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Processing of emotions has been an enduring topic of interest in neuroimaging research, but studies have mostly used facial emotional stimuli. The aim of this study was to determine neural networks involved in emotion processing using scenic emotional visual stimuli. One hundred and twenty photographs from the International Affective Picture System (IAPS), including ecological scenes of disgust, fear, happiness, and sadness, were presented to 40 healthy participants while they underwent functional magnetic imaging resonance (fMRI). Afterwards they evaluated the emotional content of the pictures in an offline task. The occipito-temporal cortex and the amygdala-hippocampal complex showed a non-specific emotion-related activation, which was more marked in response to negative emotions than to happiness. The temporo-parietal cortex and the ventral anterior cingulate gyrus showed deactivation, with the former being marked for all emotions except fear and the latter being most marked for disgust. The fusiform gyrus showed activation in response to disgust and deactivation in response to happiness or sadness. Brain regions involved in processing of scenic emotion therefore resemble those reported for facial expressions of emotion in that they respond to a range of different emotions, although there appears to be specificity in the intensity and direction of the response.

Peak-based meta-analyses of neuroimaging studies create, for each study, a brain map of effect size or peak likelihood by convolving a kernel with each reported peak. A kernel is a small matrix applied in order that voxels surrounding the peak have a value similar to, but slightly lower than that of the peak. Current kernels are isotropic, i.e., the value of a voxel close to a peak only depends on the Euclidean distance between the voxel and the peak. However, such perfect spheres of effect size or likelihood around the peak are rather implausible: a voxel that correlates with the peak across individuals is more likely to be part of the cluster of significant activation or difference than voxels uncorrelated with the peak. This paper introduces anisotropic kernels, which assign different values to the different neighboring voxels based on the spatial correlation between them. They are specifically developed for effect-size signed differential mapping (ES-SDM), though might be easily implemented in other meta-analysis packages such as activation likelihood estimation (ALE). The paper also describes the creation of the required correlation templates for gray matter/BOLD response, white matter, cerebrospinal fluid, and fractional anisotropy. Finally, the new method is validated by quantifying the accuracy of the recreation of effect size maps from peak information. This empirical validation showed that the optimal degree of anisotropy and full-width at half-maximum (FWHM) might vary largely depending on the specific data meta-analyzed. However, it also showed that the recreation substantially improved and did not depend on the FWHM when full anisotropy was used. Based on these results, we recommend the use of fully anisotropic kernels in ES-SDM and ALE, unless optimal meta-analysis-specific parameters can be estimated based on the recreation of available statistical maps. The new method and templates are freely available at http://www.sdmproject.com/.

Voxel-based morphometry (VBM) is a widely-used structural neuroimaging technique for comparing meso- and macroscopic regional brain volumes between patients and controls in vivo, but some of its steps, particularly the modulation, lack an experimental validation. The aims of this study were two-fold: a) to assess the effects of modulation to detect mesoscopic (i.e. between microscopic and macroscopic) abnormalities on published, classic VBM; and b) to suggest a set of potentially optimal settings for detecting mesoscopic abnormalities with new, advanced, high-resolution diffeomorphic VBM normalization algorithms. Sensitivity and false positive rate after modulating or not in classic VBM using different software packages and spatial statistics, and after setting a range of different parameters in advanced VBM (ANTS-SyN), were calculated in 10 VBM comparisons of 32 altered vs. 32 unaltered gray matter images from different healthy controls. Simulated brain abnormalities comprised mesoscopic volume differences mainly due to cortical thinning. In classic VBM, modulation was associated with a substantial decrease of the sensitivity to detect mesoscopic abnormalities (p<0.001). Optimal settings for advanced VBM included the omission of modulation, the use of large smoothing kernels, and the application of voxel-based or threshold-free cluster enhancement (TFCE) spatial statistics. The modulation-related decrease in sensitivity was due to an increase in variance, and it was more severe in higher-resolution normalization algorithms. Findings from this study suggest the use of unmodulated VBM to detect mesoscopic abnormalities such as cortical thinning., (© 2013.)

Background: The pathological basis of tardive dyskinesia is unknown. Although its clinical features implicate the basal ganglia, imaging studies have not found clear evidence that it is associated with volume changes in these or other brain structures., Aims: To determine, using voxel-based structural imaging, whether there are regions of grey matter volume change in people with schizophrenia who also have tardive dyskinesia compared with those without tardive dyskinesia., Method: A total of 81 people with chronic schizophrenia, 32 with tardive dyskinesia and 49 without, were examined using magnetic resonance imaging (MRI) and whole-brain, optimised voxel-based morphometry. A comparison group of 61 healthy controls was also examined., Results: Compared with those without tardive dyskinesia, patients with tardive dyskinesia showed a pattern of volume reductions in predominantly subcortical regions, including the basal ganglia and the thalamus. Within the basal ganglia, volume reductions were seen in the caudate nucleus, to a lesser extent in the putamen, and only marginally in the globus pallidus. The patients with tardive dyskinesia, but not those without, showed significant volume reductions in the basal ganglia compared with the healthy controls but both groups had smaller volumes than controls in other affected areas., Conclusions: The pathological process or processes that underlie the development of tardive dyskinesia are not just neurochemical in nature, but affect brain structure.

Background: Bipolar depression has been found to be associated with changes in prefrontal cortex activity during performance of cognitive tasks. However, the role of task-related de-activations has been little investigated., Method: Forty-one bipolar depressed patients and 41 matched normal controls underwent fMRI scanning while performing baseline, 1-back and 2-back versions of the n-back task. Linear models were used to obtain maps of within-group activations and areas of differential activation between the groups., Results: The bipolar depressed patients showed reduced activation in the dorsolateral prefrontal cortex (DLPFC) bilaterally and several other regions. After controlling for differences in task performance only differences in the DLPFC and cerebellum remained. Left DLPFC activation was inversely correlated with Hamilton and MADRS scores. The patients showed failure to de-activate in the medial prefrontal cortex, an area corresponding to the anterior medial node of the default mode network., Limitations: To confirm default mode network dysfunction demonstration of resting-state connectivity abnormalities would also be required. The study was carried out on treated patients, and did not assess for presence of depressive symptoms in the healthy controls., Conclusions: Both prefrontal cortical and default mode network dysfunction appear to characterise bipolar depression. The former, but not the latter, is associated with symptom severity., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Wavelet-based methods have been developed for statistical analysis of functional MRI and PET data, where the wavelet transformation is employed as a tool for efficient signal representation. A number of studies using these approaches have reported better estimation capabilities, in terms of increased sensitivity and specificity, than the standard statistical analyses in the spatial domain. In line with these previous studies, the present report proposes a statistical analysis in the wavelet domain for the estimation of inter-group differences from structural MRI data. The procedure, called wavelet-based morphometry (WBM), was implemented under a voxel-based morphometry (VBM) style analysis. It was evaluated by comparing the gray-matter images of a group of 32 healthy subjects whose images were artificially altered to induce thinning of the cortex, with a different group of 32 healthy subjects whose images were unaltered. In order to quantify the performance of the reconstruction from a practical perspective, the same comparison was also conducted with standard VBM using SPM's Gaussian random fields and FSL's cluster-based statistics, family-wise error corrected, for datasets spatially-normalized via two different registration methods (i.e., SyN and FNIRT). The effect of using different amounts of smoothing, Battle-Lemarié filters and resolution levels in the wavelet transform was also investigated. Results support the proposed approach as a different and promising methodology to assess the structural morphometric differences between different populations of subjects., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Formal thought disorder (FTD) in schizophrenia has been found to be associated with volume reductions in the left superior temporal cortex. However, there have been negative findings and some studies have also found associations in other cortical regions., Method: Fifty-one schizophrenic patients were evaluated for presence of FTD with the Thought, Language and Communication (TLC) scale and underwent whole-brain structural MRI using optimized voxel-based morphometry (VBM). Fifty-nine matched healthy controls were also scanned., Results: Compared to 31 patients without FTD (global TLC rating 0 or 1), 20 patients with FTD (global TLC rating 2-5) showed clusters of volume reduction in the medial frontal and orbitofrontal cortex bilaterally, and in two left-sided areas approximating to Broca's and Wernicke's areas. The pattern of FTD-associated volume reductions was largely different from that found in a comparison between the healthy controls and the patients without FTD. Analysis of correlations within regions-of-interest based on the above clusters indicated that the 'fluent disorganization' component of FTD was correlated with volume reductions in both Broca's and Wernicke's areas, whereas poverty of content of speech was correlated with reductions in the medial frontal/orbitofrontal cortex., Conclusions: The findings point to a relationship between FTD in schizophrenia and structural brain pathology in brain areas involved in language and executive function., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Schizo-affective disorder has not been studied to any significant extent using functional imaging. The aim of this study was to examine patterns of brain activation and deactivation in patients meeting strict diagnostic criteria for the disorder., Method: Thirty-two patients meeting research diagnostic criteria (RDC) for schizo-affective disorder (16 schizomanic and 16 schizodepressive) and 32 matched healthy controls underwent functional magnetic resonance imaging (fMRI) during performance of the n-back task. Linear models were used to obtain maps of activations and deactivations in the groups., Results: Controls showed activation in a network of frontal and other areas and also deactivation in the medial frontal cortex, the precuneus and the parietal cortex. Schizo-affective patients activated significantly less in prefrontal, parietal and temporal regions than the controls, and also showed failure of deactivation in the medial frontal cortex. When task performance was controlled for, the reduced activation in the dorsolateral prefrontal cortex (DLPFC) and the failure of deactivation of the medial frontal cortex remained significant., Conclusions: Schizo-affective disorder shows a similar pattern of reduced frontal activation to schizophrenia. The disorder is also characterized by failure of deactivation suggestive of default mode network dysfunction.

Background: Some functional imaging abnormalities found in bipolar disorder are state related, whereas others persist into euthymia. It is uncertain to what extent these latter changes may reflect continuing subsyndromal affective fluctuations and whether those can be modulated by therapeutic interventions., Method: We report functional magnetic resonance imaging (fMRI) findings during performance of the n-back working memory task in a bipolar patient who showed a marked improvement in subsyndromal affective symptoms after receiving eye movement desensitization and reprocessing (EMDR) therapy in the context of a clinical trial., Results: The patient's clinical improvement was accompanied by marked changes in functional imaging, as compared to 30 healthy subjects. fMRI changes were noted particularly in deactivation, with failure of deactivation in the medial frontal cortex partially normalizing after treatment., Conclusions: This case supports the potential therapeutic overall benefit of EMDR in traumatized bipolar patients and suggests a possible neurobiological mechanism of action: normalization of default mode network dysfunction., (Copyright © 2013 S. Karger AG, Basel.)

Objectives: Manic patients have been found to show reduced activation in the prefrontal cortex and other regions during performance of cognitive tasks. However, little is known about de-activations associated with the disorder. This study aimed to examine, at the whole-brain level, abnormal patterns of task-related activation and de-activation during performance of a working memory task., Methods: Twenty-nine DSM-IV bipolar patients and 46 healthy controls underwent fMRI during performance of the n-back task. The patients were scanned while they were in a manic episode. Linear models were used to obtain maps of within-group activations and areas of differential activation between the groups., Results: The manic patients showed reduced activation compared to the controls in the bilateral dorsolateral prefrontal cortex and the right parietal cortex. They also showed failure of de-activation in the medial frontal cortex, extending to the temporal poles and parts of the limbic system bilaterally. The failure of activation in the dorsolateral prefrontal cortex disappeared when differences in task performance were controlled for in the analysis. However, the medial frontal failure of de-activation survived controlling for this., Conclusions: This study suggests that, in addition to reduced prefrontal activation, failure of de-activation is an important functional imaging abnormality in mania. This, together with its location in the medial prefrontal cortex, implies default mode network dysfunction in the disorder.

Background: Genetic studies have found that the interleukin-1β gene (IL1B, 2q13) influences the risk for schizophrenia, but the underlying biological mechanisms of the association are still unclear. Investigation of the effects of genetic variability in this gene on brain function could provide more information about its role in the disorder., Methods: The present study examined the effects of a functional polymorphism at IL1B gene promoter (-511C/T; rs16944) on brain correlates of working memory performance in schizophrenia. Forty-eight schizophrenia patients and 46 control subjects underwent functional magnetic resonance imaging while performing the n-back task., Results: In the pooled sample, genetic variability at this locus was associated with differential brain activation in a bilateral frontal region including the dorsolateral prefrontal cortex. There was also a significant diagnosis × genotype interaction effect in an overlapping frontal region: the IL1B polymorphism did not affect activation in the control subjects in this area, but the schizophrenia patients who were T carriers showed significantly higher activation than the CC homozygotes., Conclusions: The findings support a role for IL1B variability in the dorsolateral prefrontal cortex dysfunction classically associated with schizophrenia., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Deficits in memory and executive performance are well-established features of bipolar disorder and schizophrenia. By contrast, data on cognitive impairment in schizoaffective disorder are scarce and the findings are conflicting., Method: We used the Wechsler Memory Scale (WMS-III) and the Behavioural Assessment of the Dysexecutive Syndrome (BADS) to test memory and executive function in 45 schizophrenic patients, 26 schizomanic patients and 51 manic bipolar patients in comparison to 65 healthy controls. The patients were tested when acutely ill., Results: All three patient groups performed significantly more poorly than the controls on global measures of memory and executive functioning, but there were no differences among the patient groups. There were few differences in memory and executive function subtest scores within the patient groups. There were no differences in any test scores between manic patients with and without psychotic symptoms., Conclusions: Schizophrenic, schizomanic and manic patients show a broadly similar degree of executive and memory deficits in the acute phase of illness. Our results do not support a categorical differentiation across different psychotic categories with regard to neuropsychological deficits.

Background: It is not known whether first-episode psychosis is characterized by the same prefrontal cortex functional imaging abnormalities as chronic schizophrenia., Method: Thirty patients with a first episode of non-affective functional psychosis and 28 healthy controls underwent functional magnetic resonance imaging (fMRI) during performance of the n-back working memory task. Voxel-based analyses of brain activations and deactivations were carried out and compared between groups. The connectivity of regions of significant difference between the patients and controls was also examined., Results: The first-episode patients did not show significant prefrontal hypo- or hyperactivation compared to controls. However, they showed failure of deactivation in the medial frontal cortex. This area showed high levels of connectivity with the posterior cingulate gyrus/precuneus and parts of the parietal cortex bilaterally. Failure of deactivation was significantly greater in first-episode patients who had or went on to acquire a DSM-IV diagnosis of schizophrenia than in those who did not, and in those who met RDC criteria for schizophrenia compared to those who did not., Conclusions: First-episode psychosis is not characterized by hypo- or hyperfrontality but instead by a failure of deactivation in the medial frontal cortex. The location and connectivity of this area suggest that it is part of the default mode network. The failure of deactivation seems to be particularly marked in first-episode patients who have, or progress to, schizophrenia.

Background: Patients with schizophrenia have been found to show unawareness of cognitive impairment. However, its frequency and its relationship to lack of insight into illness are uncertain., Method: Forty-two patients with chronic schizophrenia were given tests of executive function and memory. Awareness of cognitive impairment was measured by means of discrepancy scores--differences between patient and psychologist ratings of memory and frontal/executive failures in daily life. Insight into illness was assessed using the Scale to Assess Unawareness of Mental Disorder (SUMD)., Results: A majority of the patients were found to underestimate their cognitive impairment; however, some overestimated it. Unawareness of cognitive impairment and lack of clinical insight loaded on different factors in a factor analysis, but these two factors were themselves correlated., Conclusions: The findings suggest that both unawareness and overestimation of cognitive impairment characterise patients with schizophrenia, although the former is more common. Awareness of cognitive impairment occurs independently of insight into illness at the clinical level, although the two phenomena may be linked at a deeper level., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Recent published data and treatment guidelines have created uncertainty about the use of lamotrigine in affective disorders, especially in acute bipolar depression. Furthermore, unpublished data on lamotrigine in mania, mixed episodes, unipolar depression and rapid cycling are still waiting to be integrated into the literature. Therefore, we critically reviewed the position of lamotrigine in the acute and long-term treatment of affective disorders. Studies were identified by searching English language articles published in MEDLINE using the key words: lamotrigine, bipolar depression, unipolar depression, mania, mixed episode, long-term treatment, rapid-cycling. Results of unpublished trials were obtained from the GlaxoSmithKline website. Lamotrigine showed efficacy in the prophylaxis of bipolar disorder, more so in depressive than manic episodes. There was no evidence of effectiveness in the acute treatment of mania, mixed episodes, unipolar depression or rapid-cycling bipolar I disorder. Its effect in the acute treatment of bipolar depression is at most small. Based on current evidence, lamotrigine is indicated for the prophylaxis of bipolar disorder with predominantly depressive episodes. Its effectiveness in the acute treatment of bipolar depression is open to debate, and practical considerations limit its usefulness here. There are no grounds for recommending its use in manic or mixed states, in rapidly-cycling bipolar I or in unipolar depression.

Background: Cognitive impairment is an established feature of schizophrenia. However, little is known about its relationship to the structural and functional brain abnormalities that characterise the disorder. Aims To identify structural and/or functional brain abnormalities associated with schizophrenic cognitive impairment., Method: We carried out structural magnetic resonance imaging (MRI) and voxel-based morphometry in 26 participants who were cognitively impaired and 23 who were cognitively preserved, all with schizophrenia, plus 39 matched controls. Nineteen of those who were cognitively impaired and 18 of those who were cognitively preserved plus 34 controls also underwent functional MRI during performance of a working memory task., Results: No differences were found between the participants who were cognitively intact and those who were cognitively impaired in lateral ventricular volume or whole brain volume. Voxel-based morphometry also failed to reveal clusters of significant difference in grey and white matter volume between these two groups. However, during performance of the n-back task, the participants who were cognitively impaired showed hypoactivation compared with those who were cognitively intact in the dorsolateral prefrontal cortex among other brain regions., Conclusions: Cognitive impairment in schizophrenia is not a function of the structural brain abnormality that accompanies the disorder but has correlates in altered brain function.

A 58-year old woman with chronic schizophrenia developed worsening parkinsonian symptoms over the previous 6 years, and was eventually diagnosed as having Parkinson's disease. Antipsychotics were stopped because they worsened these symptoms. Antiparkinsonian treatment led to a significant increase in delusions and behavioural disorganisation. The patient underwent electroconvulsive-therapy which improved both her psychiatric and motor symptoms. After treatment, 123I-Ioflupane uptake was mildly increased in the left caudate nucleus, but uptake in right caudate nucleus was lower than in a pretreatment scan.

Background: There is increasing evidence of default mode network (DMN) dysfunction in schizophrenia. It has also been suggested that brain structural changes are maximal in a medial frontal area which overlaps with the anterior midline node of this network., Methods: Brain deactivations were examined in 14 schizophrenic patients and 14 controls during performance of two tasks requiring identification or labelling of facial emotions. Grey matter and white matter volumes were compared using voxel-based morphometry., Results: Relative to the controls, the schizophrenic patients showed failure to deactivate in the anterior and posterior midline nodes of the default mode network, as well as other areas considered to be part of the network. Grey matter volume reductions in the patients were found in medial cortical regions which overlapped with the same parts of the network. The functional and structural changes showed significant correlations in a number of medial cortical areas., Conclusions: Failure of deactivation in the default mode network is seen in schizophrenic patients when they perform facial emotion tasks. This failure is more extensive than that seen during performance of working memory tasks. The study also supports recent findings of brain structural changes in schizophrenia in the territory of the default mode network., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background: Studies of procedural learning in schizophrenia have been inconsistent, sometimes finding it to be preserved and sometimes impaired. This study examined three factors that could account for the variability among findings: type of task, presence of general intellectual impairment, and the extrapyramidal side effects of neuroleptic treatment., Methods: Forty-three patients with schizophrenia and 22 normal control subjects were examined with three different paradigms: the pursuit rotor, mirror reading, and probabilistic learning ("weather prediction"). A subgroup of intellectually preserved patients was also examined. Patients with and without tardive dyskinesia and with and without Parkinsonism were also compared., Results: The schizophrenic patients showed learning comparable to the control subjects on the pursuit rotor and mirror reading but were impaired on the probabilistic learning task. However, this last difference disappeared when the subgroup of intellectually preserved patients was compared with a subgroup of matched control subjects. Patients with and without tardive dyskinesia or Parkinsonism showed similar learning on all three tasks, but patients with tardive dyskinesia showed poorer overall performance than those without., Conclusions: Procedural learning tends to be preserved in schizophrenia, and when impairment is found, differences in the overall level of intellectual function might be the determining factor., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Abnormal interactions between areas of the brain have been pointed as possible causes for schizophrenia. However, the nature of these disturbances and the anatomical location of the regions involved are still unclear. Here, we describe a method to estimate maps of net levels of connectivity in the resting brain, and we apply it to look for differential patterns of connectivity in schizophrenia. This method uses partial coherences as a basic measure of covariability, and it minimises the effect of major physiological noise. When overall (net) connectivity maps of a sample of 40 patients with schizophrenia were compared with the maps from a matched sample of 40 controls, a single area of abnormality was found. It is an area of patient hyper-connectivity and is located frontally, in medial and orbital structures, clearly overlapping the anterior node of the default mode network (DMN). When this area is used as a region of interest in a second-level analysis, it shows functional hyper-connections with several cortical and subcortical structures. Interestingly, the most significant abnormality is found with the caudate, which has a bilateral pattern of abnormality, pointing to a possible DMN-striatum deviant relation in schizophrenia. However, hyper-connectivity observed with other regions (right hippocampus and amygdala, and other cortical structures) suggests a more pervasive alteration of brain connectivity in this disease., (Copyright © 2010 Wiley-Liss, Inc.)

There is a growing interest in finding ways to summarize the local connectivity properties of the brain through single brain maps. Here we propose a method based on the conditional mutual information (CMI) in the frequency domain. CMI maps quantify the amount of non-redundant covariability between each site and all others in the rest of the brain, partialling out the joint variability due to gross physiological noise. Average maps from a sample of 45 healthy individuals scanned in the resting state show a clear and symmetric pattern of connectivity maxima in several regions of cortex, including prefrontal, orbitofrontal, lateral-parietal, and midline default mode network components; and in subcortical nuclei, including the amygdala, thalamus, and basal ganglia. Such cortical and subcortical hotspots of functional connectivity were more clearly evident at lower frequencies (0.02-0.1 Hz) than at higher frequencies (0.1-0.2 Hz) of endogenous oscillation. CMI mapping can also be easily applied to perform group analyses. This is exemplified by exploring effects of normal aging on CMI in a sample of healthy controls and by investigating correlations between CMI and positive psychotic symptom scores in a sample of 40 schizophrenic patients. Both the normative aging and schizophrenia studies reveal functional connectivity trends that converge with reported findings from other studies, thus giving further support to the validity of the proposed method.

The Val158Met polymorphism in the COMT gene has been found to be associated with differences in brain activation in both healthy subjects and patients with schizophrenia. The predominant finding has been increased prefrontal activation associated with the Val allele; however, genotype-related de-activations have not been studied. In this study 42 schizophrenia patients and 31 controls underwent fMRI while performing the n-back task. Brain differences related to presence/absence of disease and presence/absence of the Val/Val genotype were examined. Both disease and Val/Val genotype were associated with failure of de-activation in a cluster centred in the medial prefrontal cortex. There was no interaction between disease and genotype at this location, but clusters where there were significant interactions emerged in the right prefrontal cortex and left temporal/parietal cortex. These findings suggest that Val158Met polymorphism influences task-related de-activations in the default mode network in both healthy subjects and schizophrenia patients to an equivalent extent. However the Val158Met polymorphism also has disease-specific effects on DLPFC activation in schizophrenia., (Copyright © 2010. Published by Elsevier Inc.)

Neuroimaging studies have found evidence of altered brain structure and function in schizophrenia, but have had complex findings regarding the localization of abnormality. We applied multimodal imaging (voxel-based morphometry (VBM), functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) combined with tractography) to 32 chronic schizophrenic patients and matched healthy controls. At a conservative threshold of P=0.01 corrected, structural and functional imaging revealed overlapping regions of abnormality in the medial frontal cortex. DTI found that white matter abnormality predominated in the anterior corpus callosum, and analysis of the anatomical connectivity of representative seed regions again implicated fibres projecting to the medial frontal cortex. There was also evidence of convergent abnormality in the dorsolateral prefrontal cortex, although here the laterality was less consistent across techniques. The medial frontal region identified by these three imaging techniques corresponds to the anterior midline node of the default mode network, a brain system which is believed to support internally directed thought, a state of watchfulness, and/or the maintenance of one's sense of self, and which is of considerable current interest in neuropsychiatric disorders.

Background: Identification of facial emotions has been found to be impaired in schizophrenia but there are uncertainties about the neuropsychological specificity of the finding., Method: Twenty-two patients with schizophrenia and 20 healthy controls were given tests requiring identification of facial emotion, judgement of the intensity of emotional expressions without identification, familiar face recognition and the Benton Facial Recognition Test (BFRT). The schizophrenia patients were selected to be relatively intellectually preserved., Results: The patients with schizophrenia showed no deficit in identifying facial emotion, although they were slower than the controls. They were, however, impaired on judging the intensity of emotional expression without identification. They showed impairment in recognizing familiar faces but not on the BFRT., Conclusions: When steps are taken to reduce the effects of general intellectual impairment, there is no deficit in identifying facial emotions in schizophrenia. There may, however, be a deficit in judging emotional intensity. The impairment found in naming familiar faces is consistent with other evidence of semantic memory impairment in the disorder.

Background/aims: Cluster analysis has had limited success in establishing whether there are subtypes of schizophrenia. Grade of membership (GoM) analysis is a multivariate statistical technique which has advantages when, as in schizophrenia, individuals conforming to pure types are uncommon and mixed forms are frequent., Methods: GoM analysis was applied to 118 chronic schizophrenic patients. The patients were of all clinical subtypes, including 13 with simple schizophrenia. Both current and 'lifetime' symptoms were assessed, and two different rating systems were used., Results: Specifying 3 pure types resulted in robust findings across analyses. One pure type corresponded to paranoid schizophrenia, one to simple schizophrenia and the third combined elements of hebephrenic and catatonic schizophrenia. Specifying 4 pure types split the original 3 pure types in ways which were not clinically intuitive., Conclusion: GoM analysis divides schizophrenia into subtypes along conventional lines, with the proviso that hebephrenic and catatonic schizophrenic patients are not separable, at least in the chronic stage of the illness., (Copyright 2009 S. Karger AG, Basel.)

Dyke-Davidoff-Masson syndrome, or cerebral hemiatrophy, is a pre- or perinatally acquired entity characterized by predominantly neurologic symptoms, such as seizures, facial asymmetry, contralateral hemiplegia, and mental retardation. Psychiatric symptoms are rarely reported. We report the first case of left cerebral hemiatrophy and a late onset of treatment-resistant schizoaffective disorder after a stressful life event. The patient finally responded well to clozapine. The clinical history and results from structural neuroimaging are highlighted to discuss the possible developmental bias for psychotic disorders.

Background: Functional imaging studies using working memory tasks have documented both prefrontal cortex (PFC) hypo- and hyperactivation in schizophrenia. However, these studies have often failed to consider the potential role of task-related deactivation., Method: Thirty-two patients with chronic schizophrenia and 32 age- and sex-matched normal controls underwent functional magnetic resonance imaging (fMRI) scanning while performing baseline, 1-back and 2-back versions of the n-back task. Linear models were used to obtain maps of activations and deactivations in the groups., Results: The controls showed activation in the expected frontal regions. There were also clusters of deactivation, particularly in the anterior cingulate/ventromedial PFC and the posterior cingulate cortex/precuneus. Compared to the controls, the schizophrenic patients showed reduced activation in the right dorsolateral prefrontal cortex (DLPFC) and other frontal areas. There was also an area in the anterior cingulate/ventromedial PFC where the patients showed apparently greater activation than the controls. This represented a failure of deactivation in the schizophrenic patients. Failure to activate was a function of the patients' impaired performance on the n-back task, whereas the failure to deactivate was less performance dependent., Conclusions: Patients with schizophrenia show both failure to activate and failure to deactivate during performance of a working memory task. The area of failure of deactivation is in the anterior prefrontal/anterior cingulate cortex and corresponds to one of the two midline components of the 'default mode network' implicated in functions related to maintaining one's sense of self.

The symptoms of major psychotic illness are diverse and vary widely across individuals. Furthermore, the prepsychotic phase is indistinct, providing little indication of the precise pattern of symptoms that may subsequently emerge. Likewise, although in some individuals who have affected family members the occurrence of disease may be predicted, the specific symptom profile may not. An important question, therefore, is whether predictive physiological markers of symptom expression can be identified. We conducted a placebo-controlled, within-subjects study in healthy individuals to investigate whether individual variability in baseline physiology, as assessed using functional magnetic resonance imaging, predicted psychosis elicited by the psychotomimetic drug ketamine and whether physiological change under drug reproduced those reported in patients. Here we show that brain responses to cognitive task demands under placebo predict the expression of psychotic phenomena after drug administration. Frontothalamic responses to a working memory task were associated with the tendency of subjects to experience negative symptoms under ketamine. Bilateral frontal responses to an attention task were also predictive of negative symptoms. Frontotemporal activations during language processing tasks were predictive of thought disorder and auditory illusory experiences. A subpsychotic dose of ketamine administered during a second scanning session resulted in increased basal ganglia and thalamic activation during the working memory task, paralleling previous reports in patients with schizophrenia. These results demonstrate precise and predictive brain markers for individual profiles of vulnerability to drug-induced psychosis.

Background: Increased semantic priming is an influential theory of thought disorder in schizophrenia. However, studies to date have had conflicting findings., Aims: To investigate semantic memory in patients with schizophrenia with and without thought disorder., Method: Data were pooled from 36 studies comparing patients with schizophrenia and normal controls in semantic priming tasks. Data from 18 studies comparing patients with thought disorder with normal controls, and 13 studies comparing patients with and without thought disorder were also pooled., Results: There was no support for altered semantic priming in schizophrenia as a whole. Increased semantic priming in patients with thought disorder was supported, but this was significant only in comparison with normal controls and not in comparison with patients without thought disorder. Stimulus onset asynchrony (SOA) and general slowing of reaction time moderated the effect size for priming in patients with thought disorder., Conclusions: Meta-analysis provides qualified support for increased semantic priming as a psychological abnormality underlying thought disorder. However, the possibility that the effect is an artefact of general slowing of reaction time in schizophrenia has not been excluded.

Here we develop a measure of functional connectivity describing the degree of covariability between a brain region and the rest of the brain. This measure is based on previous formulas for the mutual information (MI) between clusters of regions in the frequency domain. Under the current scenario, the MI can be given as a simple monotonous function of the multiple coherence and it leads to an easy visual representation of connectivity patterns. Computationally efficient formulas, adequate for short time series, are presented and applied to functional magnetic resonance imaging (fMRI) data measured in subjects (N=34) performing a working memory task or being at rest. While resting state coherence in high (0.17-0.25 Hz) and middle (0.08-0.17 Hz) frequency intervals is bilaterally salient in several limbic and temporal areas including the insula, the amygdala, and the primary auditory cortex, low frequencies (<0.08 Hz) have greatest connectivity in frontal structures. Results from the comparison between resting and N-back conditions show enhanced low frequency coherence in many of the areas previously reported in standard fMRI activation studies of working memory, but task related reductions in high frequency connectivity are also found in regions of the default mode network. Finally, potentially confounding effects of head movement and regional volume on MI are identified and addressed.

Background: A form of confabulation has been documented in schizophrenia and appears to be related to the symptom of thought disorder. It is unclear whether it is associated with the same pattern of neuropsychological deficits as confabulation in neurological patients., Method: Thirty-four patients with chronic schizophrenia, including those with and without thought disorder, and 17 healthy controls were given a fable recall task to elicit confabulation. They were also examined on a range of executive, episodic and semantic memory tests., Results: Confabulation was seen at a significantly higher rate in the schizophrenic patients than the controls, and predominated in those with thought disorder. Neuropsychologically, it was not a function of general intellectual impairment, and was not clearly related to episodic memory or executive impairment. However, there were indications of an association with semantic memory impairment., Conclusions: The findings support the existence of a form of confabulation in schizophrenia that is related to thought disorder and has a different neuropsychological signature to the neurological form of the symptom.

Objective: Investigators have reported that weight gain attributed to clozapine is associated with its clinical response. However, weight gain is a nonspecific physiological variable that, in itself, does not explain the mechanism underlying this relation. Alternatively, other biological variables that are often associated with weight gain, such as serum lipids, may assist in explaining this observation. The primary objective of this study was to determine whether an increase in serum lipids is associated with improvement in schizophrenia symptoms during steady state treatment with clozapine., Methods: The data for this study represent a subset of data from a randomized, double-blinded trial that evaluated subjects with schizophrenia who demonstrated a poor treatment response to clozapine. While continuing their clozapine therapy, subjects were randomly assigned to receive either risperidone 3 mg daily or placebo for 8 weeks. This course of treatment was followed by an optional (open-label) 18 weeks of augmentation with risperidone. In the present study, we included all subjects from the previously reported trial who had fasting lipid analyses and Positive and Negative Syndrome Scale (PANSS) scores from days 7 and 63 (n = 55). For the primary analyses, we used multiple regression to examine the association between serum lipid concentrations and PANSS scores, after controlling for weight., Results: The analyses showed that the change in serum lipid concentration predicted change in symptoms over that of change in weight. Specifically, an increase in serum triglyceride concentration was associated with a decrease in the total PANSS score (p = 0.037). In addition, an increase in either serum total cholesterol concentration (p = 0.007), serum triglyceride concentration (p = 0.017) or their combined effect (p = 0.010) was associated with a decrease in PANSS negative subscale scores., Conclusion: Elevation of serum lipids is associated with an improvement in schizophrenia symptoms in subjects treated with clozapine. Although the mechanism is unclear, serum lipids may play a role in influencing clozapine's therapeutic activity.

Mutual information tools have been recently applied to quantify the connectivity between brain regions in functional magnetic resonance imaging (fMRI). Here we develop measures of mutual information between clusters of brain regions in the frequency domain. The properties and limitations of the method are exemplified through a single resting state fMRI dataset, and with a comparison involving frontostriatal connections in schizophrenic patients and healthy controls.

Introduction: A number of studies have suggested that deluded patients show a "jumping to conclusions" reasoning style on probabilistic reasoning tasks. In order to systematically explore the cognitive underpinnings of this task, we compared deluded and nondeluded patients on a number of experimental manipulations to investigate the role of memory and task pragmatics on performance., Methods: In Study 1, the performance of deluded and nondeluded schizophrenia patient groups was compared to nonpsychiatric controls on a battery of probabilistic reasoning tests. In Study 2, two variants of the standard "beads in jars" task were compared in order to explore the possible role of working memory load on task performance., Results: In Study 1, there were no significant differences between any of the groups on any of the probabilistic reasoning tasks. In Study 2, we found a significant difference between the two schizophrenic groups and the controls, but no difference in performance between deluded and nondeluded patient groups. The deluded group responded fastest in the memory intensive condition., Conclusions: Deluded and nondeluded schizophrenic patients perform similarly on probabilistic reasoning tasks and only show the "jumping to conclusions" response pattern under some conditions but not under others. Memory demands may influence the appearance of this pattern of responding in schizophrenia.

Background: The psychosis-inducing effect of ketamine is important evidence supporting the glutamate hypothesis of schizophrenia. However, the symptoms the drug produces have not been described systematically., Aim: To examine the effects of ketamine in healthy people using a structured psychiatric interview., Method: Ketamine (200 ng/ml) or placebo was administered by continuous infusion to 15 healthy volunteers. Symptoms were rated using the Present State Examination, the Thought, Language and Communication Scale and the Scale for Assessment of Negative Symptoms., Results: Ketamine induced a range of perceptual distortions, but not hallucinations. Referential ideas were seen in nearly half the sample. There were only mild and infrequent ratings on the thought disorder scale. Affective flattening and alogia were seen in some volunteers., Conclusions: Ketamine does not reproduce the full picture of schizophrenia. The main point of similarity concerns referential thinking. Phenomena resembling negative symptoms are also seen, but the distinction of these from the drug's sedative effects requires further elucidation.

Context: Establishing a neurobiological account of delusion formation that links cognitive processes, brain activity, and symptoms is important to furthering our understanding of psychosis., Objective: To explore a theoretical model of delusion formation that implicates prediction error-dependent associative learning processes in a pharmacological functional magnetic resonance imaging study using the psychotomimetic drug ketamine., Design: Within-subject, randomized, placebo-controlled study., Setting: Hospital-based clinical research facility, Addenbrooke's Hospital, Cambridge, England. The work was completed within the Wellcome Trust and Medical Research Council Behavioral and Clinical Neuroscience Institute, Cambridge., Participants: Fifteen healthy, right-handed volunteers (8 of whom were male) with a mean +/- SD age of 29 +/- 7 years and a mean +/- SD predicted full-scale IQ of 113 +/- 4 were recruited from within the local community by advertisement., Interventions: Subjects were given low-dose ketamine (100 ng/mL of plasma) or placebo while performing a causal associative learning task during functional magnetic resonance imaging. In a separate session outside the scanner, the dose was increased (to 200 ng/mL of plasma) and subjects underwent a structured clinical interview., Main Outcome Measures: Brain activation, blood plasma levels of ketamine, and scores from psychiatric ratings scales (Brief Psychiatric Ratings Scale, Present State Examination, and Clinician-Administered Dissociative States Scale)., Results: Low-dose ketamine perturbs error-dependent learning activity in the right frontal cortex (P = .03). High-dose ketamine produces perceptual aberrations (P = .01) and delusion-like beliefs (P = .007). Critically, subjects showing the highest degree of frontal activation with placebo show the greatest occurrence of drug-induced perceptual aberrations (P = .03) and ideas or delusions of reference (P = .04)., Conclusions: These findings relate aberrant prediction error-dependent associative learning to referential ideas and delusions via a perturbation of frontal cortical function. They are consistent with a model of delusion formation positing disruptions in error-dependent learning.

Background: The treatment of schizophrenia with multiple antipsychotic drugs is common, but the benefits and risks are not known., Methods: In a randomized, double-blind study, we evaluated patients with schizophrenia and a poor response to treatment with clozapine. The patients continued to take clozapine and were randomly assigned to receive eight weeks of daily augmentation with 3 mg of risperidone or with placebo. This course of treatment was followed by an optional 18 weeks of augmentation with risperidone. The primary outcome was reduction in the total score for severity of symptoms on the Positive and Negative Syndrome Scale (PANSS). The secondary outcomes included cognitive functioning., Results: A total of 68 patients were randomly assigned to treatment. In the double-blind phase, the mean total score for the severity of symptoms decreased from baseline to eight weeks in both the risperidone and the placebo groups. There was no statistically significant difference in symptomatic benefit between augmentation with risperidone and placebo: 9 of 34 patients receiving placebo and 6 of 34 receiving risperidone responded to treatment (P=0.38). The mean difference in the change in PANSS scores from baseline to eight weeks between those receiving risperidone and those receiving placebo was 0.1 (95 percent confidence interval, -7.3 to 7.0). The verbal working-memory index showed a small decline in the risperidone group and a small improvement in the placebo group (P=0.02 for the comparison between the two groups in the change from baseline). The increase in fasting blood glucose levels was mildly greater in the risperidone group than in the placebo group (16.2 vs. 1.8 mg per deciliter [0.90 vs. 0.10 mmol per liter], P=0.04). The incidence and severity of other side effects did not differ between the two groups., Conclusions: In this short-term study, the addition of risperidone to clozapine did not improve symptoms in patients with severe schizophrenia. (ClinicalTrials.gov number, NCT00272584)., (Copyright 2006 Massachusetts Medical Society.)

Ketamine is increasingly used to model the cognitive deficits and symptoms of schizophrenia. We investigated the extent to which ketamine administration in healthy volunteers reproduces the deficits in episodic recognition memory and agency source monitoring reported in schizophrenia. Intravenous infusions of placebo or 100 ng/ml ketamine were administered to 12 healthy volunteers in a double-blind, placebo-controlled, randomized, within-subjects study. In response to presented words, the subject or experimenter performed a deep or shallow encoding task, providing a 2(drug) x 2(depth of processing) x 2(agency) factorial design. At test, subjects discriminated old/new words, and recalled the sources (task and agent). Data were analyzed using multinomial modelling to identify item recognition, source memory for agency and task, and guessing biases. Under ketamine, item recognition and cued recall of deeply encoded items were impaired, replicating previous findings. In contrast to schizophrenia, there was a reduced tendency to externalize agency source guessing biases under ketamine. While the recognition memory deficit observed with ketamine is consistent with previous work and with schizophrenia, the changes in source memory differ from those reported in schizophrenic patients. This difference may account for the pattern of psychopathology induced by ketamine.

It is not known whether there is a core abnormality that occurs in all cases of schizophrenia. The cognitive dysmetria hypothesis proposes that there is such an abnormality which is characterized cognitively by a disruption in control and coordination processes, and functionally by abnormal inter-regional connectivity within the cortico-cerebellar-thalamo-cortical circuit (CCTCC). In the current study, we used functional MRI (fMRI) to investigate these two key aspects of the hypothesis. Since patients with schizophrenia show deficits in attention which have been characterized extensively using the continuous performance task (CPT) and since functional imaging studies have also demonstrated that this task engages the CCTCC, we used this task to investigate whether two patient groups with distinct symptom profiles would show functional dysconnectivity within this network. Three groups of subjects participated in the study: healthy volunteers (n = 12), schizophrenia patients with both negative and positive symptoms (n = 11) and schizophrenia patients with primarily positive symptoms (n = 11). Patient groups were matched for age of illness onset and medication, and to the control group for age, gender and handedness. Subjects were scanned using fMRI whilst they performed a modified version of the CPT, involving both degraded and non-degraded stimuli. Stimulus degradation has been shown to produce decrements in sensitivity, which is thought to reflect increased demands on the limited capacity of visual attention. Between-group comparisons revealed that patients with schizophrenia, irrespective of symptomatology, showed attenuation of the anterior cingulate and cerebellar response to stimulus degradation in comparison with control subjects. We also observed disruptions of inter-regional brain integration in schizophrenia. A task-specific relationship between the medial superior frontal gyrus and both anterior cingulate and the cerebellum was disrupted in both patient groups in comparison with controls. In addition, patients with negative symptoms showed impaired behavioural performance, and abnormal task-related connectivity between anterior cingulate and supplementary motor area. These findings are consistent with theoretical accounts of schizophrenia as a disorder of functional integration, and with the cognitive dysmetria hypothesis, which posits a disconnection within the CCTCC as a fundamental abnormality in schizophrenia, independent of diagnostic subtype. Furthermore, these data show evidence of additional functional deficits in patients with negative symptoms, deficits which may explain the accompanying attentional impairment.

Rationale: The precise nature of the impact of the N-methyl-D-aspartate antagonist, ketamine, upon human episodic memory, has yet to be elucidated fully., Objectives: This study sought to assess the effects of ketamine on the sub-processes facilitating memory encoding and retrieval., Methods: We evaluated the effects of the drug on a series of memory performance measures depending upon whether it was administered at the encoding or retrieval stage and on the nature of the encoding task used. Twelve healthy volunteers participated in a double-blind, placebo-controlled, randomized, within-subjects study. Intravenous infusions of placebo, 50 ng/ml ketamine or 100 ng/ml ketamine were administered. We investigated the effects of ketamine on three key aspects of episodic memory: encoding vs retrieval processes, source memory, and depth of processing. Data were analysed using both multinomial modelling and standard measures of item discrimination and response bias., Results: Deleterious effects of ketamine on episodic memory were primarily attributable to its effects on encoding, rather than retrieval processes. Recognition memory was impaired for items encoded at an intermediate level of processing, but preserved for shallowly and deeply encoded items. Increased source guessing bias was also observed when encoding took place under ketamine., Conclusions: The effects of ketamine upon episodic memory seem, therefore, to predominate at encoding. Furthermore, our results are also consistent with a specific impairment of encoding processes that result in subsequent recollective, as opposed to familiarity-based, retrieval. The observed effects are compatible with memory deficits seen in schizophrenia and thus provide some support for the ketamine model of the disease.

Modafinil, a novel cognitive enhancer, selectively improves neuropsychological task performance in healthy volunteers and adult patients with attention deficit hyperactivity disorder (ADHD). It has been argued that persistent cognitive deficits in patients with schizophrenia are responsible for the failure of many patients to rehabilitate socially even when psychotic symptoms are in remission. The present study examined the potential of modafinil as a cognitive enhancer in schizophrenia. Twenty chronic patients with a diagnosis of schizophrenia were entered into a double-blind, randomized, placebo-controlled crossover study using a 200 mg dose of modafinil. Modafinil had some cognitive enhancing properties in schizophrenia similar to those observed in healthy adults and adult patients with ADHD. Improvement was seen on short-term verbal memory span, with trends towards improved visual memory and spatial planning. This was accompanied by slowed response latency on the spatial planning task. No effect on stop-signal performance was seen. Importantly, significant improvement in attentional set shifting was seen, despite no effect of modafinil on this task being seen in healthy volunteers or ADHD patients. Modafinil may have potential as an important therapy for cognitive impairment in patients with schizophrenia, particularly because of its beneficial effects on attentional set shifting., (Copyright 2004 Nature Publishing Group)

We investigated the effects of subdissociative dose ketamine on executive processes during a working memory task. A total of 11 healthy volunteers participated in a double-blind, placebo-controlled, randomized, within-subjects study. They attended on three occasions, receiving intravenous infusions of placebo, a lower ketamine dose, and a higher ketamine dose. On each occasion, they underwent a series of tasks engaging working memory function in verbal and visuo-spatial domains. Further tasks explored aspects of long-term memory, planning, attention, and perceptual processing. With respect to working memory/executive function, a highly specific pattern of impairment was observed. Impairments were seen only at the higher dose of ketamine and restricted to a subgroup of the verbal working memory tasks: While visuo-spatial working memory showed no evidence of impairment, and while simple maintenance processes during verbal working memory were also unimpaired, higher dose ketamine produced a significant impairment in the manipulation of information within working memory. This process-specific effect of ketamine was reflected in a drug-by-task interaction. The specificity of this ketamine effect suggests that the earliest effect of NMDA receptor blockade is in higher order control of executive function rather than in more basic maintenance processes.