Elevated levels of circulating IL-18BP and perturbed regulation of IL-18 in schizophrenia.

BACKGROUND: The pleiotropic pro-inflammatory cytokine Interleukin (IL)-18 has been proposed to play a role in schizophrenia, since elevated circulating levels of its protein and altered frequencies of genetic variants in its molecular system are reported in schizophrenic patients. METHODS: We analyzed 77 patients with schizophrenia diagnosis (SCZ) and 77 healthy control subjects (HC) for serum concentration of both IL-18 and its natural inhibitor, the IL-18 binding protein (IL-18BP). RESULTS: We confirmed that serum levels of total IL-18 are significantly increased in SCZ, as compared to HC. However, due to a highly significant increase in levels of circulating IL-18BP in SCZ, as compared to HC, the levels of free, bioactive IL-18 are not significantly different between the two groups. In addition, the relationships between the levels of IL-18 and its inhibitor, as well as between the two molecules and age appear dissimilar for SCZ and HC. In particular, the elevated levels of IL-18BP, likely a consequence of the body's attempt to counteract the early prominent inflammation which characterizes schizophrenia, are maintained in earlier and later stages of the disease. However, the IL-18BP elevation appears ineffective to balance the IL-18 system in younger SCZ patients, while in older patients the levels of circulating bioactive IL-18 are comparable to those of HC, if not lower. CONCLUSIONS: In conclusion, these findings indicate that the IL-18 system is perturbed in schizophrenia, supporting the idea that this pro-inflammatory cytokine might be part of a pathway of genetic and environmental components for vulnerability to the disease.

Neural correlates of local contextual processing deficits in schizophrenic patients.

Deficits in processing contextual information are one of the main features of cognitive dysfunction in schizophrenia, but the neurophysiologic substrate underlying this dysfunction is poorly understood. We used ERPs to investigate local contextual processing in schizophrenic patients. Local context was defined as the occurrence of a short predictive series of stimuli occurring before delivery of a target event. Response times of predicted targets were faster in controls compared to patients. Schizophrenia patients failed to generate the P3b latency shift between predicted and random targets that was observed in controls and demonstrated a prominent reduction of the peak of an early latency context dependent positivity. The current study provides evidence of contextual processing deficits in schizophrenia patients by demonstrating alteration in the behavioral and neural correlates of local contextual processing.

Impaired inter-hemispheric facilitatory connectivity in schizophrenia.

OBJECTIVES: To investigate the inter-hemispheric connections between the dorsal premotor cortex (dPM) and contralateral primary motor cortex (M1) in schizophrenia. METHODS: Sixteen medicated, nine unmedicated schizophrenia patients and 20 healthy age-matched subjects were studied by twin-coil Transcranial Magnetic Stimulation. To activate distinct facilitatory and inhibitory transcallosal pathways between dPM and the contralateral M1, the intensity of dPM stimulation was adjusted to be either suprathreshold (110% of resting motor threshold) or subthreshold (80% of active motor threshold). Interstimulus intervals between conditioning stimulus and test stimulus were 6, 8 and 15 ms. RESULTS: Schizophrenia patients had comparable efficacy of the inhibitory pathway. On the other hand, medicated patients showed less facilitation of contralateral M1 following dPM stimulation at 80% of active motor threshold, at interstimulus interval=8 ms. The individual amount of facilitation induced by dPM conditioning at 80% of active motor threshold at interstimulus interval=8 ms correlated negatively with negative symptoms. CONCLUSIONS: Inter-hemispheric facilitatory dPM-M1 connectivity is selectively altered in schizophrenia. SIGNIFICANCE: This study produced evidence that dPM-M1 connectivity is dysfunctional and that correlates with negative symptoms. These results converge with previous studies which strongly hypothesize that inter- and intra-hemispheric connectivity disturbances may play a major role in schizophrenia.

Suicidal attempts and increased right amygdala volume in schizophrenia.

Suicide is a major cause of death in schizophrenia. Neurobiological studies suggest that suicidality is associated with abnormal brain structure and connectivity in fronto-temporo-limbic regions. However, it is still unclear whether suicidality in schizophrenia is related to volumetric abnormalities in subcortical structures that play a key role in emotion regulation, aggression and impulse control. Therefore, we aimed to examine whether the volume of selected subcortical regions is associated with previous suicidal attempts and self-aggression in schizophrenia. For this cross-sectional study, we recruited 50 outpatients with schizophrenia and 50 healthy controls (HC) matched for age and gender. Fourteen patients had a history of one or more suicide attempts. Different forms of aggression were assessed using the Modified Overt Aggression Scale. All participants underwent structural MR imaging at 3 Tesla. Physical volumetric measures were calculated for the lateral ventricles, thalamus, hippocampus, amygdala, caudate, putamen, pallidum and accumbens using an automatic segmentation method on T1-weighted high-resolution (voxel size 1×1×1mm(3)) images. Multivariate and follow-up univariate ANOVAs revealed a selective increase in volume in the right amygdala of patients with a history of suicidality compared both to patients without such a history and HC. Moreover, in the entire patient group increased right amygdala volume was related to increased self-aggression. Our findings suggest that right amygdala hypertrophy may be a risk factor for suicide attempts in patients with schizophrenia and this could be relevant for suicide prevention.

Hippocampi, thalami, and accumbens microstructural damage in schizophrenia: a volumetry, diffusivity, and neuropsychological study.

Volumetric abnormalities in the subcortical structures have been described in schizophrenia. However, it still has to be clarified if subtle microstructural damage is also present. Thus, we aimed to detect subcortical volume and mean diffusivity (MD) alterations in 45 patients with diagnosis of schizophrenia compared with 45 age-, gender-, and educational attainment-matched healthy comparison (HC) participants, by using a combined volumetry and diffusion tensor imaging (DTI) method. A secondary aim was to identify the neuropsychological correlates of subcortical abnormalities in the schizophrenic group. We found thalami and hippocampi bilaterally and left accumbens to show MD increase in the schizophrenic group. No volumetric decrease was found. Moreover, significant correlations between the MD values in subcortical structures (right thalamus and hippocampus and left accumbens) and working memory performance were found. Thus, subcortical microstructural alterations are present in schizophrenia even in absence of volumetric abnormalities. Furthermore, microstructural damage in subcortical areas is linked to working memory, suggesting the presence of a subtle microstructural subcortical dysfunction in the pathoetiological mechanism underlying high cognitive load performances in schizophrenia. Finally, our findings indicate that MD is a more sensitive marker of brain tissue deficits than signal intensity variations measured in T1-weighted imaging data, consistently with previous reports. Thus, DTI appears to be an invaluable tool to investigate subcortical pathology in schizophrenia, greatly enhancing the ability to detect subtle brain changes in this complex disorder.

Cortico-subcortical underpinnings of narrative processing impairment in schizophrenia.

Cortical and subcortical gray matter volumes were correlated with a set of linguistic scores in a group of schizophrenia patients. Lexical informativeness was positively associated with the volume of the left frontal cortical and accumbal areas, while left hippocampal atrophy and right ventricle enlargement predicted increased production of semantic paraphasias. Global coherence impairment was predicted by left accumbal volume reduction and left ventricle enlargement. These data confirm that the brain structure of specific cortical and subcortal areas, as determined by magnetic resonance imaging, is related to the compromised semantic retrieval and language control in schizophrenia.

Abnormal brain lateralization and connectivity in schizophrenia.

Schizophrenia is a complex disorder mainly characterized by thought disturbances, hallucinations, and decay of social and cognitive performances. From past attempts to identify the exclusive brain lesions responsible for specific domains of schizophrenia symptoms such as delusion and auditory hallucinations, recent data pointed towards network alterations leading to abnormal brain asymmetry and connectivity as important determinants of schizophrenia pathophysiology. Several contributions have reported reduced brain lateralization in schizophrenia, causing a failure of left hemisphere dominance. Evidence of altered connectivity among distinct cortical areas is also accumulating. The aim of the present article is to critically review such contributions.

Reduced fronto-temporal connectivity is associated with frontal gray matter density reduction and neuropsychological deficit in schizophrenia.

OBJECTIVES: A "disconnectivity model" of schizophrenia has been proposed, but it is still unclear if white matter abnormalities are associated with gray matter changes and if they may be the anatomic substrate of cognitive impairment, which is a core symptom of the disorder. The first objective was to detect if white matter microstructure alterations in schizophrenia are associated with or independent of gray matter change, using an optimized method for white matter (Tract-Based Spatial Statistics) and gray matter analyses (whole-brain voxel-wise approach). The second objective was to identify the neuropsychological correlates of white matter abnormalities in the schizophrenic group, using a comprehensive neuropsychological battery. METHODS: In this case-control study 43 schizophrenic patients and 43 healthy volunteers were consecutively enrolled and matched for age and gender. RESULTS: Fractional anisotropy reduction was found in 6 fronto-temporal clusters (corrected p-values <0.05) in schizophrenic group in comparison with healthy volunteers, and 3 clusters showed fractional anisotropy increase (corrected p-values <0.05). Two of the clusters showing reduced fractional anisotropy were associated with reduced gray matter density in neuroanatomically-related regions in schizophrenic subjects (p-values ranging from 0.001 to 0.026). Executive, constructional-praxis, and working memory deficits were significant predictors of fractional anisotropy reduction in 4 clusters in the schizophrenic group (p-values ranging from <0.0001 to 0.0017). CONCLUSIONS: Our data support the disconnectivity hypothesis in schizophrenia, enlightening a link between reduced fronto-temporal connectivity and "frontal" cognitive deficits. Reduced gray matter density may be involved primarily in the pathogenesis of some of these disconnected areas.

The language of schizophrenia: an analysis of micro and macrolinguistic abilities and their neuropsychological correlates.

Language disturbance is one of the main diagnostic features in schizophrenia and abnormalities of brain language areas have been consistently found in schizophrenic patients. The main aim of this study was to describe the impairment of micro and macrolinguistic abilities in a group of twenty-nine schizophrenic patients during the phase of illness stability compared to forty-eight healthy participants matched for age, gender and educational level. Microlinguistic abilities refer to lexical and morpho-syntactic skills, whereas macrolinguistic abilities relate to pragmatic and discourse level processing. Secondary aims were to detect the effect of macrolinguistic on microlinguistic ability, and the neuropsychological impairment associated with the linguistic deficit. The linguistic assessment was performed on story-telling. Three narratives were elicited with the help of a single-picture stimulus and two cartoon stories with six pictures each. A modified version of the Mental Deterioration Battery was used to assess selective cognitive performances. A series of t-tests indicated that all the macrolinguistic variables were significantly impaired in schizophrenic patients in at least one of the three story-tellings. Furthermore, the limited impairment found in microlinguistic abilities was influenced by macrolinguistic performance. Multivariate stepwise regression analyses suggested that reduced attention performances and deficit in executive functions were predictors of linguistic impairment. Language production in schizophrenia is impaired mainly at the macrolinguistic level of processing. It is disordered and filled with irrelevant pieces of information and derailments. Such erratic discourse may be linked to the inability to use pragmatic rules and to cognitive deficits involving factors such as attention, action planning, ordering and sequencing.

Connectivity between posterior parietal cortex and ipsilateral motor cortex is altered in schizophrenia.

BACKGROUND: Recent advances have highlighted the hypothesis of schizophrenia as a disorder causing defective connectivity among distinct cortical regions. Neurophysiological evidence supporting this hypothesis, however, is still lacking. METHODS: In the present study, we used a novel twin-coil transcranial magnetic stimulation (tcTMS) approach to investigate ipsilateral parieto-motor connectivity in 20 schizophrenic patients (14 medicated, 6 unmedicated) and in 15 healthy age-matched volunteers. RESULTS: In healthy subjects, a conditioning TMS pulse applied over the ipsilateral posterior parietal cortex (PPC) at 90% of resting motor threshold (RMT) intensity was able to increase the excitability of the hand area of the right primary motor cortex, with peaks at interstimulus intervals (ISIs) of 4 and 15 msec. This paradigm of stimulation failed to reveal any facilitatory parieto-motor interaction in medicated and unmedicated schizophrenic patients. The between-group difference in paired-pulse facilitation was not ISI-specific. In following analyses, we found that the effects across ISIs induced by PPC conditioning at 90% RMT correlated with the Global Assessment Functioning score and with the negative subscale of the Positive and Negative Syndrome Scale, showing that patients with a better global functioning and lower negative symptoms had less impaired connectivity. Moreover the same parameter correlated with illness duration. CONCLUSIONS: Parieto-motor connectivity is impaired in schizophrenia. Cortico-cortical disconnection might be a core feature of schizophrenia.