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.

Testing models of thalamic dysfunction in schizophrenia using neuroimaging.

Neural models of schizophrenia have implicated the thalamus in deficits of early sensory processing and multimodal integration. We have reviewed the existing neuroimaging literature for evidence in support of models that propose abnormalities of thalamic relay nuclei, the mediodorsal thalamic nucleus, and large-scale cortico-thalamic networks. Thalamic volume reduction was found in some but not all studies. Studies of the early stages of schizophrenia suggest that thalamic volume reduction is present early in the course of the illness. Functional imaging studies have revealed task related abnormalities in several cortical and subcortical areas including the thalamus, suggesting a disruption of distributed thalamocortical networks. Chemical imaging studies have provided evidence for a loss of thalamic neuronal integrity in schizophrenia. There is, at present, inadequate data to support the hypothesis that schizophrenia is associated with abnormalities of sensory relay or association nuclei. There is evidence for a perturbation of cortico-thalamic networks, but further research is needed to elucidate the underlying mechanisms at the cellular and systems levels. The challenges ahead include better delineation of thalamic structure and function in vivo, the combination of genetic and imaging techniques to elucidate the genetic contributions to a thalamic phenotype of schizophrenia, and longitudinal studies of thalamic structure and function.

Hippocampal neurons in schizophrenia.

The hippocampus is crucial for normal brain function, especially for the encoding and retrieval of multimodal sensory information. Neuropsychiatric disorders such as temporal lobe epilepsy, amnesia, and the dementias are associated with structural and functional abnormalities of specific hippocampal neurons. More recently we have also found evidence for a role of the hippocampus in the pathophysiology of schizophrenia. The most consistent finding is a subtle, yet significant volume difference in schizophrenia. Here we review the cellular and molecular basis of smaller hippocampal volume in schizophrenia. In contrast to neurodegenerative disorders, total hippocampal cell number is not markedly decreased in schizophrenia. However, the intriguing finding of a selective loss of hippocampal interneurons deserves further study. Two neurotransmitter receptors, the GABAA and AMPA/kainate glutamate receptors, appear to be abnormal, whereas changes of the NMDA glutamate receptor are less robust. The expression of several genes, including those related to the GABAergic system, neurodevelopment, and synaptic function, is decreased in schizophrenia. Taken together, recent studies of hippocampal cell number, protein expression, and gene regulation point towards an abnormality of hippocampal architecture in schizophrenia.

Neuroimaging studies of the hippocampus in schizophrenia.

Three neuroimaging techniques, morphometric neuroimaging, magnetic resonance spectroscopy, and functional neuroimaging, have provided evidence for abnormal hippocampal structure and function in schizophrenia. Hippocampal volume reduction is now one of the most consistent structural abnormalities found in schizophrenia: it is present at the onset of the illness and, to a lesser degree, in first-degree relatives of schizophrenic probands. Decreased levels of N-acetyl-aspartate point towards a cellular basis of such volume changes. Functional neuroimaging studies have demonstrated abnormal levels of hippocampal activity at rest, during the experience of auditory hallucinations, and during the performance of memory retrieval tasks. These results of neuroimaging studies complement evidence from post-mortem and behavioral studies, which have found regionally specific abnormalities of the hippocampus and of memory function in schizophrenia.

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.

Neuroimaging of declarative memory in schizophrenia.

The past three decades have seen tremendous growth in our understanding of the cerebral underpinnings of schizophrenia. including the neural correlates of the cognitive impairment seen in this syndrome. In this article we review the role that structural and functional neuroimaging has played in elucidating the cerebral basis for the declarative memory deficits associated with schizophrenia. Memory impairment in schizophrenia appears to involve abnormal connectivity between the prefrontal cortex and three regions important in normal learning and memory: the hippocampus, thalamus, and cerebellum.

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.

Prefrontal regions supporting spontaneous and directed application of verbal learning strategies: evidence from PET.

The prefrontal cortex has been implicated in strategic memory processes, including the ability to use semantic organizational strategies to facilitate episodic learning. An important feature of these strategies is the way they are applied in novel or ambiguous situations-failure to initiate effective strategies spontaneously in unstructured settings is a central cognitive deficit in patients with frontal lobe disorders. The current study examined strategic memory with PET and a verbal encoding paradigm that manipulated semantic organization in three encoding conditions: spontaneous, directed and unrelated. During the spontaneous condition, subjects heard 24 words that were related in four categories but presented in mixed order, and they were not informed of this structure beforehand. Any semantic reorganization was, therefore, initiated spontaneously by the subject. In the directed condition, subjects were given a different list of 24 related words and explicitly instructed to notice relationships and mentally group related words together to improve memory. The unrelated list consisted of 24 unrelated words. Behavioural measures included semantic clustering, which assessed active regrouping of words into semantic categories during free recall. In graded PET contrasts (directed > spontaneous > unrelated), two distinct activations were found in left inferior prefrontal cortex (inferior frontal gyrus) and left dorsolateral prefrontal cortex (middle frontal gyrus), corresponding to levels of semantic clustering observed in the behavioural data. Additional covariate analyses in the first spontaneous condition indicated that blood flow in orbitofrontal cortex (OFC) was strongly correlated with semantic clustering scores during immediate free recall. Thus, blood flow in OFC during encoding predicted which subjects would spontaneously initiate effective strategies during free recall. Our findings indicate that OFC performs an important, and previously unappreciated, role in strategic memory by supporting the early mobilization of effective behavioural strategies in novel or ambiguous situations. Once initiated, lateral regions of left prefrontal cortex control verbal semantic organization.

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.

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.

Anatomic and molecular principles of psychopharmacology. A primer for psychiatrists.

Psychopharmacology uses chemicals to modulate human brain function. Three basic principles of neurotransmission may help to understand the current practice of clinical psychopharmacology. First, the anatomic organization of neurotransmitter systems determines their behavioral affiliation. Second, neurotransmitter receptors modulate the electrical properties (via ion channels) or the biochemical properties (via second-messenger systems) of neurons. Third, the intracellular integration of receptor-mediated responses leads to immediate or delayed effects on neuronal function.

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.

Neural models of schizophrenia.

Hallucinations and delusions - two diagnostic features of psychosis shared across the spectrum of heterogeneous schizophrenia constructs - can be described in terms of the pathophysiology of sensory information processing: hallucination is the impaired ability to classify representations as internally or externally generated, while delusion is the immutable linking of representations with each other in the absence of external dependency. The key anatomical systems in higher-order information processing are the cortex, thalamus, basal ganglia, and medial temporal lobe, each of which is modulated by neurotransmitter projection systems. Preliminary evidence, concentrating to date on the dorsolateral prefontal cortex, thalamus, and hippocampal region of the medial temporal lobe, points to neural circuitry dysfunction within and between each system in psychosis. This may account for specific symptoms and associated cognitive deficits such as memory impairment, attention deficit, and language disturbance.

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.

A method for assessing the accuracy of intersubject registration of the human brain using anatomic landmarks.

Several groups have developed methods for registering an individual's 3D MRI by deforming a standard template. This achievement leads to many possibilities for segmentation and morphology that will impact nuclear medical research in areas such as activation and receptor studies. Accordingly, there is a need for methods that can assess the accuracy of intersubject registration. We have developed a method based on a set of 128 anatomic landmarks per hemisphere, both cortical and subcortical, that allows assessment of both global and local transformation accuracy. We applied our method to compare the accuracy of two standard methods of intersubject registration, AIR 3.0 with fifth-order polynomial warping and the Talairach stereotaxic transformation (Talairach and Tournoux, 1988). SPGR MRI's (256 x 256 x 160) of six normal subjects (age 18-24 years) were derformed to match a standard template volume. To assess registration accuracy the landmarks were located on both the template volume and the transformed volumes by an experienced neuroanatomist. The resulting list of coordinates was analyzed graphically and by ANOVA to compare the accuracy of the two methods and the results of the manual analysis. ANOVA performed over all 128 landmarks showed that the Woods method was more accurate than Talairach (left hemisphere F = 2.8, P < 0.001 and right hemisphere F =2.4, P < 0.006). The Woods method provided a better brain surface transformation than did Talairach (F = 18.0, P < 0.0001), but as expected there was a smaller difference for subcortical structures and both had an accuracy <1 mm for the majority of subcortical landmarks. Overall, both the Woods and Talairach method located about 70% of landmarks with an error of 3 mm or less. More striking differences were noted for landmark accuracy

Neuroimaging of hallucinations: a review of the literature.

While hallucinations have been described for over two millennia, their cause remains unclear. Brain-based models suggest that abnormal cerebral excitation and a lack of normal cerebral inhibition may play primary roles, but evaluation of these hypotheses has been hampered by difficulty in studying the hallucinatory state. Recent advances in neuroimaging have provided researchers with tools to study a variety of mental states, including hallucinations. We review the literature regarding the structural and functional neural correlates of hallucinations. Despite small sample sizes and methodological differences, several studies describe similar results: hallucinations are associated with sensory modality-specific activation in cerebral areas involved in normal sensory processing. Furthermore, neural activation may be specifically related to distinct phenomenological features of the hallucinatory experience. Further work is needed to better understand the neural basis of hallucinations.

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.

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.