Statistical shape analysis of corpus callosum in delusional disorder.

Neurobiological foundations of delusional disorder (DD) have been studied less with neuroimaging techniques when compared to other psychotic disorders. The present study aimed to delineate the neural substrates of DD by investigating neuroanatomical characteristics of the corpus callosum (CC) with statistical shape analysis (SSA) conducted on magnetic resonance images (MRI). Twenty (female:male=1:1) DSM-5 DD patients and 20 age- and gender-matched healthy individuals were included. High-resolution 3D T1 Turbo Field Echo MRI images were scanned with a 1.5 T MR device. The landmarks that were selected to determine the shape differences in CC were identified based on previous studies. Furthermore, constructed landmarks were determined and employed to better assess regional shape differences. There was no significant difference in the CC area in the mid-sagittal images between the DD patients and controls. However, DD patients exhibited a pattern of structural CC changes in various regions. The study findings emphasizes the variable subregional nature of CC in DD patients. Future SSA studies with larger samples could shed further light on DD etiology, diagnosis, classification and treatment options.

Structural and functional retinal alterations in patients with paranoid schizophrenia.

Ophthalmological methods have increasingly raised the interest of neuropsychiatric specialists. While the integrity of the retinal cell functions can be evaluated with the electroretinogram (ERG), optical coherence tomography (OCT) allows a structural investigation of retinal layer thicknesses. Previous studies indicate possible functional and structural retinal alterations in patients with schizophrenia. Twenty-five patients with paranoid schizophrenia and 25 healthy controls (HC) matched for age, sex, and smoking status participated in this study. Both, ERG and OCT were applied to obtain further insights into functional and structural retinal alterations. A significantly reduced a-wave amplitude and thickness of the corresponding para- and perifoveal outer nuclear layer (ONL) was detected in patients with paranoid schizophrenia with a positive correlation between both measurement parameters. Amplitude and peak time of the photopic negative response (PhNR) and thickness of the parafoveal ganglion cell layer (GCL) were decreased in patients with schizophrenia compared to HC. Our results show both structural and functional retinal differences between patients with paranoid schizophrenia and HC. We therefore recommend the comprehensive assessment of the visual system of patients with schizophrenia, especially to further investigate the effect of antipsychotic medication, the duration of illness, or other factors such as inflammatory or neurodegenerative processes. Moreover, longitudinal studies are required to investigate whether the functional alterations precede the structural changes.

Looking into a Deluded Brain through a Neuroimaging Lens.

Delusions are irrational, tenacious, and incorrigible false beliefs that are the most common symptom of a range of brain disorders including schizophrenia, Alzheimer's, and Parkinson's disease. In the case of schizophrenia and other primary delusional disorders, their appearance is often how the disorder is first detected and can be sufficient for diagnosis. At this time, not much is known about the brain dysfunctions leading to delusions, and hindering our understanding is that the complexity of the nature of delusions, and their very unique relevance to the human experience has hampered elucidation of their underlying neurobiology using either patients or animal models. Advances in neuroimaging along with improved psychiatric and cognitive modeling offers us a new opportunity to look with more investigative power into the deluded brain. In this article, based on data obtained from neuroimaging studies, we have attempted to draw a picture of the neural networks involved when delusion is present and evaluate whether different manifestations of delusions engage different regions of the brain.

The role of dopamine dysregulation and evidence for the transdiagnostic nature of elevated dopamine synthesis in psychosis: a positron emission tomography (PET) study comparing schizophrenia, delusional disorder, and other psychotic disorders.

There have been few studies performed to examine the pathophysiological differences between different types of psychosis, such as between delusional disorder (DD) and schizophrenia (SZ). Notably, despite the different clinical characteristics of DD and schizophrenia (SZ), antipsychotics are deemed equally effective pharmaceutical treatments for both conditions. In this context, dopamine dysregulation may be transdiagnostic of the pathophysiology of psychotic disorders such as DD and SZ. In this study, an examination is made of the dopamine synthesis capacity (DSC) of patients with SZ, DD, other psychotic disorders, and the DSC of healthy subjects. Fifty-four subjects were recruited to the study, comprising 35 subjects with first-episode psychosis (11 DD, 12 SZ, 12 other psychotic disorders) and 19 healthy controls. All received an 18F-DOPA positron emission tomography (PET)/magnetic resonance (MR) scan to measure DSC (Kocc;30-60 value) within 1 month of starting antipsychotic treatment. Clinical assessments were also made, which included Positive and Negative Syndrome Scale (PANSS) measurements. The mean Kocc;30-60 was significantly greater in the caudate region of subjects in the DD group (ES = 0.83, corrected p = 0.048), the SZ group (ES = 1.40, corrected p = 0.003) and the other psychotic disorder group (ES = 1.34, corrected p = 0.0045), compared to that of the control group. These data indicate that DD, SZ, and other psychotic disorders have similar dysregulated mechanisms of dopamine synthesis, which supports the utility of abnormal dopamine synthesis in transdiagnoses of these psychotic conditions.

Do neurobiological differences exist between paranoid and non-paranoid schizophrenia? Findings from the bipolar schizophrenia network on intermediate phenotypes study.

Subtypes of schizophrenia, constructed using clinical phenomenology to resolve illness heterogeneity, have faced criticism due to overlapping symptomatology and longitudinal instability; they were therefore dropped from the Diagnostic Statistical Manual-5. Cognitive and imaging findings comparing paranoid (P-SZ) and non-paranoid (disorganized, residual and undifferentiated; NP-SZ) schizophrenia have been limited due to small sample sizes. We assessed P-SZ and NP-SZ using symptomatology, cognition and brain structure and predicted that there would be few neurobiological differences. P-SZ (n = 237), NP-SZ (n = 127) and controls (n = 430) were included from a multi-site study. In a subset of this sample, structural imaging measures (P-SZ, n = 133; NP-SZ, n = 67; controls, n = 310) were calculated using Freesurfer 6.0. Group contrasts were run using analysis of covariance, controlling for age, sex, race and site, p-values were corrected using False Discovery Rate (FDR) and were repeated excluding the residual subtype. Compared to NP-SZ (with and without the residual subtype), P-SZ displayed fewer negative symptoms, faster speed of processing, larger bilateral hippocampus, right amygdala and their subfield volumes. Additionally, NP-SZ (with residual subtype) displayed fewer depressive symptoms and higher left transverse temporal cortical thickness (CT) but NP-SZ without residual subtype showed lower GAF scores and worse digit sequencing compared to P-SZ. No differences in positive symptoms and functioning (global or social) were detected. Subtle but significant differences were seen in cognition, symptoms, CT and subcortical volumes between P-SZ and NP-SZ. While the magnitude of these differences is not large enough to justify them as distinct categories, the paranoid- nonparanoid distinction in schizophrenia merits further investigation.

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.

FDG-PET in Cotard syndrome before and after treatment: can functional brain imaging support a two-factor hypothesis of nihilistic delusions?

Introduction: Cotard syndrome is a neuropsychiatric entity recognised by the presence of nihilistic delusions. Although different models have been proposed for the development of monothematic delusions, including Cotard syndrome, functional neuroanatomical models are lacking.Methods: A case report of a 19-year old male with autoimmune encephalitis and Cotard syndrome, in whom Positron Emission Tomography (18F-FDG-PET) scans were performed before and after successful treatment with electroconvulsive therapy (ECT), is presented. Literature review on brain imaging is provided to discuss a functional neuroanatomical model of Cotard syndrome, in accordance with the two-factor theory of delusions.Results: The patient's 18F-FDG-PET showed marked insular and prefrontal metabolic abnormalities. Except for insular hypometabolism, metabolic abnormalities improved after ECT. Previously reported structural neuroimaging studies in Cotard syndrome showed a predominance of right hemisphere lesions, in which frontal lobes were more frequently involved, followed by parietal and temporal lesions. Functional neuroimaging studies reported abnormalities in frontoparietal circuits as well as midline structures included in the "default mode network".Conclusions: Abnormalities in the functioning of the insular cortex and the prefrontal cortex could be related to the development of nihilistic delusions when a two-factor theory of delusions is considered.

Aberrant myelination of the cingulum and Schneiderian delusions in schizophrenia: a 7T magnetization transfer study.

BACKGROUND: The structural integrity of the anterior cingulum has been repeatedly observed to be abnormal in patients with schizophrenia. More recently, aberrant myelination of frontal fasciculi, especially, cingulum has been proposed to underlie delayed corollary discharges that can affect sense of agency and contribute to delusions of control (Schneiderian delusions). Using the magnetization transfer phenomenon at an ultra-high field 7T MRI, we investigated the putative myelin content of cingulum bundle in patients with schizophrenia. METHODS: Seventeen clinically stable patients with schizophrenia and 20 controls were recruited for this 7T MRI study. We used a region-of-interest method and extracted magnetization transfer ratio (MTR) from left and right dorsal cingulum bundles and estimated patients v. controls differences. We also related the cingulum MTR values to the severity of Schneiderian delusions. RESULTS: Patients had a significant reduction in the MTR, indicating reduced myelin content, in the cingulum bundle (right cingulum Hedges' g = 0.91; left cingulum g = 0.03). The reduced MTR of left cingulum was associated with higher severity of Schneiderian delusions (τ = -0.45, p = 0.026) but no such relationship was seen for the right cingulum MTR (τ = -0.136, p = 0.50) among patients. The association between the left cingulum MTR and Schneiderian delusions was not explained by the presence of other delusions, hallucinations, disorganization or negative symptoms. CONCLUSIONS: Dysmyelination of the cingulum bundle is seen in a subgroup of patients with schizophrenia and may be involved in the mechanism of Schneiderian delusions.

Cortical folding abnormalities in patients with schizophrenia who have persistent auditory verbal hallucinations.

In schizophrenia temporal cortical volume loss differs between patients presenting with persistent auditory verbal hallucinations (pAVH) in contrast to those without hallucinatory symptoms (nAVH). However, it is unknown whether this deficit reflects a neural signature of neurodevelopmental origin or if abnormal temporal cortical volume is reflective of factors which may be relevant at later stages of the disorder. Here, we tested the hypothesis that local gyrification index (LGI) in regions of the temporal cortex differs between patients with pAVH (n=10) and healthy controls (n=14), and that abnormal temporal LGI discriminates between pAVH and nAVH (n=10). Structural magnetic resonance imaging at 3T along with surface-based data analysis methods was used. Contrary to our expectations, patients with pAVH showed lower LGI in Broca´s region compared to both healthy persons and nAVH. Compared to nAVH, those individuals presenting with pAVH also showed lower LGI in right Broca's homologue and right superior middle frontal cortex, together with increased LGI in the precuneus and superior parietal cortex. Regions with abnormal LGI common to both patient samples were found in anterior cingulate and superior frontal areas. Inferior cortical regions exhibiting abnormal LGI in pAVH patients were associated with overall symptom load (BPRS), but not with measures of AVH symptom severity. The pattern of abnormal cortical folding in this sample suggests a neurodevelopmental signature in Broca's region, consistent with current AVH models emphasizing the pivotal role of language circuits and inner speech. Temporal cortical deficits may characterize patients with pAVH during later stages of the disorder.

Transdiagnostic deviant facial recognition for implicit negative emotion in autism and schizophrenia.

Impaired facial affect recognition (FAR) is observed in schizophrenia and autism spectrum disorder (ASD) and has been linked to amygdala and fusiform gyrus dysfunction. ASD patient's impairments seem to be more pronounced during implicit rather than explicit FAR, whereas for schizophrenia data are inconsistent. However, there are no studies comparing both patient groups in an identical design. The aim of this three-group study was to identify (i) whether FAR alterations are equally present in both groups, (ii) whether they are present rather during implicit or explicit FAR, (iii) and whether they are conveyed by similar or disorder-specific neural mechanisms. Using fMRI, we investigated neural activation during explicit and implicit negative and neutral FAR in 33 young-adult individuals with ASD, 20 subjects with paranoid-schizophrenia and 25 IQ- and gender-matched controls individuals. Differences in activation patterns between each clinical group and controls, respectively were found exclusively for implicit FAR in amygdala and fusiform gyrus. In addition, the ASD group additionally showed reduced activations in medial prefrontal cortex (PFC), bilateral dorso-lateral PFC, ventro-lateral PFC, posterior-superior temporal sulcus and left temporo-parietal junction. Although subjects with ASD showed more widespread altered activation patterns, a direct comparison between both patient groups did not show disorder-specific deficits in neither patient group. In summary, our findings are consistent with a common neural deficit during implicit negative facial affect recognition in schizophrenia and autism spectrum disorders.

Altered corticostriatal pathway in first-episode paranoid schizophrenia: Resting-state functional and causal connectivity analyses.

Neuroimaging studies suggest the abnormal structure and function of basal ganglion may contribute to the pathophysiology of schizophrenia. However, little is investigated about the both aberrant functional and causal connectivity of striatum in first-episode paranoid schizophrenia (FEPS). Resting-state functional magnetic resonance imaging was used to characterize the functional connectivity (FC) and casual connectivity within the corticostriatal circuit in 31 patients with FEPS and 33 healthy controls. Degree centrality (DC) was used to explore the regions influenced in schizophrenia at the whole-brain level. Subsequently, a seed-based Granger causality analysis was performed to analyze the causal connectivity. We identified reduced DC of the bilateral putamen in the patients, compared to the controls. In the causal connectivity analysis, we found causal dysconnectivity between the putamen and several regions of default mode network, right orbital part of inferior frontal cortex and right fusiform in the patients. Further, the abnormal causal effect was associated with cognitive impairment in FEPS. The present study highlighted the abnormal functional and causal integrity of the striatum in the patients with FEPS during resting state and suggests a potentially implicated role for the cortical-striatal circuit, especially the striatal-default mode network loop, in the pathophysiology of schizophrenia.

Brain connectivity changes occurring following cognitive behavioural therapy for psychosis predict long-term recovery.

Little is known about the psychobiological mechanisms of cognitive behavioural therapy for psychosis (CBTp) and which specific processes are key in predicting favourable long-term outcomes. Following theoretical models of psychosis, this proof-of-concept study investigated whether the long-term recovery path of CBTp completers can be predicted by the neural changes in threat-based social affective processing that occur during CBTp. We followed up 22 participants who had undergone a social affective processing task during functional magnetic resonance imaging along with self-report and clinician-administered symptom measures, before and after receiving CBTp. Monthly ratings of psychotic and affective symptoms were obtained retrospectively across 8 years since receiving CBTp, plus self-reported recovery at final follow-up. We investigated whether these long-term outcomes were predicted by CBTp-led changes in functional connections with dorsal prefrontal cortical and amygdala during the processing of threatening and prosocial facial affect. Although long-term psychotic symptoms were predicted by changes in prefrontal connections during prosocial facial affective processing, long-term affective symptoms were predicted by threat-related amygdalo-inferior parietal lobule connectivity. Greater increases in dorsolateral prefrontal cortex connectivity with amygdala following CBTp also predicted higher subjective ratings of recovery at long-term follow-up. These findings show that reorganisation occurring at the neural level following psychological therapy can predict the subsequent recovery path of people with psychosis across 8 years. This novel methodology shows promise for further studies with larger sample size, which are needed to better examine the sensitivity of psychobiological processes, in comparison to existing clinical measures, in predicting long-term outcomes.

Phosphodiesterase 10A in Schizophrenia: A PET Study Using [(11)C]IMA107.

OBJECTIVE: Phosphodiesterase 10A (PDE10A) is an enzyme present in striatal medium spiny neurons that degrades the intracellular second messengers triggered by dopamine signaling. The pharmaceutical industry has considerable interest in PDE10A inhibitors because they have been shown to have an antipsychotic-like effect in animal models. However, the status of PDE10A in schizophrenia is unknown. Using a newly developed and validated radioligand, [(11)C]IMA107, the authors report the first in vivo assessment of PDE10A brain expression in patients with schizophrenia. METHOD: The authors compared PDE10A availability in the brains of 12 patients with chronic schizophrenia and 12 matched healthy comparison subjects using [(11)C]IMA107 positron emission tomography (PET). Regional estimates of the binding potential (BPND) of [(11)C]IMA107 were generated from dynamic PET scans using the simplified reference tissue model with the cerebellum as the reference tissue for nonspecific binding. RESULTS: There was no significant difference in [(11)C]IMA107 BPND between schizophrenia patients and comparison subjects in any of the brain regions studied (thalamus, caudate, putamen, nucleus accumbens, globus pallidus, and substantia nigra). There was also no significant correlation between [(11)C]IMA107 BPND and the severity of psychotic symptoms or antipsychotic dosage. CONCLUSIONS: Patients with schizophrenia have normal availability of PDE10A in brain regions thought to be involved in the pathophysiology of this disorder. The findings do not support the proposal of an altered PDE10A availability in schizophrenia. The implication of this finding for future drug development is discussed.

Positron emission tomography experience with 2-[¹8F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[¹8F]FA) in the living human brain of smokers with paranoid schizophrenia.

Utilizing postmortem data (Breese et al. [2000] Neuropsychopharmacology 23:351-364), we hypothesized that the densities of high-affinity neuronal α4ß2 nicotinic acetylcholine receptors (nAChRs) in the brain exist in a continuum from highest to lowest as follows: smokers without schizophrenia > smokers with schizophrenia > nonsmokers without schizophrenia > nonsmokers with schizophrenia. Application of the Kruskal-Wallis Test (Statacorp, 2003) to the postmortem data (Breese et al. [2000] Neuropsychopharmacology 23:351-364) confirmed the hypothesized order in the cortex and the hippocampus and attained significance in the caudate and the thalamus. Positron emission tomography (PET) was performed for 60 min at 6 h after the intravenous administration of 444 megabequerels [MBq] (12 mCi) 2-[¹8F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[¹8F]FA), a radiotracer for high-affinity neuronal α4ß2 nAChRs, as a bolus plus continuous infusion to 10 adults (seven men and three women) (six smokers including five with paranoid schizophrenia and four nonsmokers) ranging in age from 22 to 56 years (mean 40.1, standard deviation 13.6). The thalamic nondisplaceable binding potential (BP(ND) ) was 1.32 ± 0.19 (mean ± standard deviation) for healthy control nonsmokers; 0.50 ± 0.19 for smokers with paranoid schizophrenia; and 0.51 for the single smoker without paranoid schizophrenia. The thalamic BP(ND) s of nonsmokers were significantly higher than those of smokers who smoked cigarettes a few hours before the scans (P = 0.0105) (StataCorp, 2003), which was likely due to occupancy of nAChRs by inhaled nicotine in smokers. Further research is needed to rule out the effects of confounding variables.

Delusional infestation: neural correlates and antipsychotic therapy investigated by multimodal neuroimaging.

INTRODUCTION: In delusional infestation (DI), as with other non-schizophrenic psychotic disorders, little is known about the neural basis and the mechanisms of antipsychotic treatment. We aimed at investigating the brain circuitry involved in DI and the role of postsynaptic D2 receptors in mediating the effects of antipsychotics by means of multimodal neuroimaging. METHODS: In Case 1, a patient with DI (initially drug-induced), cerebral glucose metabolism and dopaminergic neurotransmission were studied in the untreated state (FDG-PET, FDOPA-PET, 123I-FP-CIT-SPECT, and IBZM-SPECT) and after effective aripiprazole treatment (FDG-PET and IBZM-SPECT), with negative drug screenings at both imaging sessions. In Case 2 (DI secondary to mild vascular encephalopathy) cerebral perfusion and gray matter volume changes were investigated in the untreated state and compared to N=8 [corrected] age-matched healthy controls (MRI-based CASL and VBM). RESULTS: In Case 1, before treatment, glucose metabolism was left-dominant in the thalamus and the putamen. Pre- and postsynaptic dopaminergic neurotransmissions were altered in the striatum, again mainly the left putamen. Full remission to aripiprazole was associated with 63 to 78% striatal D2 receptor occupancy and glucose metabolism changes in the bilateral thalamus. In Case 2, significant perfusion and GMV changes were observed in the bilateral putamen, frontal and parietal somatosensory cortices as compared to controls. Symptoms partially remitted to ziprasidone therapy. DISCUSSION/CONCLUSION: Six imaging techniques were first used to study the neural basis of DI and mechanisms of antipsychotic therapy. The study provides first low-level evidence in vivo evidence of fronto-striato-thalamo-parietal network to mediate core symptoms of DI, i.e. a priori brain regions involved in judgment (frontal cortex), sensory gating (thalamus) and body perception (dorsal striatum, thalamus and somatic cortices). This is also the first report of effective treatment with aripiprazole in drug-induced DI and with ziprasidone in organic DI, adding to existing limited evidence that SGAs are helpful in various forms of DI. Effective antipsychotic treatment seems to depend on blocking striatal D2 receptors with similar occupancy rates as in schizophrenia. Larger samples are needed to confirm our preliminary findings and further evaluate their relevance for the different forms of DI.

Porencephaly and psychosis: a case report and review of the literature.

BACKGROUND: Malformations of the cerebral cortex are often associated with developmental delay and psychoses. Porencephaly is a rare congenital disorder of central nervous system involving a cyst or a cavity filled with cerebrospinal fluid, in brain's parenchyma. CASE PRESENTATION: We present a 25 years old woman with her first psychotic episode. She also suffers from porencephaly in the frontotemporal lobes region. It is emphasized that the two consistently abnormal brain regions in schizophrenia research had significant damage in this patient since birth. There is a total of only five cases of schizencephaly or porencephaly associated with psychosis in the scientific literature. Their clinical characteristics as well as the imaging results are described. CONCLUSION: It is unclear if porencephaly and psychosis concur by chance or are causally related. The area where the porencephalic cysts appear seems to be of relevance. This case highlights the need for further research.

Classification of schizophrenic patients and healthy controls using [18F] fluorodopa PET imaging.

Striatal dopaminergic overactivity has been implicated in the pathophysiology of schizophrenia on the basis of in vivo neuroimaging studies. In particular, elevated striatal dopamine synthesis and storage has been repeatedly demonstrated in schizophrenia using the radiotracer 6-[18F] fluoro-l-DOPA ([18F] DOPA) and positron emission tomography (PET). Conventionally analysed [18F] DOPA PET imaging lacks the sensitivity or specificity to be used diagnostically. The aim of this study was to determine if the application of an Artificial Neural Network (ANN) would improve classification of images, and increase the sensitivity and specificity of [18F] DOPA as a potential diagnostic test for schizophrenia. We tested an ANN model in the discrimination of schizophrenic patients from normal controls using [18F] DOPA rate constants within the anterior-posterior subdivisions of the striatum, and compared the model with a general linear analysis of the same data. Participating in the study were 19 patients diagnosed with paranoid schizophrenia and 31 healthy subjects. Maximum classification was achieved using laterality quotients, - the ANN model correctly identified 94% of the controls and 89% of the patients, equivalent to 89% sensitivity and 94% specificity. Using all bilateral striatal regions correctly categorised 74% of the controls and 84% of the patients, equivalent to 84% sensitivity and 74% specificity. In comparison, the general linear analysis performed poorly, correctly classifying only 58% of the controls and 63% of the patients. Overall, these analyses have shown the potential utility of pattern recognition tools in the classification of psychiatric patients based upon molecular imaging of a single target.