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Hippocampal injury and chronic schizophrenia
Correspondence
BIOL PSYCHIATRY 1991;29:508-517
expressed as cortex/cerebellum ratio). Similar specific neurotransmitter challenge tests in combination with SPET might be productive techniques to investigate psychiatric disorders. David P. Geaney j Nigel Soper 2 Basil J. Shepstone 3 Guy M. Goodwin 4 Philip J. Cowen 5
tDepartment of Psychiatry Warneford Hospital, Oxford 2Radcliff Hospital, Oxford 3Department of Radiology, Oxford 4Royal Edinburgh Hospital, Edinburgh 5Littlemore Hospital, Oxford
Hippocampal Injury and Chronic Schizophrenia To the Editor: Dr. Luchins's (1990) interesting speculation about the possible role of hippocampal injury in the development of certain bizarre behaviors seen in patients with chronic schizophrenia complements the rapidly expanding literature about pathological findings in the hippccampus of patients with this illness. In his discussion, Dr. Luchins wonders how Iris "theory" compares with others, and flatters me by singling out a recent theoretical paper (Weinberger 1987). Because his comments may raise some misunderstandings about the thesis expounded in that paper, I feel a clarification is indicated. The primary thesis of that article had to do with the role of cerebral muturatlon in the pathogenesis of schizophrenia and the possibility that an early developmental condition might become clinically meaningful many years later because it affects the function of later maturing neural systems. The importance of the dorsolateral prefrontal cortex (DLPFC) was as an effector of this mechanism, not necessarily as a site of primary anatomic abnormality. In fact, the same article clearly states that the neuroahatomic defect is probably in the limbic system, that the mechanism of positive symptoms is related to dysfunction of the limbic system, and that the existence of the DLPFC dysfunction is related
509
References Cowen PJ (1987): Psychotmpic drugs and human 5-HT neuroendocrinology. Trends Pharmacol Sci 8:105-108. Geaney DP, Soper N, Shel~tone BI, Cowen PJ ( 1 ~ ) : Effect of central cholinergic stimulation on regional cerebral blood flow in Alz~imer disease. Lancet 335:14841487. Pazos A, Hoyer D, Dietl NLM, Pa}acios JM (1988~: Autoradiography of serotonin receptors. In Osborne NN, Hamon M (eds), Neuronal Serotonin. New York: Wiley, pp 507-543. Raichle ME, Grabb RL, Gado MH, Eichling JO: Ter-Pogossian MM (1976): Correlation between regional cerebral blood flow and oxidative metabolism: in vivo stuches i~ man. Arch Neurot 33:523-526.
to connectivity of the DLPFC and not to an intrinsic neuroanatomic defect. We have consistently interpreted our research dam about DLPFC dysfunction in schizophrenia as being suggestive of a defect in functional connectivity, not of a primary lesion of DLPFC pA2e]nberger et al 1986, 1988; 5emian et al 1987: Weinberger 1988; Weinberger et al 1988). Fortunately, the brain does not function like the United Nations, with a group of loosely related regional entities competing for limited resources. The development of functional mapping techniques for studying ~uman and animal brains makes it clear that behavior involves the recruitment of specific neural networks. In particular, recent data in monkeys during working memory tasks, analogous to the Wisconsin Card Sorting Task that we have used in our rCBF studies, indicate that these tasks involve the recruitment of a network that includes the anterior hippocampus and the DLPFC (Friedman et al 1990). Dysfunction of this network, perhaps because of h/ppocampal damage in schizophrenia, could conceivably result in a prefrontal physiological abnormality similar to what we have reported. In fact, to the extent that hippocampal damage is related to cerebral ventricular enlargement (Suddath et al 1989), our data have supported this possibility,, and we have consistently interpreted them in these terms (Berman et ai 1987). The developmental factor is probably relevant to the function of this network because of the delayed
510
Correspondence
BIOL PSYCHIATRY 1991;2~.508-517
maturation of its executive component, namely, the DLPFC. Daniel R. Weinberger
Clinical Brain Disorders Branch, DIRP, NIMH, Neurosciences Center Saint Elizabeths Hospital Washington, DL 2C332
References Berman KF, Weinberger DR, Shelton RC, Zec RF (1987): A relationship between anatomical and physiological brain pathology in schizophrenia: Lateral cerebral ventricular size predicts cortical blood flow. Am J Psychiatry 144:1277-1282. Friedman HR, Janas JD, Goldman-Rakic PS (1990): Enhancement of metabolic activity in the diencephalon of monkeys performing working memory tasks: A 2-deoxyglucose study in behaving Rhesus monkeys, J Cogn Neurosci 2:18-31, 1990. Luchins DJ (1990): A possible role of hippocampal dysfunction in schizophrenic symptomatology. Biol Psychietr3" 28:87-9 I. Suddath RL, Casanova M, Gotdberg T. Daniel D, Kelsoe J, Weinberger DR (1089): Temporal lobe pathology in schizophrenia: A quantitative MRI study. Am J Psyct,; ,t" 146:464-472. Weinberge DR (!987~. Implications of normal brain developm0nt for the pathogenesis of schizophrenia. Arch Gen Ps chiatrv 44:660-669, Weinbe~e~ DR ( 1988): Schizophrenia and the frontal lobes. Trends :Veurosci 11:367-370. Weinberge '_~R, Berman KF. Zec RF ( i986): Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow (rCBF) evidence Arch Gen Psychiatry 43:i 14-125. Weinberger DR, Berman KF, lllowsky B (1988): Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia, lII. A new cohort and evidence for a monoaminergic mechanism.Arch Gen Psychiatry 45:609615.
Response To the Editor: Although it is not explicitly stated in his letter, Dr. Weinberger has written extensively on the nature of the dysfunctional "cox nectivity" of the dorsal lateral prefrontal cortex (DLPFC) he believes underlies schizophrenia. His group has interpreted its finding
o ~,decreased DLPFC regional blood flow in schizophrenics carrying out the Wisconsin Card Sorting Test (WCST) as evidence for dysfunction of mesocortical dopamine pathways to DLPFC (Weinberger et al 1986). I believe such findings can be more parsimoniously understood as secondary to a now welldocumented hippocampal lesion. An extensive body of animal work, elegantly summarized by Matthysse (1986), indicates that in animals hippocampal lesions interfere with the ability to "'shift hypothesis." in the same vein, Hermann et al (1988) have shown that individuals with temporal lobe epilepsy (which is frequently associated with hippocampal pathology) show decreased WCST performance compared to those with other forms of epilepsy or normals, and that these individual's performance improves after resection of the pathological temporal lobe. That the hippocampus is involved in "frontal" tasks similar to the WCST is supported by the monkey studies of Friedman et al (1990), discussed by Dr. Weinberger, showing increased anterior hippocampal and DLPFC cerebral blood flow while performing such tasks. The existence of two direct pathways from hippocampus to DLPFC (Goldman-Rakic et al 1984) would suggest that hippocampal influences on DLPFC need not ~ mediated through mesocortical dopamine pathways. I would argue that the failure to activate DLPFC in schizophrenics during the WCST is not due to dysfunction of either the DLPFC or its mesocortical dopaminergic connections, but reflects an inability to successfully carry out the task because of hippocampal dysfunction. Although the NIMH group (Goldberg et al 1987) has found schizophrenics unable to benefit from training on the WCST, published studies (Hashima et al 1987) and our own unpublisheJ data suggest many patients with schizophrenia (unlike those with frontal lesions) can improve with training. A potentially critical test of the role of DLPFC in schizophrenic would involve studying cerebral blood flow or metabolism in these schizophrenics before and after such training. If DLPFC activation increases in proportion to improved performance it would argue against DLPFC dysfunction underlying schizophrenia. If, on the other hand, the improved WCST r~erformance occurred in the absence of DLPFC activation it would support the importance of DLPFC dysfunction in schizophrenia. Daniel J. Luchins
BIOL PSYCHIATRY 1991;29:508-517
expressed as cortex/cerebellum ratio). Similar specific neurotransmitter challenge tests in combination with SPET might be productive techniques to investigate psychiatric disorders. David P. Geaney j Nigel Soper 2 Basil J. Shepstone 3 Guy M. Goodwin 4 Philip J. Cowen 5
tDepartment of Psychiatry Warneford Hospital, Oxford 2Radcliff Hospital, Oxford 3Department of Radiology, Oxford 4Royal Edinburgh Hospital, Edinburgh 5Littlemore Hospital, Oxford
Hippocampal Injury and Chronic Schizophrenia To the Editor: Dr. Luchins's (1990) interesting speculation about the possible role of hippocampal injury in the development of certain bizarre behaviors seen in patients with chronic schizophrenia complements the rapidly expanding literature about pathological findings in the hippccampus of patients with this illness. In his discussion, Dr. Luchins wonders how Iris "theory" compares with others, and flatters me by singling out a recent theoretical paper (Weinberger 1987). Because his comments may raise some misunderstandings about the thesis expounded in that paper, I feel a clarification is indicated. The primary thesis of that article had to do with the role of cerebral muturatlon in the pathogenesis of schizophrenia and the possibility that an early developmental condition might become clinically meaningful many years later because it affects the function of later maturing neural systems. The importance of the dorsolateral prefrontal cortex (DLPFC) was as an effector of this mechanism, not necessarily as a site of primary anatomic abnormality. In fact, the same article clearly states that the neuroahatomic defect is probably in the limbic system, that the mechanism of positive symptoms is related to dysfunction of the limbic system, and that the existence of the DLPFC dysfunction is related
509
References Cowen PJ (1987): Psychotmpic drugs and human 5-HT neuroendocrinology. Trends Pharmacol Sci 8:105-108. Geaney DP, Soper N, Shel~tone BI, Cowen PJ ( 1 ~ ) : Effect of central cholinergic stimulation on regional cerebral blood flow in Alz~imer disease. Lancet 335:14841487. Pazos A, Hoyer D, Dietl NLM, Pa}acios JM (1988~: Autoradiography of serotonin receptors. In Osborne NN, Hamon M (eds), Neuronal Serotonin. New York: Wiley, pp 507-543. Raichle ME, Grabb RL, Gado MH, Eichling JO: Ter-Pogossian MM (1976): Correlation between regional cerebral blood flow and oxidative metabolism: in vivo stuches i~ man. Arch Neurot 33:523-526.
to connectivity of the DLPFC and not to an intrinsic neuroanatomic defect. We have consistently interpreted our research dam about DLPFC dysfunction in schizophrenia as being suggestive of a defect in functional connectivity, not of a primary lesion of DLPFC pA2e]nberger et al 1986, 1988; 5emian et al 1987: Weinberger 1988; Weinberger et al 1988). Fortunately, the brain does not function like the United Nations, with a group of loosely related regional entities competing for limited resources. The development of functional mapping techniques for studying ~uman and animal brains makes it clear that behavior involves the recruitment of specific neural networks. In particular, recent data in monkeys during working memory tasks, analogous to the Wisconsin Card Sorting Task that we have used in our rCBF studies, indicate that these tasks involve the recruitment of a network that includes the anterior hippocampus and the DLPFC (Friedman et al 1990). Dysfunction of this network, perhaps because of h/ppocampal damage in schizophrenia, could conceivably result in a prefrontal physiological abnormality similar to what we have reported. In fact, to the extent that hippocampal damage is related to cerebral ventricular enlargement (Suddath et al 1989), our data have supported this possibility,, and we have consistently interpreted them in these terms (Berman et ai 1987). The developmental factor is probably relevant to the function of this network because of the delayed
510
Correspondence
BIOL PSYCHIATRY 1991;2~.508-517
maturation of its executive component, namely, the DLPFC. Daniel R. Weinberger
Clinical Brain Disorders Branch, DIRP, NIMH, Neurosciences Center Saint Elizabeths Hospital Washington, DL 2C332
References Berman KF, Weinberger DR, Shelton RC, Zec RF (1987): A relationship between anatomical and physiological brain pathology in schizophrenia: Lateral cerebral ventricular size predicts cortical blood flow. Am J Psychiatry 144:1277-1282. Friedman HR, Janas JD, Goldman-Rakic PS (1990): Enhancement of metabolic activity in the diencephalon of monkeys performing working memory tasks: A 2-deoxyglucose study in behaving Rhesus monkeys, J Cogn Neurosci 2:18-31, 1990. Luchins DJ (1990): A possible role of hippocampal dysfunction in schizophrenic symptomatology. Biol Psychietr3" 28:87-9 I. Suddath RL, Casanova M, Gotdberg T. Daniel D, Kelsoe J, Weinberger DR (1089): Temporal lobe pathology in schizophrenia: A quantitative MRI study. Am J Psyct,; ,t" 146:464-472. Weinberge DR (!987~. Implications of normal brain developm0nt for the pathogenesis of schizophrenia. Arch Gen Ps chiatrv 44:660-669, Weinbe~e~ DR ( 1988): Schizophrenia and the frontal lobes. Trends :Veurosci 11:367-370. Weinberge '_~R, Berman KF. Zec RF ( i986): Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow (rCBF) evidence Arch Gen Psychiatry 43:i 14-125. Weinberger DR, Berman KF, lllowsky B (1988): Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia, lII. A new cohort and evidence for a monoaminergic mechanism.Arch Gen Psychiatry 45:609615.
Response To the Editor: Although it is not explicitly stated in his letter, Dr. Weinberger has written extensively on the nature of the dysfunctional "cox nectivity" of the dorsal lateral prefrontal cortex (DLPFC) he believes underlies schizophrenia. His group has interpreted its finding
o ~,decreased DLPFC regional blood flow in schizophrenics carrying out the Wisconsin Card Sorting Test (WCST) as evidence for dysfunction of mesocortical dopamine pathways to DLPFC (Weinberger et al 1986). I believe such findings can be more parsimoniously understood as secondary to a now welldocumented hippocampal lesion. An extensive body of animal work, elegantly summarized by Matthysse (1986), indicates that in animals hippocampal lesions interfere with the ability to "'shift hypothesis." in the same vein, Hermann et al (1988) have shown that individuals with temporal lobe epilepsy (which is frequently associated with hippocampal pathology) show decreased WCST performance compared to those with other forms of epilepsy or normals, and that these individual's performance improves after resection of the pathological temporal lobe. That the hippocampus is involved in "frontal" tasks similar to the WCST is supported by the monkey studies of Friedman et al (1990), discussed by Dr. Weinberger, showing increased anterior hippocampal and DLPFC cerebral blood flow while performing such tasks. The existence of two direct pathways from hippocampus to DLPFC (Goldman-Rakic et al 1984) would suggest that hippocampal influences on DLPFC need not ~ mediated through mesocortical dopamine pathways. I would argue that the failure to activate DLPFC in schizophrenics during the WCST is not due to dysfunction of either the DLPFC or its mesocortical dopaminergic connections, but reflects an inability to successfully carry out the task because of hippocampal dysfunction. Although the NIMH group (Goldberg et al 1987) has found schizophrenics unable to benefit from training on the WCST, published studies (Hashima et al 1987) and our own unpublisheJ data suggest many patients with schizophrenia (unlike those with frontal lesions) can improve with training. A potentially critical test of the role of DLPFC in schizophrenic would involve studying cerebral blood flow or metabolism in these schizophrenics before and after such training. If DLPFC activation increases in proportion to improved performance it would argue against DLPFC dysfunction underlying schizophrenia. If, on the other hand, the improved WCST r~erformance occurred in the absence of DLPFC activation it would support the importance of DLPFC dysfunction in schizophrenia. Daniel J. Luchins