A functional neuroanatomy of hallucinations in schizophrenia

Silbersweig, David; Stern, Emily; Frith, C. D.; Cahill, Connie; Holmes, Andrew P.; Grootoonk, S.; Seaward, James R.; McKenna, Peter; Chua, Se; Schnorr, L.; Jones, Terry; Frackowiak, R. S. J.

doi:10.1038/378176a0

Cited by 851 publications

(451 citation statements)

References 24 publications

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“…The advantage of clozapine over a firstgeneration antipsychotic medication was also found in partially responsive, community-based, schizophrenic patients (Kane et al, 2001;Buchanan et al, 1998;Breier et al, 1994). There is now convincing evidence that the ACC is involved in a distributed neural network that mediates psychosis (Cleghorn et al, 1992;Silbersweig et al, 1995;Szechtman et al, 1998;Shergill et al, 2000). rCBF in ACC significantly correlates with psychosis levels in unmedicated SV Lee et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Clozapine but not Haloperidol Re-establishes Normal Task-Activated rCBF Patterns in Schizophrenia within the Anterior Cingulate Cortex

Lahti

Holcomb

Weiler

et al. 2003

Neuropsychopharmacol

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Our previous work has identified that unmedicated volunteers with schizophrenia have regional cerebral blood flow (rCBF) activation patterns inappropriately related to the cognitive demand of a task in anterior cingulate cortex (ACC). Using positron emission tomography (PET) with 15 O water, we compared task-induced rCBF patterns induced by haloperidol or clozapine in individuals with schizophrenia. We hypothesized that clozapine, given its superior clinical action, would tend to normalize the abnormal task-activated response in ACC more than haloperidol. Schizophrenia volunteers (SVs) (n ¼ 6) and normal volunteers (NVs) (n ¼ 12) were trained to perform a tone discrimination task with 70-80% accuracy. They were then scanned during three task conditions: (1) Rest, (2) sensory motor control (SMC) task, and (3) decision task (DEC). SVs were initially scanned after withdrawal of all psychotropic medication and again after treatment with therapeutic doses of haloperidol (n ¼ 5) and/or clozapine (n ¼ 5). rCBF values, sampled in the grown maxima of the task-activated ACC cluster, were analyzed between groups and task conditions. Task performance was similar across the unmedicated, haloperidol-and clozapine-medicated SV groups. There was a reduction in accuracy in the haloperidol SV group compared to the NVs. Group and task conditions affected rCBF in the ACC. Clozapine, but not haloperidol, reversed the abnormal ACC rCBF pattern in unmedicated SV to normal. The clozapine-treated SV group showed a rCBF pattern similar to the NV group in that ACC activation was not observed during the control task but occurred during the decision condition. The pattern seen in the haloperidoltreated SV group was similar to the unmedicated SV group in that ACC activation was seen during the control task and no further activation was seen during the DEC. We report that clozapine, but not haloperidol, normalizes anterior cingulate rCBF patterns in schizophrenia during a cognitive task. Based on these preliminary data, we propose that this pattern may account for the superior therapeutic effect of clozapine and represents a surrogate marker of this action.

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Section: Discussionmentioning

confidence: 99%

Clozapine but not Haloperidol Re-establishes Normal Task-Activated rCBF Patterns in Schizophrenia within the Anterior Cingulate Cortex

Lahti

Holcomb

Weiler

et al. 2003

Neuropsychopharmacol

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“…Thus, these excitatory alterations could be used to delineate the neuronal circuits that, when functioning abnormally, produce psychotic behavior. Because of the important role of the EC in the processing of sensory input (Jones 1993) and disturbances in the neuronal organization and activity repeatedly observed in the EC neurons in schizophrenic brains (Falkai et al 1988;Arnold et al 1991;Bogerts 1993;Jakob and Beckmann 1994;Silbersweig et al 1995), caudal EC is a strong candidate for the brain area that is affected in schizophrenia. The relatively large number of affected neurons in the cEC and the wealth of information concerning the connectivity and physiology of the entorhinal-hippocampal system render this brain area a good candidate for a model system.…”

Section: Discussionmentioning

confidence: 99%

“…This suggests that these brain areas may constitute a neuronal circuit, which responds by excitation to the administration of NMDA-receptor antagonists. It is also interesting to note that brain areas which are activated in schizophrenic patients experiencing hallucinations includes parahippocampal gyrus (which mostly consists of entorhinal cortex) and cingulate cortex, areas where MK-801 induce c-fos expression (Silbersweig et al 1995). PET method used for these human studies do not, however, allow a cellular or even layer-specific identification of the affected cells.…”

Section: Discussionmentioning

confidence: 99%

“…CT scans of brains of schizophrenic patients have consistently demonstrated loss of gray matter in parahippocampal gyrus (Roberts 1990). Furthermore, a recent study where schizophrenic patients were scanned in PET scan while they experienced hallucinations found increased neuronal activity in the entorhinal cortex associated with hallucinations (Silbersweig et al 1995). Unfortunately, the spatial resolution of imaging studies is not high enough to localize the neuronal population that is the source of aberrant activity and it is very difficult to identify the normal identity of the disturbed neurons in post-mortem morphological studies.…”

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confidence: 99%

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Excitatory Actions of NMDA Receptor Antagonists in Rat Entorhinal Cortex and Cultured Entorhinal Cortical Neurons

Väisänen

Lindén

Lakso

et al. 1999

Neuropsychopharmacology

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We have characterized excitatory effects of non-competitive NMDA receptor antagonists MK-801, PCP, and ketamine in the rat entorhinal cortex and in cultured primary entorhinal cortical neurons using expression of immediate early gene c-fos as an indicator. NMDA receptor antagonists produced a strong and dose-dependent increase in c-fos mRNA and protein expression confined to neurons in the layer III of the caudal entorhinal cortex. Induction of c-fos mRNA is delayed and it is inhibited by antipsychotic drugs. Cultured entorhinal neurons are killed by high doses of MK-801 and PCP but c-fos expression is not induced in these neurons indicating that this in vitro model does not fully replicate the in vivo effects of PCP-like drugs in the entorhinal cortex. Excitatory effects of the NMDA receptor antagonists may be connected with the psychotropic side effects of these drugs and might become a useful modelNMDA receptor antagonists, such as phencyclidine, ketamine, and MK-801 (dizocilpine) produce in humans psychotogenic side effects which clinically closely resemble schizophrenia and are characterized by distorted body image, hallucinations, vivid dreams, and delirium (Johnson and Jones 1990;Javitt and Zukin 1991). Ketamine also frequently induces psychotic "emergence reactions" in adults (Krystal et al. 1994). Because of these parallels between the psychotomimetic state produced by the NMDA receptor antagonists and schizophrenia, PCP-induced psychosis has widely been used as an experimental model of schizophrenia (Javitt and Zukin 1991).In a series of pioneering studies, Olney and coworkers demonstrated that NMDA receptor antagonists produce reversible neurotoxic effects in neurons in the posterior cingulate and retrosplenial cortices (RSC) of rat brain (Olney et al. 1989(Olney et al. , 1991 Farber 1995a, 1995b). These effects are characterized by reversible intracellular vacuolization (Olney et al. 1989) and induction of mRNAs for c-fos (Dragunow and Faull 1990;Hughes et al. 1993;Näkki et al. 1996), heat shock protein 70 (HSP70) (Sharp et al. 1991(Sharp et al. , 1994Näkki et al. 1995), and brain-derived neurotrophic factor (BDNF) Hughes et al. 1993). Induction of cfos and BDNF is typically observed in activated neurons and we therefore tentatively call these effects "ex- citatory" to distinguish them from the prevention of excitation, which is the typical effect of NMDA receptor antagonists in other brain areas. These excitatory actions may be connected with the psychotomimetic side effects produced by PCP-like drugs Farber 1995a, 1995b). We have previously observed that MK-801 increases mRNA for BDNF not only in the retrosplenial cortex but also in the entorhinal cortex (EC) . EC is the input and output station of the information going to and coming from the hippocampus (Jones 1993;Amaral and Witter 1995). It is thought that the EC-hippocampus loop is very important in the processing of sensory information and defects in its normal function might produce cognitive disturbances (Jones 1993). Therefore, neurons i...

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“…The nervous system in these patients behaves as if it were actually processing the speech of an external speaker. Hence their perception of their own thinking as originating from the outside world (Silbersweig et al, 1995;McGuire et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Looking for the agent: an investigation into consciousness of action and self-consciousness in schizophrenic patients

et al. 1997

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Looking for the agent: an investigation into consciousness of action and self-consciousness in schizophrenic patients. Cognition, Elsevier, 1997, 65, pp.71-86. Looking for the agent: an investigation into consciousness of action and self-consciousness in schizophrenic patients AbstractThe abilities to attribute an action to its proper agent and to understand its meaning when it is produced by someone else are basic aspects of human social communication. Several psychiatric syndromes, such as schizophrenia, seem to lead to a dysfunction of the awareness of one's own action as well as of recognition of actions performed by others. Such syndromes offer a framework for studying the determinants of agency, the ability to correctly attribute actions to their veridical source. Thirty normal subjects and 30 schizophrenic patients with and without hallucinations and/or delusional experiences were required to execute simple finger and wrist movements, without direct visual control of their hand. The image of either their own hand or an alien hand executing the same or a different movement was presented on a TV-screen in real time. The task for the subjects was to discriminate whether the hand presented on the screen was their own or not. Hallucinating and deluded schizophrenic patients were more impaired in discriminating their own hand from the alien one than the non-hallucinating ones, and tended to misattribute the alien hand to themselves. Results are discussed according to a model of action control. A tentative description of the mechanisms leading to action consciousness is proposed.

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A functional neuroanatomy of hallucinations in schizophrenia

Cited by 851 publications

References 24 publications

Clozapine but not Haloperidol Re-establishes Normal Task-Activated rCBF Patterns in Schizophrenia within the Anterior Cingulate Cortex

Clozapine but not Haloperidol Re-establishes Normal Task-Activated rCBF Patterns in Schizophrenia within the Anterior Cingulate Cortex

Excitatory Actions of NMDA Receptor Antagonists in Rat Entorhinal Cortex and Cultured Entorhinal Cortical Neurons

Looking for the agent: an investigation into consciousness of action and self-consciousness in schizophrenic patients

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