Impaired recruitment of the hippocampus during conscious recollection in schizophrenia.

Poor attention and impaired memory are enduring and core features of schizophrenia. These impairments have been attributed either to global cortical dysfunction or to perturbations of specific components associated with the dorsolateral prefrontal cortex (DLPFC), hippocampus and cerebellum. Here, we used positron emission tomography (PET) to dissociate activations in DLPFC and hippocampus during verbal episodic memory retrieval. We found reduced hippocampal activation during conscious recollection of studied words, but robust activation of the DLPFC during the effort to retrieve poorly encoded material in schizophrenic patients. This finding provides the first evidence of hippocampal dysfunction during episodic memory retrieval in schizophrenia.

Schizophrenia and cognitive function.

Schizophrenia is often associated with cognitive deficits, particularly within the domains of memory and language. Specific cognitive deficits have recently been linked to psychotic phenomena, including verbal hallucinations and disorganized speech. Impairments of working and semantic memory are primarily due to dysfunction of the frontal cortex, temporal cortex, and hippocampus. Cognitive skills in schizophrenia predict social functioning and may serve as outcome measures in the development of effective treatment strategies.

Intracellular modulation of NMDA receptor function by antipsychotic drugs.

The present study deals with the functional interaction of antipsychotic drugs and NMDA receptors. We show that both the conventional antipsychotic drug haloperidol and the atypical antipsychotic drug clozapine mediate gene expression via intracellular regulation of NMDA receptors, albeit to different extents. Data obtained in primary striatal culture demonstrate that the intraneuronal signal transduction pathway activated by haloperidol, the cAMP pathway, leads to phosphorylation of the NR1 subtype of the NMDA receptor at (897)Ser. Haloperidol treatment is likewise shown to increase (897)Ser-NR1 phosphorylation in rats in vivo. Mutation of (896)Ser and (897)Ser to alanine, which prevents phosphorylation at both sites, inhibits cAMP-mediated gene expression. We conclude that antipsychotic drugs have the ability to modulate NMDA receptor function by an intraneuronal signal transduction mechanism. This facilitation of NMDA activity is necessary for antipsychotic drug-mediated gene expression and may contribute to the therapeutic benefits as well as side effects of antipsychotic drug treatment.

Hippocampal neuron number in schizophrenia. A stereological study.

Neuropathologic and neuroradiologic studies have reported hippocampal abnormalities in schizophrenics. We estimated the total number of neurons in the hippocampus of schizophrenics and controls to elucidate the neuronal basis of such changes. Thirteen brains of schizophrenics and 13 control brains closely matched for sex and age were studied. A new stereological method was applied to serial coronal sections through the whole hippocampus. Total hippocampal volume was reduced in the schizophrenic sample, more pronounced on the left side, but mean differences were not significant. The volumes of the pyramidal cell layer in the four subdivisions subiculum and cornu Ammonis sectors CA 1, CA 2/3, and CA 4 were almost identical in both groups. Schizophrenics did not differ from controls with regard to nerve cell density in any of the four subdivisions. The estimates of the total number of neurons in the hippocampal subdivisions were not different between schizophrenics and controls. The data do not support the hypothesis that hippocampal abnormalities are caused by neuronal cell loss. However, they are consistent with the suggestion that white matter changes in the hippocampus may play a role in the pathogenesis of schizophrenia.

Limbic structures and lateral ventricle in schizophrenia. A quantitative postmortem study.

Volume reduction of limbic structures in the medial temporal lobe of schizophrenics has been described in postmortem analyses of two brain collections. A total of 30 hemispheres of schizophrenics and 30 hemispheres of controls taken from a new collection of brains and closely matched for sex and age were examined. We applied computer-assisted stereologic methods to serial coronal sections of complete hemispheres. Volumetric measurement of amygdala, hippocampal formation, and lateral ventricle was performed. We found no significant volume reduction of amygdala and hippocampal formation in schizophrenics. Bilateral enlargement of the lateral ventricle was found in the schizophrenic group, but mean differences were not significant, and no correlation with limbic structure volumes was found. We postulate methodologic issues of postmortem volumetric measurements and matching of samples as possible reasons for the failure to replicate previous findings.

Functional imaging of memory retrieval in deficit vs nondeficit schizophrenia.

BACKGROUND: Neuroimaging studies have provided evidence of abnormal frontal and temporal lobe function in schizophrenia. Frontal cortex abnormalities have been associated with negative symptoms and temporal lobe abnormalities with positive symptoms. The deficit and nondeficit forms of schizophrenia were predicted to differ in prefrontal cortical activity, but not in medial temporal lobe activity. METHODS: Regional cerebral blood flow was studied using oxygen 15 positron emission tomography during 3 different memory retrieval conditions in 8 control subjects, 8 patients with the deficit syndrome, and 8 patients without the deficit syndrome. Behavioral and positron emission tomography data were analyzed using a mixed-effects model to test for population differences. RESULTS: In all memory conditions, frontal cortex activity was higher in patients without the deficit syndrome than in patients with the deficit syndrome. During the attempt to retrieve poorly encoded words, patients without the deficit syndrome recruited the left frontal cortex to a significantly greater degree than did patients with the deficit syndrome. The 2 schizophrenia subtypes did not differ in the activity or recruitment of the hippocampus during memory retrieval. CONCLUSION: Frontal cortex function during memory retrieval is differentially impaired in deficit and nondeficit schizophrenia, whereas hippocampal recruitment deficits are not significantly different between the 2 schizophrenia groups.

Neural correlates of out-group bias predict social impairment in patients with schizophrenia.

BACKGROUND: Social impairments are a hallmark feature of schizophrenia and are a key predictor of functional disability. Deficits in social information processing likely underlie social impairment; however, this relationship is understudied. We previously demonstrated that patients with schizophrenia fail to habituate to neutral faces, providing evidence for an alteration in basic social information processing. It remains unknown whether patients with schizophrenia also show deficits in processing of more complex social information. Out-group bias provides an excellent opportunity to test complex social information processing because the bias requires basic face processing skills, the ability to discriminate between groups, as well as the ability to categorize oneself into a salient social group. METHODS: Study participants were 23 patients with schizophrenia and 21 controls. Using functional magnetic resonance imaging, habituation of response to 120 s of repeated presentations of faces was assessed in participants who viewed either same-gender faces or opposite-gender faces. The interaction between face gender (same/opposite) and group was examined in three key regions: amygdala, hippocampus, and visual cortex. Social impairment was measured using the PANSS and correlations between social impairment and out-group effect (main effect of face type) were performed in patients. RESULTS: Patients with schizophrenia had aberrant neural responses to opposite-gender faces (interaction, p<.05 corrected). Healthy controls showed an immediate heightened response to opposite-gender faces relative to same-gender faces; but in patients this effect was substantially delayed (~70s). In patients with schizophrenia, the out-group bias was significantly correlated with social impairment. Patients with no social impairment showed a heightened neural response to opposite-gender faces after 30s, whereas patients with mild-moderate social impairment failed to ever show a heightened response. CONCLUSION: Alterations in neural responses during out-group processing predicted degree of social impairment in patients with schizophrenia; thus, neural responses to opposite-gender faces may provide a novel measure for studies of treatment response and disease outcome.

Antipsychotic drugs and neuroplasticity: insights into the treatment and neurobiology of schizophrenia.

This paper reviews the evidence that antipsychotic drugs induce neuroplasticity. We outline how the synaptic changes induced by the antipsychotic drug haloperidol may help our understanding of the mechanism of action of antipsychotic drugs in general, and how they may help to elucidate the neurobiology of schizophrenia. Studies have provided compelling evidence that haloperidol induces anatomical and molecular changes in the striatum. Anatomical changes have been documented at the level of regional brain volume, synapse morphology, and synapse number. At the molecular level, haloperidol has been shown to cause phosphorylation of proteins and to induce gene expression. The molecular responses to conventional antipsychotic drugs are predominantly observed in the striatum and nucleus accumbens, whereas atypical antipsychotic drugs have a subtler and more widespread impact. We conclude that the ability of antipsychotic drugs to induce anatomical and molecular changes in the brain may be relevant for their antipsychotic properties. The delayed therapeutic action of antipsychotic drugs, together with their promotion of neuroplasticity suggests that modification of synaptic connections by antipsychotic drugs is important for their mode of action. The concept of schizophrenia as a disorder of synaptic organization will benefit from a better understanding of the synaptic changes induced by antipsychotic drugs.

Cortex, white matter, and basal ganglia in schizophrenia: a volumetric postmortem study.

Postmortem volumetry of cortex, white matter, and basal ganglia was performed in 23 brains of schizophrenic patients and 23 brains of controls closely matched for gender, age, and hemisphere. Stereological methods were applied to serial coronal sections of complete hemispheres. We found no significant volume changes of cortex and white matter in schizophrenics. Striatal volume of schizophrenics was increased bilaterally reaching a significant level on the left side. Volumes of the globus pallidus were increased in both hemispheres reaching a significant level on the right side. After psychopathological differentiation, basal ganglia volume increase was also found in the subgroup of paranoid-hallucinatory schizophrenics.

Abnormalities in the thalamus and prefrontal cortex during episodic object recognition in schizophrenia.

BACKGROUND: Many patients with schizophrenia demonstrate memory deficits. We studied patterns of brain activity during episodic recognition of new and previously seen three-dimensional objects. METHODS: We used (15)O positron emission tomography to study regional cerebral blood flow in eight normal subjects and nine patients with schizophrenia during a visual object recognition task. RESULTS: In comparison with control subjects, patients with schizophrenia showed less regional cerebral blood flow increases in the pulvinar region of the right thalamus and the right prefrontal cortex during the recognition of new objects and significantly greater left prefrontal cortex regional cerebral blood flow increases during the recognition of previously seen objects. Patients with schizophrenia exhibited alarm rates to new objects similar to those of control subjects, but significantly lower recognition rates for previously seen objects. CONCLUSIONS: Schizophrenia is associated with attenuated right thalamic and right prefrontal activation during the recognition of novel visual stimuli and with increased left prefrontal cortical activation during impaired episodic recognition of previously seen visual stimuli. This study provides further evidence for abnormal thalamic and prefrontal cortex function in schizophrenia.

Acetylcholinesterase-rich pyramidal neurons in Alzheimer's disease.

The distribution of acetylcholinesterase (AChE)-rich pyramidal neurons was studied in the cortices of 7 Alzheimer's Disease (AD) patients and 4 normal-aged subjects. Both groups showed a characteristic distribution of these neurons with the highest density in motor and premotor areas, moderate density in association cortices, and low density in limbic-paralimbic areas. Three areas (Brodmann areas 6,22, and 24) were chosen for quantitative analysis. The number of pyramidal neurons that display an AChE-rich staining pattern was significantly reduced in AD patients. Nerve cell density was not significantly different in adjacent Nissl-stained sections. The density of AChE-rich (cholinergic) fibers was also decreased in all three cortical areas of the AD patients but was not correlated with the number of AChE-rich neurons. Loss of AChE-rich neurons was more pronounced in areas with high counts of tangles. These findings show that layer 3 and 5 pyramidal neurons in AD display a reduction of AChE activity. This phenomenon can not be attributed to the well known loss of cortical neurons or cholinergic innervation in AD.

Cholinergic innervation of the human thalamus: dual origin and differential nuclear distribution.

The cholinergic innervation of the human thalamus was studied with antibodies against the enzyme choline acetyltransferase (ChAT) and nerve growth factor receptor (NGFr). Acetylcholinesterase histochemistry was used to delineate nuclear boundaries. All thalamic nuclei displayed ChAT-positive axons and varicosities. Only the medial habenula contained ChAT-positive perikarya. Some intralaminar nuclei (central medial, central lateral, and paracentral), the reticular nucleus, midline nuclei (paraventricular and reuniens), some nuclei associated with the limbic system (anterodorsal nucleus and medially situated patches in the mediodorsal nucleus) and the lateral geniculate nucleus displayed the highest density of ChAT-positive axonal varicosities. The remaining sensory relay nuclei and the nuclei interconnected with the motor and association cortex displayed a lower level of innervation. Immunoreactivity for NGFr was observed in cholinergic neurons of the basal forebrain but not in cholinergic neurons of the upper brainstem. The contribution of basal forebrain afferents to the cholinergic innervation of the human thalamus was therefore studied with the aid of NGFr-immunoreactive axonal staining. The anterior intralaminar nuclei, the reticular nucleus, and medially situated patches in the mediodorsal nucleus displayed a substantial number of NGFr-positive varicose axons, presumably originating in the basal forebrain. Rare NGFr-positive axonal profiles were also seen in many of the other thalamic nuclei. These observations suggest that thalamic nuclei affiliated with limbic structures and with the ascending reticular activating system are likely to be under particularly intense cholinergic influence. While the vast majority of thalamic cholinergic input seems to come from the upper brainstem, the intralaminar and reticular nuclei, and especially medially situated patches within the mediodorsal nucleus also appear to receive substantial cholinergic innervation from the basal forebrain.

Cholinergic innervation of the amygdaloid complex in the human brain and its alterations in old age and Alzheimer's disease.

The cholinergic innervation of the human amygdaloid complex was studied immunohistochemically with a choline acetyltransferase (ChAT) antibody in eight brains: five control and three with Alzheimer's disease (AD). All amygdaloid nuclei displayed ChAT-immunopositive axons and varicosities. The density of these axons reached levels that were higher than in any other part of the forebrain except for the striatum. The highest level of ChAT-immunopositive profiles was seen in the basolateral nucleus and the second highest in the lateral part of the central nucleus. The basomedial, accessory basal, and cortical nuclei, the amygdalohippocampal and cortico-amygdaloid transition areas, as well as the anterior amygdaloid area, showed a moderate density of ChAT-positive varicosities and fibers. The lateral nucleus displayed a relatively low density of cholinergic innervation, and there were only rare ChAT-positive fibers in the medial nucleus. Although the level of cholinergic innervation in the lateral nucleus was relatively lower than in many of the other amygdaloid nuclei, it was approximately equivalent to that of entorhinal cortex, a region that receives one of the heaviest cholinergic inputs in the cerebral cortex. The distribution of the cholinergic fibers as studied by ChAT immunohistochemistry was nearly identical to that observed with AChE histochemistry. Quantitative densitometry in control specimens showed that there was no decline of amygdaloid cholinergic input when middle-aged subjects were compared with senescent subjects. In AD there was a severe and regionally selective depletion of this innervation in the amygdaloid complex. The cortical, accessory basal, and lateral nuclei displayed the most severe loss of ChAT-positive profiles, whereas the basolateral, and especially the central, nuclei displayed relatively little change. There was no consistent relationship between the loss of cholinergic fibers and the density of amyloid plaques and neurofibrillary tangles in amygdaloid nuclei.

Haloperidol-induced Fos expression in striatum is dependent upon transcription factor cyclic AMP response element binding protein.

Haloperidol has been shown to induce rapid and transient expression of c-fos messenger RNA and Fos protein in striatal neurons via dopamine D2 receptors. Regulation of the c-fos gene by cyclic AMP and Ca2+ has been shown to be dependent on a DNA regulatory element within its promoter that binds the constitutively expressed transcription factor cyclic AMP response element binding protein. Cyclic AMP response element binding protein binds to an oligonucleotide containing the calcium/cyclic AMP response element of the c-fos promoter sequence in striatal cell extracts; the amount of binding is not regulated by haloperidol treatment. We have previously shown that haloperidol induces cyclic AMP response element binding protein phosphorylation in the striatum. Here we show by intrastriatal injection of antisense oligonucleotides that haloperidol-induced Fos expression is dependent on cyclic AMP response element binding protein. Intrastriatal injections of phosphorothioate oligonucleotides, in antisense orientation to cyclic AMP response element binding protein messenger RNA, reduce levels of cyclic AMP response element binding protein and completely prevent haloperidol-mediated induction of Fos. Oligonucleotides in sense orientation have no such effect. We observed a markedly different time course of the Fos protein inhibition by cyclic AMP response element binding protein antisense oligonucleotides compared to c-fos antisense oligonucleotides. This most likely reflects the different half-lives of c-fos and cyclic AMP response element binding protein messenger RNA and proteins. Neither cyclic AMP response element binding protein nor c-fos antisense oligonucleotide injection reduced c-Jun immunostaining in the striatum. We conclude that haloperidol induces Fos via transcription factor cyclic AMP response element binding protein.

Retrograde degeneration and colchicine protection of basal forebrain cholinergic neurons following hippocampal injections of an immunotoxin against the P75 nerve growth factor receptor.

Intracerebroventricular injection of 192 IgG antibody against the p75LNGFR rat low affinity nerve growth factor receptor conjugated with saporin, a ribosome inactivating protein, has been shown to destroy the p75LNGFR-expressing cholinergic neurons of the basal forebrain. We injected this immunotoxin into the hippocampus and studied its retrograde effect upon the cholinergic neurons of the medial septum and the vertical limb of the diagonal band of Broca. Seven days after injection, there was a nearly total depletion of cholinergic axons within the hippocampus. This depletion was associated with a marked and significant decrease in the number of cholinergic neurons of the ipsilateral medial septum and the vertical limb of the diagonal band of Broca. At longer survival times, these changes were more pronounced. Parvalbumin-positive, GABAergic neurons within the same areas of the basal forebrain were not affected by immunotoxin injections. Injections of saporin alone had no effect upon cholinergic neurons. Simultaneous injection of colchicine with the immunotoxin resulted in a significant reduction of retrograde degeneration of cholinergic neurons and relative preservation of hippocampal cholinergic axons. These observations suggest that 192 IgG-saporin is transported retrogradely from the hippocampus to the cholinergic neurons in the medial septum and the vertical limb of the diagonal band of Broca and provide a model for retrograde degeneration of basal forebrain cholinergic neurons following cortically based toxic-pathologic processes.

Thalamic deactivation during early implicit sequence learning: a functional MRI study.

Previous research has implicated the striatum in implicit sequence learning. However, imaging findings have been inconsistent with regard to activity within the thalamus during performance of such tasks. Contemporary models of cortico-striato-thalamic circuitry suggest opposing influences on thalamic activity; suppression of thalamic activity is mediated by the indirect pathway and enhancement is mediated by the direct pathway. Using functional magnetic resonance imaging, we studied activity within human thalamus during early and late phases of an implicit sequence learning task known to reliably recruit the striatum. Significant deactivation (decreased signal relative to a baseline condition) was observed within the thalamus during early implicit learning. This finding is consistent with models of cortico-striato-thalamic function and specifically supports a profile of early 'thalamic gating' via the indirect pathway.

Variations of monoamines and their metabolites in the human brain putamen.

The levels of the monoamines dopamine (DA), serotonin (5-HT) and norepinephrine (NE) and the monoaminergic metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were measured with HPLC-ECD in 42 samples from human brain putamen. The influence of gender and of age was investigated and correlations between the monoamines were established. The DAergic system shows a significant difference between males and females, with females having lower DA and higher DOPAC levels and a higher DOPAC/DA ratio than males. No gender-related differences of 5-HT and its metabolites were observed, nor of NE. Three different age groups (group 1: 0-9.9 years: group 2: 10-59.9 years; group 3: 60 years and older) were defined according to previous studies on ontogenesis and senescence in human brain. An increase in 5-HT levels, decrease in 5-HIAA levels and a decrease in the 5-HIAA/5-HT ratio were observed after the first decade of life. Changes in the DAergic system were seen in senescence, with decreasing DA levels and an increase in the HVA/DA ratio. DOPAC, HVA and the DOPAC/DA ratio are unaffected. NE is similar in all age groups. The analysis of the relation of the levels of the three monoamines proved a strong correlation between the DAergic and 5-HTergic systems. The nature of this relationship might have an impact on neuro-psychiatric disorders and brain function.

Neuropathology of schizophrenia: cortex, thalamus, basal ganglia, and neurotransmitter-specific projection systems.

This article reviews neuropathological studies in the search for an anatomical correlate of schizophrenia. Replication of many results has proven to be difficult. A consistent finding is the lack of significant gliosis in the neocortex. Intriguing findings that need further corroboration include decreased volume and cell number of the mediodorsal thalamic nucleus, cytoarchitectural alterations of the prefrontal cortex and upper layers of the anterior cingulate gyrus, and superior temporal gyrus abnormalities. Most neuropathological studies investigate regional brain volume and cell density. Highly variable shrinkage of brain tissue postmortem makes these estimates prone to bias and often not comparable across studies. So far, no strong clinicopathological correlations and no pathological criteria to diagnose schizophrenia have been established.

Adenosine A1 receptors in human hippocampus: inhibition of [3H]8-cyclopentyl-1,3-dipropylxanthine binding by antagonist drugs.

Adenosine A1 receptors were visualized in human hippocampus using [3H]8-cyclopentyl-1,3-dipropylxanthine (DPCPX) as a radioactive ligand probe. The receptor antagonists caffeine, the xanthine derivative KFM 19 and the carbamazepine analogue oxcarbazepine displaced [3H]DPCPX binding homogeneously without any marked difference between the individual layers in the investigated hippocampal subregions (n = 4). Ki's in the individual layers were in a range between 8.5 +/- 6.5 microM and 18.9 +/- 16.0 microM for caffeine and 11.5 +/- 2.8 nM and 18.1 +/- 14.1 nM for KFM 19. Ki's could not be calculated for oxcarbazepine as the IC50's were greater than 100 microM with estimated IC25's varying between 51.2 +/- 53.3 microM and 179.9 +/- 89.9 microM. Antagonism of endogenous adenosine at A1 receptors may thus explain part of the clinical effects of caffeine in humans and possibly exclusively the behavioral effects of KFM 19 in non-human primates.

Schizophrenia.

To provide the most effective care for this difficult patient population, it is helpful to remember that patients with schizophrenia have disease-intrinsic limitations that limit their ability to participate in their care. These limitations are symptoms of a disease and not volitional. For the physician to substitute for these deficits, a certain degree of flexibility as well as the willingness to use unorthodox interventions is necessary. Good medical care is as important for the patient with schizophrenia as for any other patient.