Youn T, Park HJ, Kim JJ, Kim MS, Kwon JS.
Altered hemispheric asymmetry and positive symptoms in schizophrenia: equivalent current dipole of auditory mismatch negativity.
Schizophr Res. 2003 Feb 1;59(2-3):253-60.
"The abnormality of mismatch negativity (MMN) in schizophrenia is thought to be associated with perceptional disturbance and cognitive dysfunction. The purpose of the present study was to investigate the change of the normal functional hemispheric lateralization in schizophrenia by employing the equivalent current dipole (ECD) model of auditory MMN with individual MRI and high-density electroencephalography (EEG). The MMNs resulting from auditory stimuli with passive oddball paradigm in a group of schizophrenics (n = 15), and also a group of age-, sex-, and handedness-matched normal controls, were recorded by 128 channel EEG. The location and power of ECD sources at the peak point were calculated. Individual 3-D brain magnetic resonance images (MRI) were used for realistic head modeling and for source localization. For both groups, the MMN source was determined to be located in the superior temporal gyrus (STG). However, the normal functional hemispheric asymmetry of ECD power was significantly altered in the schizophrenics (chi(2) test = 16.13, p < 0.001). Left MMN ECD power and the asymmetry coefficient (AC) were negatively correlated with the positive scores from Positive and Negative Syndrome Scale (PANSS) (r = -0.673, p = 0.008), especially with the hallucinatory behavior subscale (r = -0.677, p = 0.008). These findings support the deficits in preattentive automatic processing of auditory stimuli, especially in the left hemisphere, and indicate the correlation between positive symptoms, especially auditory hallucination, and left temporal lobe dysfunction in schizophrenia." [Abstract]

Umbricht D, Koller R, Vollenweider FX, Schmid L.
Mismatch negativity predicts psychotic experiences induced by NMDA receptor antagonist in healthy volunteers.
Biol Psychiatry. 2002 Mar 1;51(5):400-6.
"BACKGROUND: Previous studies indicate that mismatch negativity (MMN)-a preattentive auditory event-related potential (ERP)-depends on NMDA receptor (NMDAR) functioning. To explore if the strength of MMN generation reflects the functional condition of the NMDAR system in healthy volunteers, we analyzed correlations between MMN recorded before drug administration and subsequent responses to the NMDAR antagonist ketamine or the 5-HT2a agonist psilocybin. METHODS: In two separate studies, MMN was recorded to both frequency and duration deviants prior to administration of ketamine or psilocybin. Behavioral and subjective effects of ketamine and psilocybin were assessed with the Brief Psychiatric Rating Scale and the OAV Scale-a rating scale developed to measure altered states of consciousness. Correlations between ERP amplitudes (MMN, N1, and P2) and drug-induced effects were calculated in each study group and compared between them. RESULTS: Smaller MMN to both pitch and duration deviants was significantly correlated to stronger effects during ketamine, but not psilocybin administration. No significant correlations were observed for N1 and P2. CONCLUSIONS: Smaller MMN indicates a NMDAR system that is more vulnerable to disruption by the NMDAR antagonist ketamine. MMN generation appears to index the functional state of NMDAR-mediated neurotransmission even in subjects who do not demonstrate any psychopathology." [Abstract]

Umbricht D, Vollenweider FX, Schmid L, Grubel C, Skrabo A, Huber T, Koller R.
Effects of the 5-HT2A agonist psilocybin on mismatch negativity generation and AX-continuous performance task: implications for the neuropharmacology of cognitive deficits in schizophrenia.
Neuropsychopharmacology. 2003 Jan;28(1):170-81.
"Previously the NMDA (N-methyl-D-aspartate) receptor (NMDAR) antagonist ketamine was shown to disrupt generation of the auditory event-related potential (ERP) mismatch negativity (MMN) and the performance of an 'AX'-type continuous performance test (AX-CPT)--measures of auditory and visual context-dependent information processing--in a similar manner as observed in schizophrenia. This placebo-controlled study investigated effects of the 5-HT(2A) receptor agonist psilocybin on the same measures in 18 healthy volunteers. Psilocybin administration induced significant performance deficits in the AX-CPT, but failed to reduce MMN generation significantly. These results indirectly support evidence that deficient MMN generation in schizophrenia may be a relatively distinct manifestation of deficient NMDAR functioning. In contrast, secondary pharmacological effects shared by NMDAR antagonists and the 5-HT(2A) agonist (ie disruption of glutamatergic neurotransmission) may be the mechanism underlying impairments in AX-CPT performance observed during both psilocybin and ketamine administration. Comparable deficits in schizophrenia may result from independent dysfunctions of 5-HT(2A) and NMDAR-related neurotransmission." [Abstract]

Malhotra AK, Pinals DA, Adler CM, Elman I, Clifton A, Pickar D, Breier A.
Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics.
Neuropsychopharmacology. 1997 Sep;17(3):141-50.
"The N-methyl-d-aspartate (NMDA) receptor has been implicated in the pathophysiology of schizophrenia. We administered subanesthetic doses of the NMDA receptor antagonist ketamine in a double-blind, placebo-controlled design to 13 neuroleptic-free schizophrenic patients to investigate if schizophrenics will experience an exacerbation of psychotic symptoms and cognitive impairments with ketamine. We also examined whether schizophrenics experienced quantitative or qualitative differences in ketamine response in comparison to normal controls. Schizophrenics experienced a brief-ketamine-induced exacerbation of positive and negative symptoms with further decrements in recall and recognition memory. They also displayed greater ketamine-induced impairments in free recall than normals. Qualitative differences included auditory hallucinations and paranoia in patients but not in normals. These data indicate that ketamine is associated with exacerbation of core psychotic and cognitive symptoms in schizophrenia. Moreover, ketamine may differentially affect cognition in schizophrenics in comparison to normal controls." [Abstract]

Umbricht D, Koller R, Schmid L, Skrabo A, Grubel C, Huber T, Stassen H.
How specific are deficits in mismatch negativity generation to schizophrenia?
Biol Psychiatry. 2003 Jun 15;53(12):1120-31.
"BACKGROUND: Mismatch negativity (MMN) is an auditory event-related potential that provides an index of auditory sensory memory. Deficits in MMN generation have been repeatedly demonstrated in chronic schizophrenia. Their specificity to schizophrenia has not been established. METHODS: Mismatch negativity to both duration and frequency deviants was investigated in gender- and age-matched patients with schizophrenia or schizoaffective disorder (n = 26), bipolar disorder (n = 16), or major depression (n = 22) and healthy control subjects (n = 25). RESULTS: Only patients with schizophrenia demonstrated significantly smaller mean MMN than did healthy control subjects. Detailed analyses showed significantly smaller MMN to both duration and frequency deviants in patients with schizophrenia than in healthy control subjects; however, the reduction of frequency MMN in patients with schizophrenia was not significant in the comparison across all groups. Mismatch negativity topography did not differ among groups. No consistent correlations with clinical, psychopathologic, or treatment variables were observed. CONCLUSIONS: Mismatch negativity deficits, and by extension deficits in early cortical auditory information processing, appear to be specific to schizophrenia. Animal and human studies implicate dysfunctional N-methyl-D-aspartate receptor functioning in MMN deficits. Thus MMN deficits may become a useful endophenotype to investigate the genetic underpinnings of schizophrenia, particularly with regard to the N-methyl-D-aspartate receptor." [Abstract]

Daniel C. Javitt, Mitchell Steinschneider, Charles E. Schroeder, and Joseph C. Arezzo
Role of cortical N-methyl-D-aspartate receptors in auditory sensory memory and mismatch negativity generation: Implications for schizophrenia
PNAS 93: 11962-11967. 1996.
"Working memory refers to the ability of the brain to store and manipulate information over brief time periods, ranging from seconds to minutes. As opposed to long-term memory, which is critically dependent upon hippocampal processing, critical substrates for working memory are distributed in a modality-specific fashion throughout cortex. N-methyl-D-aspartate (NMDA) receptors play a crucial role in the initiation of long-term memory. Neurochemical mechanisms underlying the transient memory storage required for working memory, however, remain obscure. Auditory sensory memory, which refers to the ability of the brain to retain transient representations of the physical features (e.g., pitch) of simple auditory stimuli for periods of up to approximately 30 sec, represents one of the simplest components of the brain working memory system. Functioning of the auditory sensory memory system is indexed by the generation of a well-defined event-related potential, termed mismatch negativity (MMN). MMN can thus be used as an objective index of auditory sensory memory functioning and a probe for investigating underlying neurochemical mechanisms. Monkeys generate cortical activity in response to deviant stimuli that closely resembles human MMN. This study uses a combination of intracortical recording and pharmacological micromanipulations in awake monkeys to demonstrate that both competitive and noncompetitive NMDA antagonists block the generation of MMN without affecting prior obligatory activity in primary auditory cortex. These findings suggest that, on a neurophysiological level, MMN represents selective current flow through open, unblocked NMDA channels. Furthermore, they suggest a crucial role of cortical NMDA receptors in the assessment of stimulus familiarity/unfamiliarity, which is a key process underlying working memory performance." [Abstract/PDF]

Goff, Donald C., Coyle, Joseph T.
The Emerging Role of Glutamate in the Pathophysiology and Treatment of Schizophrenia
Am J Psychiatry 2001 158: 1367-1377
"OBJECTIVE: Research has implicated dysfunction of glutamatergic neurotransmission in the pathophysiology of schizophrenia. This review evaluates evidence from preclinical and clinical studies that brain glutamatergic neurotransmission is altered in schizophrenia, may affect symptom expression, and is modulated by antipsychotic drugs. METHOD: A comprehensive review of scientific articles published over the last decade that address the role of glutamate in the pathophysiology of schizophrenia was carried out. RESULTS: Glutamatergic neurons are the major excitatory pathways linking the cortex, limbic system, and thalamus, regions that have been implicated in schizophrenia. Postmortem studies have revealed alterations in pre- and postsynaptic markers for glutamatergic neurons in several brain regions in schizophrenia. The N-methyl-D-aspartic acid (NMDA) subtype of glutamate receptor may be particularly important as blockade of this receptor by the dissociative anesthetics reproduces in normal subjects the symptomatic manifestations of schizophrenia, including negative symptoms and cognitive impairments, and increases dopamine release in the mesolimbic system. Agents that indirectly enhance NMDA receptor function via the glycine modulatory site reduce negative symptoms and variably improve cognitive functioning in schizophrenic subjects receiving typical antipsychotics. CONCLUSIONS: Dysfunction of glutamatergic neurotransmission may play an important role in the pathophysiology of schizophrenia, especially of the negative symptoms and cognitive impairments associated with the disorder, and is a promising target for drug development." [Full Text]

Yang CQ, Kitamura N, Nishino N, Shirakawa O, Nakai H.
Isotype-specific G protein abnormalities in the left superior temporal cortex and limbic structures of patients with chronic schizophrenia.
Biol Psychiatry. 1998 Jan 1;43(1):12-9.
"BACKGROUND: The potential role of signal transducing guanine nucleotide-binding regulatory protein (G protein) in schizophrenia is largely unknown. METHODS: We immunoquantified isotypes of G protein using specific antisera against alpha and beta subunits of G protein in the superior temporal, prefrontal, and entorhinal cortices as well as the nucleus accumbens and amygdala of postmortem brains from 19 schizophrenic and 28 control subjects. RESULTS: In the left hemisphere of schizophrenics, the amount of Gi alpha, Go alpha, and Gq alpha but not that of Gs alpha or G beta decreased in the superior temporal cortex by 27%, 27%, and 16%, respectively, as compared with the values in ipsilateral controls; the amount of any G protein isotype in the prefrontal and entorhinal cortices was not changed. In the nucleus accumbens and amygdala, the paranoid type schizophrenics showed a smaller amount of Gi alpha and Go alpha than the disorganized type schizophrenics. In the right superior temporal cortex, the isotype amount did not differ between the schizophrenic and control groups. CONCLUSIONS: The decreased Gq alpha immunoreactivity in the schizophrenic left superior temporal cortex may reflect the down-regulation of Gq alpha, resulting from chronic stimulation of Gq alpha-coupled receptors, while the decreased Gi alpha and Go alpha in the nucleus accumbens and amygdala of paranoid type schizophrenics may be related to the dopaminergic hyperactivity via dopamine D2 receptors." [Abstract]

Lin XH, Kitamura N, Hashimoto T, Shirakawa O, Maeda K.
Opposite changes in phosphoinositide-specific phospholipase C immunoreactivity in the left prefrontal and superior temporal cortex of patients with chronic schizophrenia.
Biol Psychiatry. 1999 Dec 15;46(12):1665-71.
"BACKGROUND: Abnormalities in types of neurotransmitter signaling that are coupled with phosphoinositide-specific phospholipase C (PLC) have previously been reported in brains from patients with schizophrenia. PLC, a main component of this pathway, may be affected in schizophrenia. METHODS: We immunoquantified PLC beta 1, gamma 1 and delta 1 in the left prefrontal cortex and superior temporal cortex, nucleus accumbens and amygdala, and in the right superior temporal cortex of postmortem brains obtained from a total of 19 patients with schizophrenia and a total of 27 controls. RESULTS: PLC beta 1 immunoreactivities were increased in the particulate fraction from the prefrontal cortex (by 64%), although they were decreased in the particulate fraction from the left superior temporal cortex (by 28%), as compared with the values in controls. There was no difference in PLC beta 1 immunoreactivities in the nucleus accumbens, the amygdala or the right superior temporal cortex between schizophrenic patients and controls. PLC gamma 1 and delta 1 immunoreactivities did not differ between the two groups in any of the regions studied. CONCLUSIONS: Changes in PLC beta 1 immunoreactivities in the prefrontal and superior temporal cortex of patients with schizophrenia may reflect abnormalities in neurotransmissions via receptors that are coupled with the Gq alpha-PLC beta 1 cascade." [Abstract]

Shirakawa O, Kitamura N, Lin XH, Hashimoto T, Maeda K.
Abnormal neurochemical asymmetry in the temporal lobe of schizophrenia.
Prog Neuropsychopharmacol Biol Psychiatry. 2001 May;25(4):867-77.
"Neuroanatomical asymmetries are known to be present in the human brain, and loss of reversal of these asymmetries, particularly through changes in the left temporal lobe, have been found in the brains of patients with schizophrenia. In addition to disturbed neuroanatomical asymmetries, disturbed neurochemical asymmetries have also been reported in the brains of patients with schizophrenia. However, in the temporal lobe, the laterality of most of these neurochemical changes has not been specifically evaluated. Few neurochemical studies have addressed left-right differences in the superior temporal gyrus (STG). A deteriorated serotonin2A receptor-G protein qalpha (Gqalpha)-phosphoinositide-specific phospholipase C beta1(PLC beta1) cascade has been found in the left, but not right, STG of patients with schizophrenia. Not only neuroanatomical but also neurochemical evidence supports the loss or reversal of normal asymmetry of the temporal lobe in schizophrenia, which might be due to a disruption of the neurodevelopmental processes involved in hemispheric lateralization." [Abstract]

Burnet PW, Eastwood SL, Harrison PJ.
5-HT1A and 5-HT2A receptor mRNAs and binding site densities are differentially altered in schizophrenia.
Neuropsychopharmacology. 1996 Nov;15(5):442-55.
"We have investigated 5-HT1A (serotonin1A) and 5-HT2A (serotonin2A) receptor mRNA abundance and binding site densities in various neocortical and hippocampal regions of schizophrenics and control subjects. Age, agonal state (brain pH), and post mortem interval were included where necessary as covariates in our analyses. In schizophrenics, 5-HT1A binding site densities, determined autoradiographically by [3H]8-hydroxy-2,3-(dipropylamino)-tetralin ([3H]8-OH-DPAT), were significantly increased (+23%) in the dorsolateral prefrontal cortex, with a similar trend in anterior cingulate gyrus. These increases were not accompanied by any change in 5-HT1A receptor mRNA. No differences between the groups in [3H]8-OH-DPAT binding or 5-HT1A receptor mRNA were seen in superior temporal gyrus, striate cortex, or hippocampus. 5-HT2A binding sites, determined by [3H]ketanserin, were decreased in the dorsolateral prefrontal cortex (-27%) and parahippocampal gyrus (-38%) of schizophrenics, with a similar trend in cingulate gyrus, but not in superior temporal gyrus or striate cortex. 5-HT2A receptor mRNA abundance was reduced in schizophrenics in the dorsolateral prefrontal (-49%), superior temporal (-48%), anterior cingulate (-63%) and striate (-63%) cortices, but not in parahippocampal gyrus. Parallel analyses of rat brain tissue showed no changes in 5-HT1A or 5-HT2A receptor mRNAs or binding site densities after chronic administration of haloperidol. These data show that schizophrenia is associated with alterations in the expression of central 5-HT1A and 5-HT2A receptors. They confirm reports of increased 5-HT1A and decreased 5-HT2A binding site densities in prefrontal cortex, and reveal more extensive decreases in 5-HT2A receptor gene expression at the mRNA level. The resulting imbalance in the 5-HT1A to 5-HT2A receptor ratio, when considered in terms of the chemoarchitectural distribution of these receptors, may contribute to an impairment of corticocortical association pathways. The apparent dissociation of the normal relationships between the abundance of each 5-HT receptor and its mRNA in schizophrenia introduces a separate complexity to the data, which may give clues to the underlying molecular mechanisms." [Abstract]

Joyce JN, Goldsmith SG, Gurevich EV.
Limbic circuits and monoamine receptors: dissecting the effects of antipsychotics from disease processes.
J Psychiatr Res. 1997 Mar-Apr;31(2):197-217.
"There is considerable evidence for the involvement of brain dopaminergic and serotonergic systems in schizophrenia pathology. However, post-mortem studies have been limited by difficulties in separating the effects of chronic exposure to antipsychotics from that of the disease process. Our recent studies directly explored this by comparing groups that were free from antipsychotic treatment for up to a year prior to death and that were maintained on antipsychotics. We have used this approach to identify that there are prominent effects of both disease and of antipsychotic treatment. There appears to be a high association for schizophrenics between elevations of D3 receptors in target regions of the mesolimbic dopamine (DA) system and elevated numbers of 5-HT(1A) receptors in prefrontal cortex (PFc). Antipsychotic treatment was correlated with a reduction of D3 receptors in the ventral striatum and its output structures. It also led to a reduction in the number of 5-HT2 receptors in some regions of the PFc without modifying the concentration of 5-HT(1A) receptors. The limbic loop interconnecting the PFc and ventral striatum may be the site of antipsychotic regulation of certain symptoms in schizophrenia, particularly anhedonia and depression. The positive symptoms of schizophrenia are more likely to be associated with disturbances in the temporal lobe. However, dopaminergic systems in the temporal lobe have historically been thought to be underdeveloped compared to that in the basal ganglia and unlikely to be the target of antipsychotics. Our studies of the expression of the DA D2 receptor in the temporal lobe has shown a complex organization in the perirhinal and temporal cortices that is disrupted in schizophrenia. The disturbances, which might be of neurodevelopmental origin and are unrelated to antipsychotic treatment, include altered laminar distribution of the D2 receptor and modified modular organization of D2 receptors in the superior temporal gyrus. We hypothesize that modified expression of D2 receptors in these regions play a key role in the genesis of hallucinations. Treatment with antipsychotics leading to D2 receptor blockade in temporal cortex may reduce the presence of positive symptoms." [Abstract]

Ford JM, Mathalon DH.
Electrophysiological evidence of corollary discharge dysfunction in schizophrenia during talking and thinking.
J Psychiatr Res. 2004 Jan;38(1):37-46.
"Failure of corollary discharge, a mechanism for distinguishing self-generated from externally-generated percepts, has been posited to underlie certain positive symptoms of schizophrenia, including auditory hallucinations. Although originally described in the visual system, corollary discharge may exist in the auditory system, whereby signals from motor speech commands prepare auditory cortex for self-generated speech. While associated with sensorimotor systems, it might also apply to inner speech or thought, regarded as our most complex motor act. We had four aims in the studies summarized in this paper: (1) to demonstrate the corollary discharge phenomenon during talking and inner speech in human volunteers using event-related brain potentials (ERPs), (2) to demonstrate that the corollary discharge is abnormal in patients with schizophrenia, (3) to demonstrate the role of frontal speech areas in the corollary discharge during talking, and (4) to relate the dysfunction of the corollary discharge in schizophrenia to auditory hallucinations. Using EEG and ERP measures, we addressed each aim in patients with schizophrenia (DSM IV) and healthy control subjects. The N1 component of the ERP reflected dampening of auditory cortex responsivity during talking and inner speech in control subjects but not in patients. EEG measures of coherence indicated inter-dependence of activity in the frontal speech production and temporal speech reception areas during talking in control subjects, but not in patients, especially those who hallucinated. These data suggest that a corollary discharge from frontal areas where thoughts are generated fails to alert auditory cortex that they are self-generated, leading to the misattribution of inner speech to external sources and producing the experience of auditory hallucinations." [Abstract]

Feinberg I.
Efference copy and corollary discharge: implications for thinking and its disorders.
Schizophr Bull. 1978;4(4):636-40.
"Many motor commands in the nervous system are associated with corollary discharges which alter the excitability in both sensory and motor systems. These discharges may assist in the distinction between self-generated and externally produced movements; they also allow (or represent) monitoring of the motor commands before the effector response has occurred. Here, I hypothesize that this mechanism of control and integration is also present in thinking, which as Hughlings Jackson pointed out, may be considered the highest and most complex form of motor activity. I speculate that if corollary discharges are normally part of the motor mechanisms of thought, their derangement could produce many of the symptoms of schizophrenia." [Abstract]

Shergill SS, Bullmore ET, Brammer MJ, Williams SC, Murray RM, McGuire PK.
A functional study of auditory verbal imagery.
Psychol Med. 2001 Feb;31(2):241-53.
"BACKGROUND: We used functional MRI to examine the functional anatomy of inner speech and different forms of auditory verbal imagery (imagining speech) in normal volunteers. We hypothesized that generating inner speech and auditory verbal imagery would be associated with left inferior frontal activation, and that generating auditory verbal imagery would involve additional activation in the lateral temporal cortices. METHODS: Subjects were scanned, while performing inner speech and auditory verbal imagery tasks, using a 1.5 Tesla magnet. RESULTS: The generation of inner speech was associated with activation in the left inferior frontal/insula region, the left temporo-parietal cortex, right cerebellum and the supplementary motor area. Auditory verbal imagery in general, as indexed by the three imagery tasks combined, was associated with activation in the areas engaged during the inner speech task, plus the left precentral and superior temporal gyri (STG), and the right homologues of all these areas. CONCLUSIONS: These results are consistent with the use of the 'articulatory loop' during both inner speech and auditory verbal imagery, and the greater engagement of verbal self-monitoring during auditory verbal imagery." [Abstract]

SHERGILL, SUKHWINDER S., BRAMMER, MICHAEL J., FUKUDA, RIMMEI, WILLIAMS, STEVEN C. R., MURRAY, ROBIN M., McGUIRE, PHILIP K.
Engagement of brain areas implicated in processing inner speech in people with auditory hallucinations
Br J Psychiatry 2003 182: 525-531
"BACKGROUND: The neurocognitive basis of auditory hallucinations is unclear, but there is increasing evidence implicating abnormalities in processing inner speech. Previous studies have shown that people with schizophrenia who were prone to auditory hallucinations demonstrated attenuated activation of brain areas during the monitoring of inner speech. AIMS: To investigate whether the same pattern of functional abnormalities would be evident as the rate of inner speech production was varied. METHOD: Eight people with schizophrenia who had a history of prominent auditory hallucinations and eight control participants were studied using functional magnetic resonance imaging while the rate of inner speech generation was varied experimentally. RESULTS: When the rate of inner speech generation was increased, the participants with schizophrenia showed a relatively attenuated response in the right temporal, parietal, parahippocampal and cerebellar cortex. CONCLUSIONS: In people with schizophrenia who are prone to auditory hallucinations, increasing the demands on the processing of inner speech is associated with attenuated engagement of the brain areas implicated in verbal self-monitoring." [Abstract]

McGuire PK, Silbersweig DA, Wright I, Murray RM, David AS, Frackowiak RS, Frith CD.
Abnormal monitoring of inner speech: a physiological basis for auditory hallucinations.
Lancet. 1995 Sep 2;346(8975):596-600.
"Auditory verbal hallucinations ("voices") are thought to arise from a disorder of inner speech (thinking in words). We examined the neural correlates of tasks which involve inner speech in subjects with schizophrenia who hear voices (hallucinators), subjects with schizophrenia who do not (nonhallucinators), and normal controls. There were no differences between hallucinators and controls in regional cerebral blood flow during thinking in sentences. However, when imagining sentences being spoken in another person's voice--which entails both the generation and monitoring of inner speech--hallucinators had a normal left frontal response, but reduced activation in the left middle temporal gyrus and the rostral supplementary motor area, regions which were activated by both normal subjects and nonhallucinators (p < 0.001). These findings suggest that a predisposition to verbal hallucinations is associated with a failure to activate areas concerned with the monitoring of inner speech." [Abstract]

McGuire, PK, Silbersweig, DA, Wright, I, Murray, RM, Frackowiak, RS, Frith, CD
The neural correlates of inner speech and auditory verbal imagery in schizophrenia: relationship to auditory verbal hallucinations.
Br J Psychiatry 1996 169: 148-159
"BACKGROUND: Auditory verbal hallucinations are thought to arise from the disordered monitoring of inner speech (thinking in words). We tested the hypothesis that a predisposition to verbal auditory hallucinations would be associated with an abnormal pattern of brain activation during tasks which involved the generation and monitoring of inner speech. METHOD: The neural correlates of tasks which engaged inner speech and auditory verbal imagery were examined using positron emission tomography in (a) schizophrenic patients with a strong predisposition to auditory verbal hallucinations (hallucinators), (b) schizophrenic patients with no history of hallucinations (nonhallucinators), and (c) normal controls. RESULTS: There were few between-group differences in activation during the inner speech task. However, when imagining sentences spoken in another person's voice, which entails the monitoring of inner speech, hallucinators showed reduced activation in the left middle temporal gyrus and the rostral supplementary motor area, regions which were strongly activated by both normal subjects and nonhallucinators (P < 0.001). Conversely, when nonhallucinators imagined speech, they differed from both hallucinators and controls in showing reduced activation in the right parietal operculum. CONCLUSIONS: A predisposition to verbal hallucinations in schizophrenia is associated with a failure to activate areas implicated in the normal monitoring of inner speech, whereas the absence of a history of hallucinations may be linked to reduced activation in an area concerned with verbal prosody. " [Abstract]

Woodruff, Peter W.R., Wright, Ian C., Bullmore, Edward T., Brammer, Michael, Howard, Robert J., Williams, Steven C.R., Shapleske, Jane, Rossell, Susan, David, Anthony S., McGuire, Philip K., Murray, Robin M.
Auditory Hallucinations and the Temporal Cortical Response to Speech in Schizophrenia: A Functional Magnetic Resonance Imaging Study
Am J Psychiatry 1997 154: 1676-1682
"OBJECTIVE: The authors explored whether abnormal functional lateralization of temporal cortical language areas in schizophrenia was associated with a predisposition to auditory hallucinations and whether the auditory hallucinatory state would reduce the temporal cortical response to external speech. METHOD: Functional magnetic resonance imaging was used to measure the blood-oxygenation-level-dependent signal induced by auditory perception of speech in three groups of male subjects: eight schizophrenic patients with a history of auditory hallucinations (trait-positive), none of whom was currently hallucinating; seven schizophrenic patients without such a history (trait-negative); and eight healthy volunteers. Seven schizophrenic patients were also examined while they were actually experiencing severe auditory verbal hallucinations and again after their hallucinations had diminished. RESULTS: Voxel-by-voxel comparison of the median power of subjects' responses to periodic external speech revealed that this measure was reduced in the left superior temporal gyrus but increased in the right middle temporal gyrus in the combined schizophrenic groups relative to the healthy comparison group. Comparison of the trait-positive and trait-negative patients revealed no clear difference in the power of temporal cortical activation. Comparison of patients when experiencing severe hallucinations and when hallucinations were mild revealed reduced responsivity of the temporal cortex, especially the right middle temporal gyrus, to external speech during the former state. CONCLUSIONS: These results suggest that schizophrenia is associated with a reduced left and increased right temporal cortical response to auditory perception of speech, with little distinction between patients who differ in their vulnerability to hallucinations. The auditory hallucinatory state is associated with reduced activity in temporal cortical regions that overlap with those that normally process external speech, possibly because of competition for common neurophysiological resources." [Full Text]

Hubl D, Koenig T, Strik W, Federspiel A, Kreis R, Boesch C, Maier SE, Schroth G, Lovblad K, Dierks T.
Pathways that make voices: white matter changes in auditory hallucinations.
Arch Gen Psychiatry. 2004 Jul;61(7):658-68.
"BACKGROUND: The origin of auditory hallucinations, which are one of the core symptoms of schizophrenia, is still a matter of debate. It has been hypothesized that alterations in connectivity between frontal and parietotemporal speech-related areas might contribute to the pathogenesis of auditory hallucinations. These networks are assumed to become dysfunctional during the generation and monitoring of inner speech. Magnetic resonance diffusion tensor imaging is a relatively new in vivo method to investigate the directionality of cortical white matter tracts. OBJECTIVE: To investigate, using diffusion tensor imaging, whether previously described abnormal activation patterns observed during auditory hallucinations relate to changes in structural interconnections between the frontal and parietotemporal speech-related areas. METHODS: A 1.5 T magnetic resonance scanner was used to acquire twelve 5-mm slices covering the Sylvian fissure. Fractional anisotropy was assessed in 13 patients prone to auditory hallucinations, in 13 patients without auditory hallucinations, and in 13 healthy control subjects. Structural magnetic resonance imaging was conducted in the same session. Based on an analysis of variance, areas with significantly different fractional anisotropy values between groups were selected for a confirmatory region of interest analysis. Additionally, descriptive voxel-based t tests between the groups were computed. RESULTS: In patients with hallucinations, we found significantly higher white matter directionality in the lateral parts of the temporoparietal section of the arcuate fasciculus and in parts of the anterior corpus callosum compared with control subjects and patients without hallucinations. Comparing patients with hallucinations with patients without hallucinations, we found significant differences most pronounced in the left hemispheric fiber tracts, including the cingulate bundle. CONCLUSION: Our findings suggest that during inner speech, the alterations of white matter fiber tracts in patients with frequent hallucinations lead to abnormal coactivation in regions related to the acoustical processing of external stimuli. This abnormal activation may account for the patients' inability to distinguish self-generated thoughts from external stimulation." [Abstract]

Michael D. Hunter , Timothy D. Griffiths , Tom F. D. Farrow , Ying Zheng , Iain D. Wilkinson , Nakul Hegde , William Woods , Sean A. Spence , and Peter W. R. Woodruff
A neural basis for the perception of voices in external auditory space
Brain 126: 161-169. 2002.
"We used functional imaging of normal subjects to identify the neural substrate for the perception of voices in external auditory space. This fundamental process can be abnormal in psychosis, when voices that are not true external auditory objects (auditory verbal hallucinations) may appear to originate in external space. The perception of voices as objects in external space depends on filtering by the outer ear. Psychoses that distort this process involve the cerebral cortex. Functional magnetic resonance imaging was carried out on 12 normal subjects using an inside-the-scanner simulation of ‘inside head’ and ‘outside head’ voices in the form of typical auditory verbal hallucinations. Comparison between the brain activity associated with the two conditions allowed us to test the hypothesis that the perception of voices in external space (‘outside head’) is subserved by a temperoparietal network comprising association auditory cortex posterior to Heschl’s gyrus [planum temporale (PT)] and inferior parietal lobule. Group analyses of response to ‘outside head’ versus ‘inside head’ voices showed significant activation solely in the left PT. This was demonstrated in three experiments in which the predominant lateralization of the stimulus was to the right, to the left or balanced. These findings suggest a critical involvement of the left PT in the perception of voices in external space that is not dependent on precise spatial location. Based on this, we suggest a model for the false perception of externally located auditory verbal hallucinations." [Full Text]

Bentaleb LA, Beauregard M, Liddle P, Stip E.
Cerebral activity associated with auditory verbal hallucinations: a functional magnetic resonance imaging case study.
J Psychiatry Neurosci. 2002 Mar;27(2):110-5.
"Among the many theories that have been advanced to explain the mechanism by which auditory verbal hallucinations (AVH) arise, 2 that have received a degree of empirical support are: the hypothesis that AVHs arise from misinterpreted inner speech and the proposal that they arise from aberrant activation of the primary auditory cortex. To test these hypotheses, we were fortunate to be able to study the interesting and rare case of a woman with schizophrenia who experienced continuous AVH which disappeared when she listened to loud external speech. Functional magnetic resonance imaging (fMRI) was used to measure the patient's brain activity in the temporal and inferior frontal regions during the AVHs and while the she was listening to external speech. The brain activity of a matched control subject was also recorded under the same experimental conditions. AVHs were associated with increased metabolic activity in the left primary auditory cortex and the right middle temporal gyrus. Our results suggest a possible interaction between these areas during AVHs and also that the hypotheses of defective internal monitoring and aberrant activation are not mutually exclusive. Potential limitations to the generalization of our results are discussed." [Abstract] [PDF]

Kircher TT, Brammer M, Bullmore E, Simmons A, Bartels M, David AS.
The neural correlates of intentional and incidental self processing.
Neuropsychologia. 2002;40(6):683-92.
"The neuroscientific study of the 'Self' is just beginning to emerge. We used functional Magnetic Resonance Imaging (fMRI) to investigate cerebral activation while subjects processed words describing personality traits and physical features, in two experiments with contrasting designs: incidental and intentional. In the first experiment (intentional self processing), subjects were presented with personality trait adjectives and made judgements as to their self descriptiveness (versus non self descriptiveness). In the second experiment (incidental self processing), subjects categorised words according to whether they described physical versus psychological attributes, while unaware that the words had been arranged in blocks according to self descriptiveness. The subjects had previously rated all words for self descriptiveness 6 weeks prior to the scanning session. A reaction time advantage was present in both experiments for self descriptive trait words, suggesting a facilitation effect. Common areas of activation for the two experiments included the left superior parietal lobe, with adjacent regions of the lateral prefrontal cortex also active in both experiments. Differential signal changes were present in the left precuneus for the intentional and the right middle temporal gyrus for the incidental experiment. The results suggest that self processing involves distinct processes and can occur on more than one cognitive level with corresponding functional neuroanatomic correlates in areas previously implicated in the awareness of one's own state." [Abstract]

Tracy J, Flanders A, Madi S, Natale P, Delvecchio N, Pyrros A, Laskas J.
The brain's response to incidental intruded words during focal text processing.
Neuroimage. 2003 Jan;18(1):117-26.
"The functional neuroanatomy associated with processing single words incidentally, outside focal attention, was investigated. We asked subjects (n = 15) to listen, focus on, and comprehend a story narrative, and then single, unrelated but meaningful words were intruded into the ongoing narrative. We also manipulated the type of intruded word, using either neutral or emotionally valent words, to evaluate the extent of semantic processing and a potential encoding advantage for one type of material. Analyses emphasized the areas of activation unique to the intruded words as distinguished from the narrative text. Subjects were normal, healthy adults (n = 15). Compared to narrative text, the intruded words were associated with activation in the right middle temporal gyrus (BA 39) and posterior cingulate/precuneus regions (BA 30, 23). We conclude that the intruded words did make contact with word-level lexical but not necessarily semantic structures in the middle temporal region. The data suggested that the intruded words were processed by a "nonexecutive" monitoring system implemented by a pairing of activation in posterior, medial structures such as the posterior cingulate with deactivation in brain stem structures. This pattern induced a shift to more passive, less effortful, nonstrategic monitoring of the words. Thus, attention processing, not semantic processing, changes best characterized the brain activation unique to the intruded words. This posterior, medial region is discussed as a substrate dedicated to processing a second, incidental stream of information and thereby providing a crucial mechanism for implementing dual processing of the kind examined here." [Abstract]

Shergill, Sukhwinder S., Brammer, Michael J., Williams, Steven C. R., Murray, Robin M., McGuire, Philip K.
Mapping Auditory Hallucinations in Schizophrenia Using Functional Magnetic Resonance Imaging
Arch Gen Psychiatry 2000 57: 1033-1038
"BACKGROUND: Perceptions of speech in the absence of an auditory stimulus (auditory verbal hallucinations) are a cardinal feature of schizophrenia. Functional neuroimaging provides a powerful means of measuring neural activity during auditory hallucinations, but the results from previous studies have been inconsistent. This may reflect the acquisition of small numbers of images in each subject and the confounding effects of patients actively signaling when hallucinations occur. METHODS: We examined 6 patients with schizophrenia who were experiencing frequent auditory hallucinations, using a novel functional magnetic resonance imaging method that permitted the measurement of spontaneous neural activity without requiring subjects to signal when hallucinations occurred. Approximately 50 individual scans were acquired at unpredictable intervals in each subject while they were intermittently hallucinating. Immediately after each scan, subjects reported whether they had been hallucinating at that instant. Neural activity when patients were and were not experiencing hallucinations was compared in each subject and the group as a whole. RESULTS: Auditory hallucinations were associated with activation in the inferior frontal/insular, anterior cingulate, and temporal cortex bilaterally (with greater responses on the right), the right thalamus and inferior colliculus, and the left hippocampus and parahippocampal cortex (P<.0001). CONCLUSIONS: Auditory hallucinations may be mediated by a distributed network of cortical and subcortical areas. Previous neuroimaging studies of auditory hallucinations may have identified different components of this network." [Abstract]

Green MF, Hugdahl K, Mitchell S.
Dichotic listening during auditory hallucinations in patients with schizophrenia.
Am J Psychiatry. 1994 Mar;151(3):357-62.
"OBJECTIVE: Auditory hallucinations are a serious problem for a large subgroup of psychotic patients who do not respond optimally to neuroleptic medication. It has been hypothesized that hearing imaginary voices involves the same physiological processes as those involved in hearing real voices, but this hypothesis has not been conclusively confirmed. METHOD: In this study a consonant-vowel version of the Dichotic Listening Test was used to assess the functional integration of the left hemisphere in hallucinating and nonhallucinating psychotic patients. The test was administered under three conditions: a nonforced attention condition, a condition in which attention was forced to the left ear, and one in which attention was forced to the right ear. RESULTS: The nonhallucinating patients showed the normal right ear advantage, which indicates a left hemisphere superiority in the processing of linguistic stimuli. In contrast, the hallucinating patients showed no ear advantage. Neither group was able to modify its performance when instructed to attend to either the left or the right ear. A subgroup of patients was tested in both hallucinating and nonhallucinating states, but the ear asymmetry was not noticeably different between these states. CONCLUSIONS: The results suggest that auditory hallucinations are associated with abnormalities in left hemisphere functioning and that these abnormalities might not be limited to the time of the auditory hallucinations. It is hypothesized that a relatively enduring left hemisphere abnormality may leave some patients at risk for auditory hallucinations." [Abstract]

Lennox BR, Park SB, Medley I, Morris PG, Jones PB.
The functional anatomy of auditory hallucinations in schizophrenia.
Psychiatry Res. 2000 Nov 20;100(1):13-20.
"We used continuous whole brain functional magnetic resonance imaging (fMRI) with a 3-T magnet to map the cerebral activation associated with auditory hallucinations in four subjects with schizophrenia. The subjects experienced episodes of hallucination whilst in the scanner so that periods of hallucination could be compared with periods of rest in the same individuals. Group analysis demonstrated shared areas of activation in right and left superior temporal gyri, left inferior parietal cortex and left middle frontal gyrus. When the data were examined on an individual basis, the temporal cortex and prefrontal cortex areas were activated during episodes of hallucination in all four subjects. These findings support the theory that auditory hallucination reflects abnormal activation of normal auditory pathways." [Abstract]

Dierks T, Linden DE, Jandl M, Formisano E, Goebel R, Lanfermann H, Singer W.
Activation of Heschl's gyrus during auditory hallucinations.
Neuron. 1999 Mar;22(3):615-21.
"Apart from being a common feature of mental illness, auditory hallucinations provide an intriguing model for the study of internally generated sensory perceptions that are attributed to external sources. Until now, the knowledge about the cortical network that supports such hallucinations has been restricted by methodological limitations. Here, we describe an experiment with paranoid schizophrenic patients whose on- and offset of auditory hallucinations could be monitored within one functional magnetic resonance imaging (fMRI) session. We demonstrate an increase of the blood oxygen level-dependent (BOLD) signal in Heschl's gyrus during the patients' hallucinations. Our results provide direct evidence of the involvement of primary auditory areas in auditory verbal hallucinations and establish novel constraints for psychopathological models." [Abstract]

Ishii R, Shinosaki K, Ikejiri Y, Ukai S, Yamashita K, Iwase M, Mizuno-Matsumoto Y, Inouye T, Yoshimine T, Hirabuki N, Robinson SE, Takeda M.
Theta rhythm increases in left superior temporal cortex during auditory hallucinations in schizophrenia: a case report.
Neuroreport. 2000 Sep 28;11(14):3283-7.
"Auditory hallucinations (AH), the perception of sounds and voices in the absence of external stimuli, remain a serious problem for a large subgroup of patients with schizophrenia. Functional imaging of brain activity associated with AH is difficult, since the target event is involuntary and its timing cannot be predicted. Prior efforts to image the patterns of cortical activity during AH have yielded conflicting results. In this study, MEG was used to directly image the brain electrophysiological events associated with AH in schizophrenia. We observed an increase in theta rhythm, as sporadic bursts, in the left superior temporal area during the AH states, whereas there was steady theta band activity in the resting state. The present finding suggests strong association of the left superior temporal cortex with the experience of AH in this patient. This is consistent with the hypothesis that AH arises from areas of auditory cortex subserving receptive language processing." [Abstract]

Ford JM, Mathalon DH, Whitfield S, Faustman WO, Roth WT.
Reduced communication between frontal and temporal lobes during talking in schizophrenia.
Biol Psychiatry. 2002 Mar 15;51(6):485-92.
"BACKGROUND: Communication between the frontal lobes, where speech and verbal thoughts are generated, and the temporal lobes, where they are perceived, may occur through the action of a corollary discharge. Its dysfunction may underlie failure to recognize inner speech as self-generated and account for auditory hallucinations in schizophrenia. METHODS: Electroencephalogram was recorded from 10 healthy adults and 12 patients with schizophrenia (DSM-IV) in two conditions: talking aloud and listening to their own played-back speech. Event-related electroencephalogram coherence to acoustic stimuli presented during both conditions was calculated between frontal and temporal pairs, for delta, theta, alpha, beta, and gamma frequency bands. RESULTS: Talking produced greater coherence than listening between frontal-temporal regions in all frequency bands; however, in the lower frequencies (delta and theta), there were significant interactions of group and condition. This finding revealed that patients failed to show an increase in coherence during talking, especially over the speech production and speech reception areas of the left hemisphere, and especially in patients prone to hallucinate. CONCLUSIONS: Reduced fronto-temporal functional connectivity may contribute to the misattribution of inner thoughts to external voices in schizophrenia." [Abstract]

Nudmamud S, Reynolds GP.
Increased density of glutamate/N-methyl-D-aspartate receptors in superior temporal cortex in schizophrenia.
Neurosci Lett. 2001 May 18;304(1-2):9-12.
"Saturable radioligand binding of [(3)H]L-689,560 to the glycine site of the N-methyl-D-aspartate (NMDA) receptor was determined bilaterally in superior temporal cortex (BA22) and prefrontal cortex (BA10) taken post mortem from patients with schizophrenia and matched control subjects. A significant increase in NMDA receptor density above control values was found bilaterally in BA22 in schizophrenia, but not in BA10. The effect was greatest in those patients described as primarily type II, in whom the effect was significantly lateralized, with a greater elevation in the left hemisphere. A significant decrease in NMDA receptor density was found in rat frontal cortex following chronic antipsychotic drug administration, indicating that prior drug treatment was unlikely to have contributed to the differences in schizophrenia." [Abstract]

Le Corre S, Harper CG, Lopez P, Ward P, Catts S.
Increased levels of expression of an NMDARI splice variant in the superior temporal gyrus in schizophrenia.
Neuroreport. 2000 Apr 7;11(5):983-6.
"Expression patterns of mRNAs for the NMDARI subunit (NRI) carboxy-terminus isoforms were investigated in postmortem brain tissue using isotopic in situ hybridization. Three brain regions (superior temporal, middle frontal and visual cortices) were examined in patients with schizophrenia (n = 6) and control subjects (n = 6). A 22% higher level of expression of the NRI isoform that contains neither spliced exon was observed in the superior temporal gyrus of patients with schizophrenia compared with controls (p = 0.01). No differences were observed in the expression of the other isoforms in the three regions studied. These data suggest that NRI alternative splicing might be abnormal in schizophrenia and reinforce previous findings implicating the superior temporal gyrus as a site of neural dysfunction in schizophrenia." [Abstract]

Lin Pei, Frank J. S. Lee, Anna Moszczynska, Brian Vukusic, and Fang Liu
Regulation of Dopamine D1 Receptor Function by Physical Interaction with the NMDA Receptors
J. Neurosci. 24: 1149-1158; doi:10.1523/JNEUROSCI.3922-03.2004
"Functional interactions between dopamine D1-like receptors and NMDA subtype glutamate receptors have been implicated in the maintenance of normal brain activity and neurological dysfunction. Although modulation of NMDA receptor functions by D1 receptor activation has been the subject of extensive investigation, little is known as to how the activation of NMDA receptors alters D1 function. Here we report that NMDA receptors regulate D1 receptor function via a direct protein–protein interaction mediated by the carboxyl tail regions of both receptors. In both cotransfected cells and cultured hippocampal neurons the activation of NMDA receptors increases the number of D1 receptors on the plasma membrane surface and enhances D1 receptor-mediated cAMP accumulation via a SNARE-dependent mechanism. Furthermore, overexpression of mini-genes encoding either NR1 or D1 carboxyl tail fragments disrupts the D1–NR1 direct protein–protein interaction and abolishes NMDA-induced changes in both D1 cell surface expression and D1-mediated cAMP accumulation. Our results demonstrate that the D1–NR1 physical interaction enables NMDA receptors to increase plasma membrane insertion of D1 receptors and provides a novel mechanism by which the activation of NMDA receptors upregulates D1 receptor function. Understanding the molecular mechanisms by which D1 and NMDA receptors functionally interact may provide insight toward elucidating the molecular neurobiological mechanisms involved in many neuropsychiatric illnesses, such as schizophrenia." [Abstract]

Long Chen, and Charles R. Yang
Interaction of Dopamine D1 and NMDA Receptors Mediates Acute Clozapine Potentiation of Glutamate EPSPs in Rat Prefrontal Cortex
J Neurophysiol 87: 2324-2336, 2002.
"The atypical antipsychotic drug clozapine effectively alleviates both negative and positive symptoms of schizophrenia via unclear cellular mechanisms. Clozapine may modulate both glutamatergic and dopaminergic transmission in the prefrontal cortex (PFC) to achieve part of its therapeutic actions. Using whole cell patch-clamp techniques, current-clamp recordings in layers V-VI pyramidal neurons from rat PFC slices showed that stimulation of local afferents (in 2 microM bicuculline) evoked mixed [AMPA/kainate and N-methyl-D-aspartate (NMDA) receptors] glutamate receptor-mediated excitatory postsynaptic potentials (EPSPs). Clozapine (1 microM) potentiated polysynaptically mediated evoked EPSPs (V(Hold) = -65 mV), or reversed EPSPs (rEPSP, V(Hold) = +20 mV) for >30 min. The potentiated EPSPs or rEPSPs were attenuated by elevating [Ca(2+)](O) (7 mM), by application of NMDA receptor antagonist 2-amino5-phosphonovaleric acid (50 microM), or by pretreatment with dopamine D1/D5 receptor antagonist SCH23390 (1 microM) but could be further enhanced by a dopamine reuptake inhibitor bupropion (1 microM). Clozapine had no significant effect on pharmacologically isolated evoked NMDA-rEPSP or AMPA-rEPSPs but increased spontaneous EPSPs without changing the steady-state resting membrane potential. Under voltage clamp, clozapine (1 microM) enhanced the frequency, and the number of low-amplitude (5-10 pA) AMPA receptor-mediated spontaneous EPSCs, while there was no such changes with the mini-EPSCs (in 1 microM TTX). Taken together these data suggest that acute clozapine can increase spike-dependent presynaptic release of glutamate and dopamine. The glutamate stimulates distal dendritic AMPA receptors to increase spontaneous EPSCs and enabled a voltage-dependent activation of neuronal NMDA receptors. The dopamine released stimulates postsynaptic D1 receptor to modulate a lasting potentiation of the NMDA receptor component of the glutamatergic synaptic responses in the PFC neuronal network. This sequence of early synaptic events induced by acute clozapine may comprise part of the activity that leads to later cognitive improvement in schizophrenia." [Full Text]

Grimwood S, Slater P, Deakin JF, Hutson PH.
NR2B-containing NMDA receptors are up-regulated in temporal cortex in schizophrenia.
Neuroreport. 1999 Feb 25;10(3):461-5.
"Saturation analyses of [3H]L-689,560, [3H]CGP 39653 and NMDA-specific [3H]ifenprodil binding revealed an equivalent increase (0.7 pmol/mg) in the number of [3H]L-689,560 and [3H]ifenprodil binding sites in superior temporal cortex (BA22) from drug-treated chronic schizophrenic patients and control subjects. No differences were observed between control and schizophrenic subjects for [3H]CGP 39653 binding in BA22, or for any of the radioligands binding to pre-motor cortex (BA6). Since [3H]L-689,560, [3H]CGP 39653 and [3H]ifenprodil label the glycine, glutamate and ifenprodil sites of the NMDA receptor complex, which are associated with NR1, NR1/NR2A and NR1/NR2B subunits respectively, our findings suggest that NR2B-containing receptors are selectively up-regulated in superior temporal cortex in schizophrenia." [Abstract]

Lee J, Rajakumar N.
Role of NR2B-containing N-methyl-D-aspartate receptors in haloperidol-induced c-Fos expression in the striatum and nucleus accumbens.
Neuroscience. 2003;122(3):739-45.
"Administration of haloperidol in rats leads to a robust induction of immediate-early genes including c-Fos throughout the striatum, which is significantly attenuated by pretreatment with the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801. The striatum expresses mainly NR1/NR2A and NR1/NR2B subtypes of NMDA receptors, each having different functional and pharmacological properties. In this study, rats were pretreated with Ro 25-6981, a selective antagonist for NR2B-containing NMDA receptors, in order to determine the relative contribution of this NMDA receptor subtype in NMDA-dependent haloperidol-induced c-Fos expression. Furthermore, to determine whether NMDA receptor subtype dependence of haloperidol-induced c-Fos expression is unique to the binding profile of haloperidol or whether it is a property of D2 receptor antagonism, the selective D2/D3 dopamine receptor antagonist, raclopride, was also used. Pretreatment with Ro 25-6981 led to a significant reduction in the number of nuclei showing c-Fos immunoreactivity in both the medial and lateral parts of the striatum. In the medial part of the striatum, this attenuation was almost as marked as that seen following pretreatment with MK-801; however, in the lateral part MK-801 pretreatment led to a significantly greater reduction in the number of c-Fos positive nuclei than did Ro 25-6981 pretreatment. This suggests that NR2B-containing NMDA receptors are involved in mediating most of the NMDA-dependent c-Fos expression in the medial striatum, but only responsible for mediating part of this induction in the lateral striatum. Furthermore, the pattern of attenuation of raclopride-induced c-Fos expression following Ro 25-6981 pretreatment was similar to that of haloperidol-induced c-Fos expression, indicating that the NMDA receptor subtype dependence of haloperidol-induced c-Fos expression is a property of D2 antagonism. The results indicate that NR2B-containing NMDA receptors are mainly involved in mediating haloperidol-induced c-Fos expression in the medial or "limbic" striatum, and suggest that NR2A-containing NMDA receptors may preferentially mediate haloperidol induced c-Fos expression in the lateral or "motor" striatum. This may have implications in the treatment of schizophrenia because co-administration of a selective blocker of NR2A-containing NMDA receptors may be able to reduce the severity of extrapyramidal motor symptoms caused by haloperidol treatment without interfering with its therapeutic effect that is presumably mediated via the medial part of the striatum." [Abstract]

Akbarian S, Sucher NJ, Bradley D, Tafazzoli A, Trinh D, Hetrick WP, Potkin SG, Sandman CA, Bunney WE Jr, Jones EG.
Selective alterations in gene expression for NMDA receptor subunits in prefrontal cortex of schizophrenics.
J Neurosci. 1996 Jan;16(1):19-30.
"NMDA receptor antagonists can induce a schizophrenia-like psychosis, but the role of NMDA receptors in the pathophysiology of schizophrenia remains unclear. Expression patterns of mRNAs for five NMDA receptor subunits (NR1/NR2A-D) were determined by in situ hybridization in prefrontal, parieto-temporal, and cerebellar cortex of brains from schizophrenics and from neuroleptic-treated and nonmedicated controls. In the cerebral cortex of both schizophrenics and controls, mRNAs for NR1, NR2A, NR2B, and NR2D subunits were preferentially expressed in layers II/III, Va, and VIa, with much higher levels in the prefrontal than in the parieto-temporal cortex. Levels of mRNA for the NR2C subunit were very low overall. By contrast, the cerebellar cortex of both schizophrenics and controls contained very high levels of NR2C subunit mRNA, whereas levels for the other subunit mRNAs were very low, except NR1, for which levels were moderate. Significant alterations in the schizophrenic cohort were confined to the prefrontal cortex. Here there was a shift in the relative proportions of mRNAs for the NR2 subunit family, with a 53% relative increase in expression of the NR2D subunit mRNA. No comparable changes were found in neuroleptic-treated or untreated controls. These findings indicate regional heterogeneity of NMDA receptor subunit expression in human cerebral and cerebellar cortex. In schizophrenics, the alterations in expression of NR2 subunit mRNA in prefrontal cortex are potential indicators of deficits in NMDA receptor-mediated neurotransmission accompanying functional hypoactivity of the frontal lobes." [Abstract]

LEWIS, DAVID A., GLANTZ, LEISA A., PIERRI, JOSEPH N., SWEET, ROBERT A.
Altered Cortical Glutamate Neurotransmission in Schizophrenia: Evidence from Morphological Studies of Pyramidal Neurons
Ann NY Acad Sci 2003 1003: 102-112
"Multiple lines of evidence from pharmacological, neuroimaging, and postmortem studies implicate disturbances in cortical glutamate neurotransmission in the pathophysiology of schizophrenia. Given that pyramidal neurons are the principal source of cortical glutamate neurotransmission, as well as the targets of the majority of cortical glutamate-containing axon terminals, understanding the nature of altered glutamate neurotransmission in schizophrenia requires an appreciation of both the types of pyramidal cell abnormalities and the specific class(es) of pyramidal cells that are affected in the illness. In this chapter, we review evidence indicating that a subpopulation of pyramidal neurons in the dorsolateral prefrontal cortex exhibits reductions in dendritic spine density, a marker of the number of excitatory inputs, and in somal volume, a measure correlated with a neuron's dendritic and axonal architecture. Specifically, pyramidal neurons located in deep layer 3 of the dorsolateral prefrontal cortex and that lack immunoreactivity for nonphosphorylated neurofilament protein may be particularly involved in the pathophysiology of schizophrenia. The presence of similar changes in pyramidal neurons located in deep layer 3 of auditory association cortex suggests that a shared property, which remains to be determined, confers cell type-specific vulnerability to a subpopulation of cortical glutamatergic neurons in schizophrenia." [Abstract]

Garey, L J, Ong, W Y, Patel, T S, Kanani, M, Davis, A, Mortimer, A M, Barnes, T R E, Hirsch, S R
Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia
J Neurol Neurosurg Psychiatry 1998 65: 446-453
"OBJECTIVE: A pilot study of the density of dendritic spines on pyramidal neurons in layer III of human temporal and frontal cerebral neocortex in schizophrenia. METHODS: Postmortem material from a group of eight prospectively diagnosed schizophrenic patients, five archive schizophrenic patients, 11 non-schizophrenic controls, and one patient with schizophrenia-like psychosis, thought to be due to substance misuse, was impregnated with a rapid Golgi method. Spines were counted on the dendrites of pyramidal neurons in temporal and frontal association areas, of which the soma was in layer III (which take part in corticocortical connectivity) and which met strict criteria for impregnation quality. Altogether 25 blocks were studied in the schizophrenic group and 21 in the controls. If more than one block was examined from a single area, the counts for that area were averaged. All measurements were made blind: diagnoses were only disclosed by a third party after measurements were completed. Possible confounding affects of coexisting Alzheimer's disease were taken into account, as were the effects of age at death and postmortem interval. RESULTS: There was a significant (p<0.001) reduction in the numerical density of spines in schizophrenia (276/mm in control temporal cortex and 112/mm in schizophrenic patients, and 299 and 101 respectively in the frontal cortex). An analysis of variance, taking out effects of age at death and postmortem interval, which might have explained the low spine density for some of the schizophrenic patients, did not affect the significance of the results. CONCLUSION: The results support the concept of there being a defect in the fine structure of dendrites of pyramidal neurons, involving loss of spines, in schizophrenia and may help to explain the loss of cortical volume without loss of neurons in this condition, although the effect of neuroleptic drugs cannot be ruled out." [Full Text]

Hoffman RE, McGlashan TH.
Neural network models of schizophrenia.
Neuroscientist. 2001 Oct;7(5):441-54.
"There is considerable neurobiological evidence suggesting that schizophrenia is associated with reduced corticocortical connectivity. The authors describ