidol, a powerful dopamine antagonist and neuroleptic, has no effect on EBC in sham-lesioned rats, but that it impairs EBC in cortically lesioned rats (see their Fig. 4), as well as restoring latent inhibition in rats with hippocampal formation lesions. Unfortunately, research on EBC with schizophrenia patients has often been challenged by methodological problems. Of particular concern, many of these studies did not take into account possible differences in spontaneous blink rates between patient and control groups. This is especially important since spontaneous blink rate, a measure of central dopaminergic activity, is elevated in patients with schizophrenia (e.g., Refs. [25–29]) and often normalized by neuroleptic treatment [30–32] (but see Ref. [33]). In short, the relatively high spontaneous blink rate of unmedicated schizophrenia patients may be a source of exaggerated CR scores. On the other hand, common neuroleptics, which are dopamine antagonists, may have the reverse effect. Similar concerns can be raised for eyeblink startle responses (alpha responses). If these short latency responses are not omitted from the analysis, they too would artificially inflate the number of CRs attributed to the unmedicated patient group, and perhaps underestimate the number of CRs in the medicated patient group compared to the control group. There are several other sources of potential confounding, at least to the extent that one wants to attribute between-group differences in CRs to conditioning per se, i.e. the basic ability to form an association between the CS and US. For example, habituation of the UR to the US may be more rapid for schizophrenia patients than for controls, as has often been reported for habituation of the orienting response (OR) component of the electrodermal response (e.g., Ref. [34]). Related considerations may also have an impact on the CS, as in latent inhibition, albeit in opposite directions for schizophrenia patients with positive and negative symptoms [35,36]. In other words, patients and controls may differ in the way that they process/encode the CS and/or the US, the results of which would affect relative numbers of CRs, but would say nothing about intrinsic associability, the latter of which is presumably of importance in building the case for using EBC data to explicate the cerebellar involvement in schizophrenia. Nevertheless, since it is still the case that delay-EBC is largely governed by cerebellar circuitry and that the cerebellum is implicated in schizophrenia, some reliable relationship between the two might have been expected. The failure to convincingly demonstrate such a connection, assuming that it exists, may have a number of sources, including the possibility that the cerebellar circuitry involved in EBC is different from that impaired in schizophrenia. Equally likely, the inconsistency of results may be related to the heterogeneity of behaviors that are subsumed under the schizophrenia diagnosis. A review of the publications listed in Table 1 indicates that classification of patients in the older articles was primarily based on reviews of case files [15–17], while the more recent ones used DSM-IV [7,9–11,13] or SCID-1 [8]. Although many of the reports, new and old, do not provide sub-classifications for schizophrenia, the ones that do point to the large differences amongst subjects across studies: paranoid and residual [10]; schizophrenic and depressed schizoaffective [7]; chronic paranoid and chronic non-paranoid [15], and a group composed of simple, paranoid, hebephrenic and mixed types [17]. The inconsistency of the EBC data that might be attributed to the heterogeneity of the subjects is exacerbated even further by small sample sizes and disproportionate numbers of males in the patient groups as compared to their control groups. In summary, medicated schizophrenia patients show poorer EBC, and non-medicated patients exhibit better or normal EBC, relative to healthy control groups. However, since no single experiment explicitly compared medicated and non-medicated patients, one cannot assume that the EBC deficits in patient groups are
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