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Implicit transitive inference and the human hippocampus: does intravenous midazolam function as a reversible hippocampal lesion?

Implicit transitive inference and the human hippocampus: does intravenous midazolam function as a... Recent advances have led to an understanding that the hippocampus is involved more broadly than explicit or declarative memory alone. Tasks which involve the acquisition of complex associations involve the hippocampus whether the learning is explicit or implicit. One hippocampal-dependent implicit task is transitive inference (TI). Recently it was suggested that implicit transitive inference does not depend upon the hippocampus (Frank, M. J., O'Reilly, R. C., & Curran, T. 2006. When memory fails, intuition reigns: midazolam enhances implicit inference in humans. Psychological Science, 17, 700–707). The authors demonstrated that intravenous midazolam, which is thought to inactivate the hippocampus, may enhance TI performance. Three critical assumptions are required but not met: 1) that deactivations of other regions could not account for the effect 2) that intravenous midazolam does indeed deactivate the hippocampus and 3) that midazolam influences explicit but not implicit memory. Each of these assumptions is seriously flawed. Consequently, the suggestion that implicit TI does not depend upon the hippocampus is unfounded. amnesic patients with damage to the hippocampus and Introduction The capacity to learn complex stimulus relations and surrounding tissue cannot perform the TI task [17]. express them flexibly is thought to require the hippocam- pus [1]. While the hippocampus has been thought to be A recent study demonstrated that the administration of necessary for explicit but not implicit forms of learning intravenous midazolam improved TI performance in and memory [2], more recent studies demonstrate hip- human participants [18] which was argued as evidence pocampal involvement in implicit tasks which require that TI is performed more easily when the hippocampus complex associations [3-8]. One task which involves both does not contribute explicit strategies. The authors argue the acquisition of complex relations, flexible expression that midazolam deactivates the hippocampus because and which may be learned implicitly is the transitive infer- benzodiazepines act on GABA-A receptors [19], which are ence task [8-13]. At study, participants learn complex rela- densely concentrated in the hippocampus [20], and tions among stimuli (e.g., A>B, B>C, C>D, D>E) and at because benzodiazepines – in particular midazolam – test, they show flexible expression when an untrained dis- temporarily impair explicit memory formation [21]. The crimination (B?D) is correctly solved (B>D). Functional assertion that intravenous midazolam improves TI per- imaging studies confirm the role of the hippocampus in formance by deactivating the hippocampus depends both implicit and explicit versions of TI [8,14-16] and, entirely upon three premises: 1) that other areas critical to TI are not affected, so that only hippocampal deactivation Page 1 of 3 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:51 http://www.behavioralandbrainfunctions.com/content/3/1/51 can explain the effect; 2) that midazolam deactivates the whether their inability to perform the inference portion of hippocampus to the point that it no longer functions in a the task was predicated by their inability to acquire the mnemonic capacity; and 3) That midazolam influences premise pairs [17]. That is, amnesics do not reliably learn explicit but not implicit memory. There are serious prob- that B>C and C>D and that alone could account for their lems with all three premises, each of which jeopardize the inability to make the correct inference B>D. While the claim that TI is performed more easily without the hip- amnesic data do not therefore allow strong conclusions pocampus [18]. about performance on just the inference portion of the task, they do tend to disconfirm the hypothesis that "midazolam should improve TI test performance by pre- Discussion In studies where midazolam has been shown to have venting participants from memorizing the stimulus pairs selective effects on the hippocampus, non-human ani- and encouraging greater implicit learning of reinforce- mals receive midazolam as a direct injection into the hip- ment value" [[18] p. 701]. Furthermore, performance dif- pocampal tissue [22]. The principle action of midazolam ferences between hippocampal amnesia and midazolam- is as a central nervous-system depressant, which is fre- induced amnesia provide further evidence that the effects quently used medicinally as a sedative or as an anti-con- of intravenous midazolam are unlikely to constitute a hip- vulsant. While midazolam may be useful as a reversible pocampal deactivation. lesion when injected directly into the hippocampus, it is not at all clear that the effects are comparable when it is Given the widespread effects of intravenous midazolam in injected intravenously. One might expect the action of regions of cortex other than the hippocampus, it is natural midazolam to be much less circumscribed when it is dis- to question whether the effects of midazolam are limited tributed globally. Indeed, midazolam has been shown to to explicit memory. Several studies show that midazolam decrease regional cerebral blood flow (rCBF) to numerous influences not just explicit, but also implicit memory per- cortical areas other than the hippocampus or surrounding formance [27,28]. While implicit memory is not as pro- cortices [23]. Thus, it is entirely possible that the effects of foundly affected as explicit memory – indeed, explicit midazolam on the TI task are attributable to deactivations performance drops to chance levels – it is nevertheless of areas other than the hippocampus. incorrect to assert that intravenous midazolam does not affect implicit performance. Of the regions shown in human imaging studies to be deactivated by normal concentrations of intravenous Conclusion midazolam, the hippocampus is not among them. Two The existing data do not permit claims about selective studies attempting to discover an effect of midazolam on effects if intravenous midazolam on the human hippoc- rCBF in the hippocampus found no such effects [23,24]. ampus. Rather, the effects of intravenous midazolam Clearly, failure to detect an effect of midazolam on the involve numerous regions of cortex, including frontal and rCBF of the hippocampus does not imply the effects do parietal regions. The assertion that intravenous mida- not exist. However, given a compromised hippocampus zolam selectively deactivates the hippocampus is at best can still mediate hippocampal-dependent tasks [25] the premature and is more likely to be incorrect. Therefore, burden of proof must be upon those who claim that intra- there is no adequate substantiation for the claim that TI is venous midazolam anesthetizes the hippocampus to the improved by hippocampal deactivation [18]. extent that it does not function effectively in a mnemonic capacity. Moreover, a third study varied the concentration Competing interests of intravenous midazolam and showed a global anesthe- The author(s) declare that they have no competing inter- tizing effect at very high dosages to which the hippocam- ests. pus and parahippocampal regions were particularly resistant compared to other regions of cortex [26]. It References 1. Eichenbaum H, Cohen NJ: From conditioning to conscious recollection: would, therefore, strain credibility to argue that the effects Memory systems of the brain Oxford University Press; 2001. of intravenous midazolam on the hippocampus account 2. Squire LR: Memory and the hippocampus: A synthesis from for its amnesic effects but simply do not reach significance findings with rats, monkeys, and humans. Psych Rev 1992, 99:195-231. when measured by rCBF. 3. Chun MM, Phelps EA: Memory deficits for implicit contextual information in amnesic subjects with hippocampal damage. Nat Neurosci 1999, 2:844-847. Furthermore, were it the case that midazolam selectively 4. Harrison LM, Duggins A, Friston KJ: Encoding uncertainty in the deactivates the hippocampus, one would expect the hippocampus. Neural Netw 2006, 19:535-546. effects of midazolam on TI [18] to yield performance lev- 5. Ryan JD, Althoff RR, Whitlow S, Cohen NJ: Amnesia is a deficit in relational memory. Psychol Sci 2000, 11:454-461. els comparable to those observed in amnesic patients, but 6. Greene AJ, Gross WL, Elsinger CLD, Rao SM: Hippocampal differ- quite the contrary, amnesics are profoundly impaired on entiation without recognition: an fMRI analysis of the con- the TI task [17]. It is unclear from amnesic performance textual cueing task. Learn Mem 2007, 14:548-553. Page 2 of 3 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:51 http://www.behavioralandbrainfunctions.com/content/3/1/51 7. Greene AJ: Human hippocampal-dependent tasks: Is aware- ness necessary or sufficient? Hippocampus 2007, 17:429-433. 8. Greene AJ, Gross WL, Elsinger C, Rao SM: An fMRI analysis of the human hippocampus: Inference, context and task aware- ness. J Cogn Neurosci 2006, 18:1156-1173. 9. Greene AJ, Spellman BA, Dusek JA, Eichenbaum HB, Levy WB: Rela- tional learning with and without awareness: transitive infer- ence using nonverbal stimuli in humans. Mem Cognit 2001, 29:893-902. 10. Frank MJ, Rudy JW, Levy WB, O'Reilly RC: When logic fails: implicit transitive inference in humans. Mem Cognit 2005, 33:742-750. 11. Martin N, Alsop B: Transitive inference and awareness in humans. Behav Processes 2004, 67:157-165. 12. Moses SN, Villate C, Ryan JD: An investigation of learning strat- egy supporting transitive inference performance in humans compared to other species. Neuropsychologia 2006, 44:1370-1387. 13. Dusek JA, Eichenbaum H: The hippocampus and memory for orderly stimulus relations. Proc Natl Acad Sci U S A 1997, 94:7109-7114. 14. Nagode JC, Pardo JV: Human hippocampal activation during transitive inference. Neuroreport 2002, 13:939-944. 15. Preston AR, Shrager Y, Dudukovic NM, Gabrieli JD: Hippocampal contribution to the novel use of relational information in declarative memory. Hippocampus 2004, 14:148-152. 16. Heckers S, Zalesak M, Weiss AP, Ditman T, Titone D: Hippocampal activation during transitive inference in humans. Hippocampus 2004, 14:153-162. 17. Smith CN, Squire LR: Declarative memory, awareness, and transitive inference. J Neurosci 2005, 25:10138-10146. 18. Frank MJ, O'Reilly RC, Curran T: When memory fails, intuition reigns: midazolam enhances implicit inference in humans. Psychol Sci 2006, 17:700-707. 19. Kristiansen U, Lambert JD: Benzodiazepine and barbiturate lig- ands modulate responses of cultured hippocampal neurones to the GABAA receptor partial agonist, 4-PIOL. Neurophar- macol 1996, 35:1181-1191. 20. Montpied P, Martin BM, Cottingham SL, Stubblefield BK, Ginns EI, Paul SM: Regional distribution of the GABAA/benzodiazepine receptor (alpha subunit) mRNA in rat brain. J Neurochem 1988, 51:1651-1654. 21. Polster MR, Gray PA, O'Sullivan G, McCarthy RA, Park GR: Com- parison of the sedative and amnesic effects of midazolam and propofol. Br J Anaesth 1993, 70:612-616. 22. Gafford GM, Parsons RG, Helmstetter FJ: Effects of post-training hippocampal injections of midazolam on fear conditioning. Learn Mem 2005, 12:573-578. 23. Veselis RA, Reinsel RA, Beattie BJ, Mawlawi OR, Feshchenko VA, DiResta GR, Larson SM, Blasberg RG: Midazolam changes cere- bral blood flow in discrete brain regions: an H2(15)O posi- tron emission tomography study. Anesthesiology 1997, 87:1106-1117. 24. Bagary M, Fluck E, File SE, Joyce E, Lockwood G, Grasby P: Is benzo- diazepine-induced amnesia due to deactivation of the left prefrontal cortex? Psychopharmacology (Berl) 2000, 150:292-299. 25. Schaefer M, Heinze HJ, Rotte M: Verbal memory encoding in patients with left-sided hippocampal sclerosis. Neuroreport 2006, 17:1219-1223. 26. Reinsel RA, Veselis RA, Dnistrian AM, Feshchenko VA, Beattie BJ, Duff MR: Midazolam decreases cerebral blood flow in the left Publish with Bio Med Central and every prefrontal cortex in a dose-dependent fashion. Int J Neuropsy- scientist can read your work free of charge chopharmacol 2000, 3:117-127. 27. Hirshman E, Passannante A, Henzler A: The effect of midazolam "BioMed Central will be the most significant development for on implicit memory tests. Brain Cogn 1999, 41:351-364. disseminating the results of biomedical researc h in our lifetime." 28. Hirshman E, Passanante A, Arndt J: The effect of midazolam on Sir Paul Nurse, Cancer Research UK the modality-match effect in implicit memory. Brain Res Cogn Brain Res 1999, 7:473-479. Your research papers will be: available free of charge to the entire biomedical community peer reviewed and published immediately upon acceptance cited in PubMed and archived on PubMed Central yours — you keep the copyright BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 3 of 3 (page number not for citation purposes) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Behavioral and Brain Functions Springer Journals

Implicit transitive inference and the human hippocampus: does intravenous midazolam function as a reversible hippocampal lesion?

Greene, Anthony
Behavioral and Brain Functions , Volume 3 (1) – Sep 24, 2007
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Springer Journals
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Copyright © 2007 by Greene; licensee BioMed Central Ltd.
Subject
Biomedicine; Neurosciences; Neurology; Behavioral Therapy; Psychiatry
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1744-9081
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10.1186/1744-9081-3-51
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Abstract

Recent advances have led to an understanding that the hippocampus is involved more broadly than explicit or declarative memory alone. Tasks which involve the acquisition of complex associations involve the hippocampus whether the learning is explicit or implicit. One hippocampal-dependent implicit task is transitive inference (TI). Recently it was suggested that implicit transitive inference does not depend upon the hippocampus (Frank, M. J., O'Reilly, R. C., & Curran, T. 2006. When memory fails, intuition reigns: midazolam enhances implicit inference in humans. Psychological Science, 17, 700–707). The authors demonstrated that intravenous midazolam, which is thought to inactivate the hippocampus, may enhance TI performance. Three critical assumptions are required but not met: 1) that deactivations of other regions could not account for the effect 2) that intravenous midazolam does indeed deactivate the hippocampus and 3) that midazolam influences explicit but not implicit memory. Each of these assumptions is seriously flawed. Consequently, the suggestion that implicit TI does not depend upon the hippocampus is unfounded. amnesic patients with damage to the hippocampus and Introduction The capacity to learn complex stimulus relations and surrounding tissue cannot perform the TI task [17]. express them flexibly is thought to require the hippocam- pus [1]. While the hippocampus has been thought to be A recent study demonstrated that the administration of necessary for explicit but not implicit forms of learning intravenous midazolam improved TI performance in and memory [2], more recent studies demonstrate hip- human participants [18] which was argued as evidence pocampal involvement in implicit tasks which require that TI is performed more easily when the hippocampus complex associations [3-8]. One task which involves both does not contribute explicit strategies. The authors argue the acquisition of complex relations, flexible expression that midazolam deactivates the hippocampus because and which may be learned implicitly is the transitive infer- benzodiazepines act on GABA-A receptors [19], which are ence task [8-13]. At study, participants learn complex rela- densely concentrated in the hippocampus [20], and tions among stimuli (e.g., A>B, B>C, C>D, D>E) and at because benzodiazepines – in particular midazolam – test, they show flexible expression when an untrained dis- temporarily impair explicit memory formation [21]. The crimination (B?D) is correctly solved (B>D). Functional assertion that intravenous midazolam improves TI per- imaging studies confirm the role of the hippocampus in formance by deactivating the hippocampus depends both implicit and explicit versions of TI [8,14-16] and, entirely upon three premises: 1) that other areas critical to TI are not affected, so that only hippocampal deactivation Page 1 of 3 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:51 http://www.behavioralandbrainfunctions.com/content/3/1/51 can explain the effect; 2) that midazolam deactivates the whether their inability to perform the inference portion of hippocampus to the point that it no longer functions in a the task was predicated by their inability to acquire the mnemonic capacity; and 3) That midazolam influences premise pairs [17]. That is, amnesics do not reliably learn explicit but not implicit memory. There are serious prob- that B>C and C>D and that alone could account for their lems with all three premises, each of which jeopardize the inability to make the correct inference B>D. While the claim that TI is performed more easily without the hip- amnesic data do not therefore allow strong conclusions pocampus [18]. about performance on just the inference portion of the task, they do tend to disconfirm the hypothesis that "midazolam should improve TI test performance by pre- Discussion In studies where midazolam has been shown to have venting participants from memorizing the stimulus pairs selective effects on the hippocampus, non-human ani- and encouraging greater implicit learning of reinforce- mals receive midazolam as a direct injection into the hip- ment value" [[18] p. 701]. Furthermore, performance dif- pocampal tissue [22]. The principle action of midazolam ferences between hippocampal amnesia and midazolam- is as a central nervous-system depressant, which is fre- induced amnesia provide further evidence that the effects quently used medicinally as a sedative or as an anti-con- of intravenous midazolam are unlikely to constitute a hip- vulsant. While midazolam may be useful as a reversible pocampal deactivation. lesion when injected directly into the hippocampus, it is not at all clear that the effects are comparable when it is Given the widespread effects of intravenous midazolam in injected intravenously. One might expect the action of regions of cortex other than the hippocampus, it is natural midazolam to be much less circumscribed when it is dis- to question whether the effects of midazolam are limited tributed globally. Indeed, midazolam has been shown to to explicit memory. Several studies show that midazolam decrease regional cerebral blood flow (rCBF) to numerous influences not just explicit, but also implicit memory per- cortical areas other than the hippocampus or surrounding formance [27,28]. While implicit memory is not as pro- cortices [23]. Thus, it is entirely possible that the effects of foundly affected as explicit memory – indeed, explicit midazolam on the TI task are attributable to deactivations performance drops to chance levels – it is nevertheless of areas other than the hippocampus. incorrect to assert that intravenous midazolam does not affect implicit performance. Of the regions shown in human imaging studies to be deactivated by normal concentrations of intravenous Conclusion midazolam, the hippocampus is not among them. Two The existing data do not permit claims about selective studies attempting to discover an effect of midazolam on effects if intravenous midazolam on the human hippoc- rCBF in the hippocampus found no such effects [23,24]. ampus. Rather, the effects of intravenous midazolam Clearly, failure to detect an effect of midazolam on the involve numerous regions of cortex, including frontal and rCBF of the hippocampus does not imply the effects do parietal regions. The assertion that intravenous mida- not exist. However, given a compromised hippocampus zolam selectively deactivates the hippocampus is at best can still mediate hippocampal-dependent tasks [25] the premature and is more likely to be incorrect. Therefore, burden of proof must be upon those who claim that intra- there is no adequate substantiation for the claim that TI is venous midazolam anesthetizes the hippocampus to the improved by hippocampal deactivation [18]. extent that it does not function effectively in a mnemonic capacity. Moreover, a third study varied the concentration Competing interests of intravenous midazolam and showed a global anesthe- The author(s) declare that they have no competing inter- tizing effect at very high dosages to which the hippocam- ests. pus and parahippocampal regions were particularly resistant compared to other regions of cortex [26]. It References 1. Eichenbaum H, Cohen NJ: From conditioning to conscious recollection: would, therefore, strain credibility to argue that the effects Memory systems of the brain Oxford University Press; 2001. of intravenous midazolam on the hippocampus account 2. Squire LR: Memory and the hippocampus: A synthesis from for its amnesic effects but simply do not reach significance findings with rats, monkeys, and humans. Psych Rev 1992, 99:195-231. when measured by rCBF. 3. Chun MM, Phelps EA: Memory deficits for implicit contextual information in amnesic subjects with hippocampal damage. Nat Neurosci 1999, 2:844-847. Furthermore, were it the case that midazolam selectively 4. Harrison LM, Duggins A, Friston KJ: Encoding uncertainty in the deactivates the hippocampus, one would expect the hippocampus. Neural Netw 2006, 19:535-546. effects of midazolam on TI [18] to yield performance lev- 5. Ryan JD, Althoff RR, Whitlow S, Cohen NJ: Amnesia is a deficit in relational memory. Psychol Sci 2000, 11:454-461. els comparable to those observed in amnesic patients, but 6. Greene AJ, Gross WL, Elsinger CLD, Rao SM: Hippocampal differ- quite the contrary, amnesics are profoundly impaired on entiation without recognition: an fMRI analysis of the con- the TI task [17]. It is unclear from amnesic performance textual cueing task. Learn Mem 2007, 14:548-553. Page 2 of 3 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:51 http://www.behavioralandbrainfunctions.com/content/3/1/51 7. Greene AJ: Human hippocampal-dependent tasks: Is aware- ness necessary or sufficient? Hippocampus 2007, 17:429-433. 8. Greene AJ, Gross WL, Elsinger C, Rao SM: An fMRI analysis of the human hippocampus: Inference, context and task aware- ness. J Cogn Neurosci 2006, 18:1156-1173. 9. Greene AJ, Spellman BA, Dusek JA, Eichenbaum HB, Levy WB: Rela- tional learning with and without awareness: transitive infer- ence using nonverbal stimuli in humans. Mem Cognit 2001, 29:893-902. 10. Frank MJ, Rudy JW, Levy WB, O'Reilly RC: When logic fails: implicit transitive inference in humans. Mem Cognit 2005, 33:742-750. 11. Martin N, Alsop B: Transitive inference and awareness in humans. Behav Processes 2004, 67:157-165. 12. Moses SN, Villate C, Ryan JD: An investigation of learning strat- egy supporting transitive inference performance in humans compared to other species. Neuropsychologia 2006, 44:1370-1387. 13. Dusek JA, Eichenbaum H: The hippocampus and memory for orderly stimulus relations. Proc Natl Acad Sci U S A 1997, 94:7109-7114. 14. Nagode JC, Pardo JV: Human hippocampal activation during transitive inference. Neuroreport 2002, 13:939-944. 15. Preston AR, Shrager Y, Dudukovic NM, Gabrieli JD: Hippocampal contribution to the novel use of relational information in declarative memory. Hippocampus 2004, 14:148-152. 16. Heckers S, Zalesak M, Weiss AP, Ditman T, Titone D: Hippocampal activation during transitive inference in humans. Hippocampus 2004, 14:153-162. 17. Smith CN, Squire LR: Declarative memory, awareness, and transitive inference. J Neurosci 2005, 25:10138-10146. 18. Frank MJ, O'Reilly RC, Curran T: When memory fails, intuition reigns: midazolam enhances implicit inference in humans. Psychol Sci 2006, 17:700-707. 19. Kristiansen U, Lambert JD: Benzodiazepine and barbiturate lig- ands modulate responses of cultured hippocampal neurones to the GABAA receptor partial agonist, 4-PIOL. Neurophar- macol 1996, 35:1181-1191. 20. Montpied P, Martin BM, Cottingham SL, Stubblefield BK, Ginns EI, Paul SM: Regional distribution of the GABAA/benzodiazepine receptor (alpha subunit) mRNA in rat brain. J Neurochem 1988, 51:1651-1654. 21. Polster MR, Gray PA, O'Sullivan G, McCarthy RA, Park GR: Com- parison of the sedative and amnesic effects of midazolam and propofol. Br J Anaesth 1993, 70:612-616. 22. Gafford GM, Parsons RG, Helmstetter FJ: Effects of post-training hippocampal injections of midazolam on fear conditioning. Learn Mem 2005, 12:573-578. 23. Veselis RA, Reinsel RA, Beattie BJ, Mawlawi OR, Feshchenko VA, DiResta GR, Larson SM, Blasberg RG: Midazolam changes cere- bral blood flow in discrete brain regions: an H2(15)O posi- tron emission tomography study. Anesthesiology 1997, 87:1106-1117. 24. Bagary M, Fluck E, File SE, Joyce E, Lockwood G, Grasby P: Is benzo- diazepine-induced amnesia due to deactivation of the left prefrontal cortex? Psychopharmacology (Berl) 2000, 150:292-299. 25. Schaefer M, Heinze HJ, Rotte M: Verbal memory encoding in patients with left-sided hippocampal sclerosis. Neuroreport 2006, 17:1219-1223. 26. Reinsel RA, Veselis RA, Dnistrian AM, Feshchenko VA, Beattie BJ, Duff MR: Midazolam decreases cerebral blood flow in the left Publish with Bio Med Central and every prefrontal cortex in a dose-dependent fashion. Int J Neuropsy- scientist can read your work free of charge chopharmacol 2000, 3:117-127. 27. Hirshman E, Passannante A, Henzler A: The effect of midazolam "BioMed Central will be the most significant development for on implicit memory tests. Brain Cogn 1999, 41:351-364. disseminating the results of biomedical researc h in our lifetime." 28. Hirshman E, Passanante A, Arndt J: The effect of midazolam on Sir Paul Nurse, Cancer Research UK the modality-match effect in implicit memory. Brain Res Cogn Brain Res 1999, 7:473-479. Your research papers will be: available free of charge to the entire biomedical community peer reviewed and published immediately upon acceptance cited in PubMed and archived on PubMed Central yours — you keep the copyright BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 3 of 3 (page number not for citation purposes)

Journal

Behavioral and Brain Functions – Springer Journals

Published: Sep 24, 2007

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