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Vol. 87, No. 4, 2009
Issue release date: August 2009
Free Access
Stereotact Funct Neurosurg 2009;87:256–265
(DOI:10.1159/000225979)

The Hippocampus and Nucleus Accumbens as Potential Therapeutic Targets for Neurosurgical Intervention in Schizophrenia

Mikell C.B. · McKhann G.M. · Segal S. · McGovern R.A. · Wallenstein M.B. · Moore H.
Department of Neurological Surgery, Columbia University, New York, N.Y., USA
email Corresponding Author

Abstract

Schizophrenia is a chronic and disabling psychiatric illness that is often refractory to treatment. Psychotic symptoms (e.g. hallucinations and delusions) in schizophrenia are reliably correlated with excess dopamine levels in the striatum, and have more recently been related to excess metabolic activity in the hippocampus. Multiple lines of evidence suggest that aberrantly high hippocampal activity may, via hippocampal connections with the limbic basal ganglia, drive excessive dopamine release into the striatum. In the present paper, we hypothesize that inhibition or stabilization of neural activity with high-frequency electrical stimulation of the hippocampus or nucleus accumbens, through different mechanisms, would treat the positive symptoms of schizophrenia. Thus, we suggest a direction for further experimentation aimed at developing neurosurgical therapeutic approaches for this devastating disease.


 goto top of outline Key Words

  • Deep brain stimulation
  • Schizophrenia
  • Neurostimulation
  • Hippocampus
  • Nucleus accumbens
  • Dopamine
  • Psychosis

 goto top of outline Abstract

Schizophrenia is a chronic and disabling psychiatric illness that is often refractory to treatment. Psychotic symptoms (e.g. hallucinations and delusions) in schizophrenia are reliably correlated with excess dopamine levels in the striatum, and have more recently been related to excess metabolic activity in the hippocampus. Multiple lines of evidence suggest that aberrantly high hippocampal activity may, via hippocampal connections with the limbic basal ganglia, drive excessive dopamine release into the striatum. In the present paper, we hypothesize that inhibition or stabilization of neural activity with high-frequency electrical stimulation of the hippocampus or nucleus accumbens, through different mechanisms, would treat the positive symptoms of schizophrenia. Thus, we suggest a direction for further experimentation aimed at developing neurosurgical therapeutic approaches for this devastating disease.

Copyright © 2009 S. Karger AG, Basel


 goto top of outline References
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  2. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Text Revision. Washington, American Psychiatric Association, 1994, p 298.
  3. Carlsson A, Lindqvist M: Effect of chlorpromazine or haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol (Copenh) 1963;20:140–144.
  4. Laruelle M, Frankle WG, Narendran R, Kegeles LS, Abi-Dargham A: Mechanism of action of antipsychotic drugs: from dopamine D(2) receptor antagonism to glutamate NMDA facilitation. Clin Ther 2005;27(suppl A):S16–S24.
  5. Gray JA, Roth BL: The pipeline and future of drug development in schizophrenia. Mol Psychiatry 2007;12:904–922.
  6. Tandon R, Carpenter WT, Davis JM: First- and second-generation antipsychotics: learning from CUtLASS and CATIE. Arch Gen Psychiatry 2007;64:977–978.
  7. Kapur S, Remington G: Atypical antipsychotics: new directions and new challenges in the treatment of schizophrenia. Annu Rev Med 2001;52:503–517.
  8. Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, D’Souza CD, Erdos J, McCance E, Rosenblatt W, Fingado C, Zoghbi SS, Baldwin RM, Seibyl JP, Krystal JH, Charney DS, Innis RB: Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci USA 1996;93:9235–9240.
  9. Abi-Dargham A, Gil R, Krystal J, Baldwin RM, Seibyl JP, Bowers M, van Dyck CH, Charney DS, Innis RB, Laruelle M: Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry 1998;155:761–767.
  10. Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS, Weiss R, Cooper TB, Mann JJ, Van Heertum RL, Gorman JM, Laruelle M: Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci USA 2000;97:8104–8109.
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 goto top of outline Author Contacts

Holly Moore, PhD
Columbia University, Department of Psychiatry
1051 Riverside Dr., Mail Unit 14
New York, NY 10032 (USA)
Tel. +1 212 543 6938, Fax +1 212 543 1017, E-Mail hm2035@columbia.edu


 goto top of outline Article Information

Published online: June 26, 2009
Number of Print Pages : 10
Number of Figures : 2, Number of Tables : 0, Number of References : 84


 goto top of outline Publication Details

Stereotactic and Functional Neurosurgery

Vol. 87, No. 4, Year 2009 (Cover Date: August 2009)

Journal Editor: Roberts D.W. (Lebanon, N.H.)
ISSN: 1011-6125 (Print), eISSN: 1423-0372 (Online)

For additional information: http://www.karger.com/SFN


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Schizophrenia is a chronic and disabling psychiatric illness that is often refractory to treatment. Psychotic symptoms (e.g. hallucinations and delusions) in schizophrenia are reliably correlated with excess dopamine levels in the striatum, and have more recently been related to excess metabolic activity in the hippocampus. Multiple lines of evidence suggest that aberrantly high hippocampal activity may, via hippocampal connections with the limbic basal ganglia, drive excessive dopamine release into the striatum. In the present paper, we hypothesize that inhibition or stabilization of neural activity with high-frequency electrical stimulation of the hippocampus or nucleus accumbens, through different mechanisms, would treat the positive symptoms of schizophrenia. Thus, we suggest a direction for further experimentation aimed at developing neurosurgical therapeutic approaches for this devastating disease.



 goto top of outline Author Contacts

Holly Moore, PhD
Columbia University, Department of Psychiatry
1051 Riverside Dr., Mail Unit 14
New York, NY 10032 (USA)
Tel. +1 212 543 6938, Fax +1 212 543 1017, E-Mail hm2035@columbia.edu


 goto top of outline Article Information

Published online: June 26, 2009
Number of Print Pages : 10
Number of Figures : 2, Number of Tables : 0, Number of References : 84


 goto top of outline Publication Details

Stereotactic and Functional Neurosurgery

Vol. 87, No. 4, Year 2009 (Cover Date: August 2009)

Journal Editor: Roberts D.W. (Lebanon, N.H.)
ISSN: 1011-6125 (Print), eISSN: 1423-0372 (Online)

For additional information: http://www.karger.com/SFN


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Tandon R, Keshavan MS, Nasrallah HA: Schizophrenia, ‘just the facts’ what we know in 2008. 2. Epidemiology and etiology. Schizophr Res 2008;102:1–18.
  2. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Text Revision. Washington, American Psychiatric Association, 1994, p 298.
  3. Carlsson A, Lindqvist M: Effect of chlorpromazine or haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol (Copenh) 1963;20:140–144.
  4. Laruelle M, Frankle WG, Narendran R, Kegeles LS, Abi-Dargham A: Mechanism of action of antipsychotic drugs: from dopamine D(2) receptor antagonism to glutamate NMDA facilitation. Clin Ther 2005;27(suppl A):S16–S24.
  5. Gray JA, Roth BL: The pipeline and future of drug development in schizophrenia. Mol Psychiatry 2007;12:904–922.
  6. Tandon R, Carpenter WT, Davis JM: First- and second-generation antipsychotics: learning from CUtLASS and CATIE. Arch Gen Psychiatry 2007;64:977–978.
  7. Kapur S, Remington G: Atypical antipsychotics: new directions and new challenges in the treatment of schizophrenia. Annu Rev Med 2001;52:503–517.
  8. Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, D’Souza CD, Erdos J, McCance E, Rosenblatt W, Fingado C, Zoghbi SS, Baldwin RM, Seibyl JP, Krystal JH, Charney DS, Innis RB: Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci USA 1996;93:9235–9240.
  9. Abi-Dargham A, Gil R, Krystal J, Baldwin RM, Seibyl JP, Bowers M, van Dyck CH, Charney DS, Innis RB, Laruelle M: Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry 1998;155:761–767.
  10. Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS, Weiss R, Cooper TB, Mann JJ, Van Heertum RL, Gorman JM, Laruelle M: Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci USA 2000;97:8104–8109.
  11. Frankle WG, Gil R, Hackett E, Mawlawi O, Zea-Ponce Y, Zhu Z, Kochan LD, Cangiano C, Slifstein M, Gorman JM, Laruelle M, Abi-Dargham A: Occupancy of dopamine D2 receptors by the atypical antipsychotic drugs risperidone and olanzapine: theoretical implications. Psychopharmacology (Berl) 2004;175:473–480.
  12. Kegeles LS, Slifstein M, Frankle WG, Xu X, Hackett E, Bae SA, Gonzales R, Kim JH, Alvarez B, Gil R, Laruelle M, Abi-Dargham A: Dose-occupancy study of striatal and extrastriatal dopamine D2 receptors by aripiprazole in schizophrenia with PET and [18F]fallypride. Neuropsychopharmacology 2008;33:3111–3125.
  13. Kapur S: Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry 2003;160:13–23.
  14. Grace AA, Bunney BS, Moore H, Todd CL: Dopamine-cell depolarization block as a model for the therapeutic actions of antipsychotic drugs. Trends Neurosci 1997;20:31–37.
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