Aberrant Gray Matter Volume and Cortical Surface in Paranoid-Type Delusional Disorder.

INTRODUCTION: Delusions are core symptoms of schizophrenia-spectrum and related disorders. Despite their clinical relevance, the neural correlates underlying such phenomena are unclear. Recent research suggests that specific delusional content may be associated with distinct neural substrates. OBJECTIVE: Here, we used structural magnetic resonance imaging to investigate multiple parameters of brain morphology in patients presenting with paranoid type delusional disorder (pt-DD, n = 14) compared to those of healthy controls (HC, n = 25). METHODS: Voxel- and surface-based morphometry for structural data was used to investigate gray matter volume (GMV), cortical thickness (CT) and gyrification. RESULTS: Compared to HC, patients with pt-DD showed reduced GMV in bilateral amygdala and right inferior frontal gyrus. Higher GMV in patients was found in bilateral orbitofrontal and in left superior frontal cortices. Patients also had lower CT in frontal and temporal regions. Abnormal gyrification in patients was evident in frontal and temporal areas, as well as in bilateral insula. CONCLUSIONS: The data suggest the presence of aberrant GMV in a right prefrontal region associated with belief evaluation, as well as distinct structural abnormalities in areas that essentially subserve processing of fear, anxiety and threat in patients with pt-DD. It is possible that cortical features of distinct evolutionary and genetic origin, i.e. CT and gyrification, contribute differently to the pathogenesis of pt-DD.

Abnormal cerebellar volume in somatic vs. non-somatic delusional disorders.

BACKGROUND: There is abundant evidence for cerebellar involvement in schizophrenia, where the cerebellum has been suggested to contribute to cognitive, affective and motor dysfunction. More recently, specific cerebellar regions have also been associated with psychotic symptoms, particularly with auditory verbal hallucinations. In contrast, little is known about cerebellar contributions to delusions, and even less is known about whether cerebellar involvement differs by delusional content. METHODS: Using structural magnetic resonance imaging at 1.0 T together with cerebellum-optimized segmentation techniques, we investigated gray matter volume (GMV) in 14 patients with somatic-type delusional disorder (S-DD), 18 patients with non-somatic delusional disorder (NS-DD) and 18 patients with schizophrenia (SZ) with persistent non-somatic delusions. A total of 32 healthy controls (HC) were included. Between-group comparisons were adjusted for age, gender, chlorpromazine equivalents and illness duration. RESULTS: Compared to HC, S-DD patients showed decreased GMV in left lobule VIIIa. In addition, S-DD patients showed decreased GMV in lobule V and increased GMV in bilateral lobule VIIa/crus II compared to NS-DD. Patients with SZ showed increased GMV in right lobule VI and VIIa/crus I compared to HC. Significant differences between HC and NS-DD were not found. CONCLUSIONS: The data support the notion of cerebellar dysfunction in psychotic disorders. Distinct cerebellar deficits, predominantly linked to sensorimotor processing, may be detected in delusional disorders presenting with predominantly somatic content.

Regional gray matter volume and structural network strength in somatic vs. non-somatic delusional disorders.

BACKGROUND: Monothematic delusional disorders are characterized by a single tenacious belief. They provide a great opportunity to study underlying brain structures in the absence of confounding symptoms that accompany delusions in schizophrenia. Delusional beliefs include persecution, jealousy or somatic delusions including infestation. It is unclear whether specific delusional content is associated with distinct neural substrates. METHODS: We used magnetic resonance imaging in patients presenting with somatic vs. non-somatic delusional disorders. Patients with delusional infestation (DI, n=18), and individuals with non-somatic delusional disorders (n=19) were included, together with healthy volunteers (n=20). Uni- and multivariate techniques for structural data analysis were applied to provide a comprehensive characterization of abnormal brain volume at both the regional and neural network level. RESULTS: Patients with DI showed lower gray matter volume in thalamic, striatal (putamen), insular and medial prefrontal brain regions in contrast to non-somatic delusional disorders and healthy controls. Importantly, these differences were consistently detected at regional and network level. Compared to healthy controls, patients with delusional disorders other than DI showed lower gray matter volume in temporal cortical regions. CONCLUSION: The data support the notion that dysfunctional somatosensory and peripersonal networks could mediate somatic delusions in patients with DI in contrast to delusional disorders without somatic content. The data also suggest putative content-specific neural signatures in delusional disorders and in delusion formation per se.

Cortical features of distinct developmental trajectories in patients with delusional infestation.

BACKGROUND: Although there is strong neuroimaging evidence that cortical alterations are a core feature of schizophrenia spectrum disorders, it still remains unclear to what extent such abnormalities occur in monothematic delusional disorders. In individuals with delusional infestation (DI), the delusional belief to be infested with pathogens, previous structural MRI studies have shown prefrontal, temporal, parietal, insular, thalamic and striatal gray matter volume changes. Differential contributions of cortical features of evolutionary and genetic origin (such as cortical thickness, area and folding) which may distinctly contribute to DI pathophysiology are unclear at present. METHODS: In this study, 18 patients with DI and 20 healthy controls (HC) underwent MRI scanning at 1.0T. Using surface-based analyses we calculated cortical thickness, surface area and local gyrification index (LGI). Whole-brain differences between patients and controls were investigated. RESULTS: Surface analyses revealed frontoparietal patterns exhibiting altered cortical thickness, surface area and LGI in DI patients compared to controls. Higher cortical thickness was found in the right medial orbitofrontal cortex (p<0.05, cluster-wise probability [CWP] corrected). Smaller surface area in patients was found in the left inferior temporal gyrus, the precuneus, the pars orbitalis of the right frontal gyrus, and the lingual gyrus (p<0.05, CWP corr.). Lower LGI was found in the left postcentral, bilateral precentral, right middle temporal, inferior parietal, and superior parietal gyri (p<0.01, CWP corr.). CONCLUSION: This study lends further support to the hypothesis that cortical features of distinct evolutionary and genetic origin differently contribute to the pathogenesis of delusional disorders. Regions in which atrophy was observed are part of neural circuits associated with perception, visuospatial control and self-awareness. The data are in line with the notion of a content-specific neural signature of DI.

Source-based morphometry reveals distinct patterns of aberrant brain volume in delusional infestation.

Little is known about the neural correlates of delusional infestation (DI), the delusional belief to be infested with pathogens. So far, evidence comes mainly from case reports and case series. We investigated brain morphology in 16 DI patients and 16 healthy controls using structural magnetic resonance imaging and a multivariate data analysis technique, i.e. source-based morphometry (SBM). In addition, we explored differences in brain structure in patient subgroups based on disease aetiology. SBM revealed two patterns exhibiting significantly (p<0.05, Bonferroni-corrected) lower grey and higher white matter volume in DI patients compared to controls. Lower grey matter volume was found in medial prefrontal cortex, anterior cingulate cortex, medial temporal lobe structures (parahippocampus and hippocampus), sensorimotor cortices, bilateral insula and thalamus and inferior parietal regions. Higher white matter volume was found in medial and middle frontal and temporal cortices, left insula and lentiform nucleus. Grey matter volume was abnormal in both "psychiatric" (primary DI and DI associated with an affective disorder) and "organic" DI (DI due to a medical condition). In contrast, aberrant white matter volume was only confirmed for the "organic" DI patient subgroup. These results suggest prefrontal, temporal, parietal, insular, thalamic and striatal dysfunction underlying DI. Moreover, the data suggest that aetiologically distinct presentations of DI share similar patterns of abnormal grey matter volume, whereas aberrant white matter volume appears to be restricted to organic cases.

Abnormal gray and white matter volume in delusional infestation.

Little is known about the neural basis of delusional infestation (DI), the delusional belief to be infested with pathogens. Case series and the response to anti-dopaminergic medication indicate disruptions in dopaminergic neurotransmission in the striatum (caudate, putamen), but did not allow for population-based inference. Here, we report the first whole-brain structural neuroimaging study to investigate gray and white matter abnormalities in DI compared to controls. In this study, we used structural magnetic resonance imaging and voxel-based morphometry to investigate gray and white matter volume in 16 DI patients and 16 matched healthy controls. Lower gray matter volume in DI patients compared to controls was found in left medial, lateral and right superior frontal cortices, left anterior cingulate cortex, bilateral insula, left thalamus, right striatal areas and in lateral and medial temporal cortical regions (p<0.05, cluster-corrected). Higher white matter volume in DI patients compared to controls was found in right middle cingulate, left frontal opercular and bilateral striatal regions (p<0.05, cluster-corrected). This study shows that structural changes in prefrontal, temporal, insular, cingulate and striatal brain regions are associated with DI, supporting a neurobiological model of disrupted prefrontal control over somato-sensory representations.

Delusional infestation: treatment outcome with antipsychotics in 17 consecutive patients (using standardized reporting criteria).

OBJECTIVE: The multietiological nature of delusional infestation (DI) implies that therapy needs to be customized according to the various forms of DI (primary/secondary). Usually, treatment of DI is difficult to achieve in psychiatric settings because of the patients' nonpsychiatric concept of the illness. METHODS: We analyzed the data of all consecutive DI patients seen in the Psychiatric Outpatient Department of the General Hospital Bruneck/Italy from 1998 to 2010, including structural brain imaging findings. Standardized reporting criteria are applied for the presentation of the cases in a naturalistic setting. RESULTS: Our sample consisted of 17 patients. Notably, 15 out of these 17 patients (88%) could be engaged in an antipsychotic treatment trial. With different, mainly second-generation antipsychotics, all but one patient profited from antipsychotics, at least after substances were changed: 12 (71%) of the cases reached full remission, and another 2 (12%) had partial remission. The average duration of treatment was remarkably long: 3.8 years. Eight cases were classified as secondary to a brain disorder or medical condition, four cases were classified as secondary to psychiatric disorders and five cases fulfilled the criteria for primary DI (i.e., delusional disorder somatic type). All cases secondary to a brain disorder/medical condition showed macroscopic brain lesions mainly in the basal ganglia. CONCLUSIONS: Our study confirmed previous experience that an excellent clinical outcome can be achieved in unselected patients with different DI forms provided that patients can be engaged in antipsychotic treatment. Although studies in DI are difficult to conduct, randomized controlled trials would be desirable to evaluate specific antipsychotic medication in DI in general and in the different forms of DI. More sophisticated investigations (single photon emission computed tomography and positron emission tomography) than structural brain imaging (magnetic resonance imaging and computed tomography) are needed to better elucidate underlying brain dysfunction in DI.

Prospects for multivariate classification of a pharmaceutical intermediate with near-infrared spectroscopy as a process analytical technology (PAT) production control supplement.

NIR spectroscopy was applied to develop a fast and reliable quality control system for a pharmaceutical substance to support information obtained through PAT surveillance of its manufacturing process. After calculating different quantitative calibrations of the substance's key quality parameters, a general classification model has been derived to capture the over-all product grade. The final spectral quality conformity model consisting of 96 representative batches - covering high process variability - was sensibilized toward five important quality parameters by their incorporation as PLS responses. The model characteristics were extensively investigated and interpreted to derive a reasonable limit for the reduced chemometric summary quality measure (Hotteling's T(2)). Through this parameter new batches can be assessed easily by their NIR spectra, using versatile test batches for confirmation. Different sets of good quality batches, bad production batches beyond the respective chemical quality limit and synthetic batches exactly at the limit could be accurately assigned through their multivariate evaluation to a large extend. However, high model sensitivity to non-relevant product properties can lead to limited applicability of the model. This may be caused by restricted bandwidth of quality parameters in production environment for calibration, repack effects and high process instability.

Online process control of a pharmaceutical intermediate in a fluidized-bed drier environment using near-infrared spectroscopy.

In the production plant of an antibiotic substance, a new fluidized-bed drier has been installed. For online process control of the drying progress and determination of the ideal drying end point, a continuous near-infrared spectroscopic (NIRS) measuring setup was implemented to rapidly and simultaneously gain all essential product information. A bypass system outside the drier combined with a robust process probe proved to provide the best sampling system geometry. The spectrometer was equipped with an additional laboratory probe for complementary offline analysis. Multivariate calibrations for product assay, water content, and residual solvent were calculated, optimized, and compared for the two probes. The final root-mean-square error of cross validation (RMSECV) for the process probe could be reduced to 0.81% for the product assay, 0.25% for water, and 0.06% for acetone. The laboratory-probe prediction values show good agreement with reference data during the testing period. The calibrations of the process probe were checked by comparing its predictions to those of the validated laboratory probe. The monitoring system could be automated to a large extent, and product quality could be improved considerably. The established technology is of high importance for the pharmaceutical industry carrying out high-throughput routine analysis because of its advantages in terms of of time and cost reductions.

Lack of Gata3 results in conotruncal heart anomalies in mouse.

The transcription factor Gata3 is an important regulator of the development of thymus, the nervous system, ear, kidney, and adrenal glands. This study analyzes the role of Gata3 in the developing heart using a mouse strain containing an nlsLacZ reporter gene fused in frame to the Gata3 gene by homologous recombination. Using in situ hybridization, RT-PCR and Gata3-LacZ histochemistry, Gata3 expression was shown in various cardiac structures up to newborn stage. During looping stages (E9.5-E11.5) Gata3-LacZ activity recapitulated endogenous Gata3 and was abundantly expressed in the endocardial ridges and endothelium of distal outflow tract. Strong reporter gene expression was also noted in the mesenchyme of ventral branchial arches, and in the epithelium. In the atrioventricular canal expression was relatively lower. In the four-chambered heart stages (E13.5-E17.5) the LacZ-staining did not recapitulate the endogenous Gata3 transcript and showed rather lineage tracing of formerly Gata3-expressing cells in the hearts. beta-Galactosidase activity was detected in the cusps of semilunar valves, aorta, pulmonary trunk, innominate and common carotid arteries, and faintly in the atrioventricular valves. Gata3-null embryos die normally between E11 and E12. Pharmacological treatment with sympathomimetic beta-adrenergic receptor agonist lengthens the survival up to E18 when malformations of the heart such as ventricular septal defect (VSD), double-outlet of right ventricle (DORV), anomalies of the aortic arch (AAA) and persistent truncus arteriosus (PTA) were detected. The specified malformations correlate with the normal developmental pattern of Gata3-LacZ expression. The short outflow tract and insufficient rotation of truncus arteriosus during looping stages might be the main reasons underlying these malformations.

Striatal lesions in delusional parasitosis revealed by magnetic resonance imaging.

INTRODUCTION: Delusional parasitosis (DP) is a syndrome characterized by the firm conviction that small living beings infest the skin. The etiology can be primary and secondary. Structural brain abnormalities in DP have only been reported in case reports often subcortical vascular encephalopathy and right-hemisphere strokes in the temporo-parietal cortex. Systematic brain imaging studies are lacking. We aimed to identify a brain region with structural lesions in patients with DP in order to better understand the pathophysiology of DP. METHODS: Nine consecutive patients with DP in a psychiatric outpatient department were assessed clinically and by means of cranial magnetic resonance imaging (MRI). RESULTS: Five of the nine cases were diagnosed as having DP as psychotic disorders due to a general medical condition while three had DP arising from pre-existing psychiatric illness and one suffered from a delusional disorder, somatic type (primary form). Four of the five DP cases secondary to a general medical condition (one case could not be analyzed) had striatal lesions predominantly in the putamen. Thalamic or cortical lesions were found in one case, respectively. In the primary DP case and all cases secondary to another psychiatric disorder basal ganglia and subcortical gray matter lesions were absent. In all medical (secondary) DP cases subcortical white matter lesions were found mainly in the centrum semiovale. Three of the five medical DP cases showed severe generalized brain atrophy which was absent in the primary DP case and in the cases secondary to other psychiatric disorders. DISCUSSION/CONCLUSION: We present the findings of the first structural MRI study in DP. Our results suggest a possible relevance of structural lesions in the striatum, predominantly the putamen, in the medical (secondary) DP-subgroup. Our findings are in line with other studies demonstrating that the putamen, in addition to its role in motor regulation, represents a brain area that mediates visuo-tactile perception. Disturbed functioning of the putamen and associated brain areas of the somatic/dorsal striato-thalamo-cortical loop might therefore play an important role in the pathophysiology of DP, which is characterized by somatic delusions, tactile misperceptions and sometimes also visual hallucinations. The involvement of the striatum and the efficacy of antidopaminergic antipsychotics indicate dopaminergic dysfunction in DP. Evidence from DP in intoxication with substances influencing the dopamine transporter (DAT) (e.g. cocaine, methylphenidate, bupropion) further supports this observation. Further neuroimaging studies in larger samples are needed to expand our preliminary knowledge obtained from this case-series study.

Gene expression analysis of Gata3-/- mice by using cDNA microarray technology.

Transcription factor Gata3 is implicated in the formation of autosomal dominant hypoparathyroidism, sensorineural deafness, and renal anomaly (HDR) syndrome. We pursued to identify the potential Gata3 target genes by profiling the gene expression pattern in E9.5 Gata3-/- mouse embryos. Altogether four independent microarray hybridizations were carried out on NIA Mouse15K cDNA arrays. We discovered two hundred and sixty one genes that are downregulated in Gata3 mutant embryos at E9.5 (with a minimal 2.0-fold change). The majority of the differentially expressed genes belong to two functional groups--genes involved in transcription regulation and cellular signaling. One of the genes discovered to be downregulated in Gata3 mutant embryos was tumor suppressor gene Disabled 2. The validity of this finding was checked by using the whole mount in situ hybridization technology. This study revealed that the sites, where Dab2 is downregulated in the mutant embryos partly overlap with the Gata3 expression domains, including the mid-embryo region, branchial arches and facio-acoustic (VII-VIII) neural crest complex. This is the first time when tumor supressor gene Dab2 is shown to be implicated in the defective phenotype of Gata3 mutant mice.

Nontumorous vascular malformations in the liver: color Doppler ultrasonographic findings.

OBJECTIVE: To investigate color Doppler and spectral wave characteristics of nontumorous vascular malformations in the liver. METHODS: From September 1995 to January 2001, 32 cases of vascular malformations were identified by means of color Doppler ultrasonography and spectral wave analysis. Computed tomography, angiography, or both were performed in all cases. RESULTS: Five arterioportal and 14 portovenous malformations, 1 arteriovenous malformation, and 4 portoportal and 8 venovenous shunts were detected. Associations with Rendu-Osler-Weber syndrome in 6 cases and with cirrhotic liver in 12 cases were found Fourteen patients were liver disease free. In 3 cases, interventional procedures were necessary to reduce portal hypertension or cardiac dysfunction. The incidence of finding vascular malformations in 12,000 patients was 0.1%. CONCLUSIONS: Nontumorous vascular malformations are rare disorders in the liver. They may appear in patients with healthy livers and in patients with portal hypertension. Color Doppler ultrasonography and spectral wave analysis are capable of showing and differentiating different types of hepatic vascular malformations.