Search

Delusions are rigid beliefs held with high certainty despite contradictory evidence. Notwithstanding decades of research, we still have a limited understanding of the computational and neurobiological alterations giving rise to delusions. In this review, we highlight a selection of recent work in computational psychiatry aimed at developing quantitative models of inference and its alterations, with the goal of providing an explanatory account for the form of delusional beliefs in psychosis. First, we assess and evaluate the experimental paradigms most often used to study inferential alterations in delusions. Based on our review of the literature and theoretical considerations, we contend that classic draws-to-decision paradigms are not well-suited to isolate inferential processes, further arguing that the commonly cited ‘jumping-to-conclusion’ bias may reflect neither delusion-specific nor inferential alterations. Second, we discuss several enhancements to standard paradigms that show promise in more effectively isolating inferential processes and delusion-related alterations therein. We further draw on our recent work to build an argument for a specific failure mode for delusions consisting of prior overweighting in high-level causal inferences about partially observable hidden states. Finally, we assess plausible neurobiological implementations for this candidate failure mode of delusional beliefs and outline promising future directions in this area.

Aim: Variants of the MTHFR gene have been associated with a wide range of diseases. Materials & methods: The present study analyzed data from clinical genotyping of MTHFR 677C>T and 1298A>C in 1405 patients in urban primary care settings. Results: Striking differences in ethnogeographic frequencies of MTHFR polymorphisms were observed. African–Americans appear to be protected from MTHFR deficiency. Hispanics and Caucasians may be at elevated risk due to increased frequencies of 677C>T and 1298A>C, respectively. Conclusion: Individuals carrying mutations for both genes were rare and doubly homozygous mutants were absent, suggesting the TTcc is extremely rare in the greater population. The results suggest multilocus MTHFR genotyping may yield deeper insight into the ethnogeographic association between MTHFR variants and disease.

Delusions, a core symptom of psychosis, are false beliefs that are rigidly held with strong conviction despite contradictory evidence. Alterations in inferential processes have long been proposed to underlie delusional pathology, but previous attempts to show this have failed to yield compelling evidence for a specific relationship between inferential abnormalities and delusional severity in schizophrenia. Using a novel, incentivized information-sampling task (a modified version of the beads task), alongside well-characterized decision-making tasks, we sought a mechanistic understanding of delusions in a sample of medicated and unmedicated patients with schizophrenia who exhibited a wide range of delusion severity. In this novel task, participants chose whether to draw beads from one of two hidden jars or to guess the identity of the hidden jar, in order to minimize financial loss from a monetary endowment, and concurrently reported their probability estimates for the hidden jar. We found that patients with higher delusion severity exhibited increased information seeking (i.e. increased draws-to-decision behaviour). This increase was highly specific to delusion severity as compared to the severity of other psychotic symptoms, working-memory capacity, and other clinical and socio-demographic characteristics. Delusion-related increases in information seeking were present in unmedicated patients, indicating that they were unlikely due to antipsychotic medication. In addition, after adjusting for delusion severity, patients as a whole exhibited decreased information seeking relative to healthy individuals, a decrease that correlated with lower socioeconomic status. Computational analyses of reported probability estimates further showed that more delusional patients exhibited abnormal belief updating characterized by stronger reliance on prior beliefs formed early in the inferential process, a feature that correlated with increased information seeking in patients. Other decision-making parameters that could have theoretically explained the delusion effects, such as those related to subjective valuation, were uncorrelated with both delusional severity and information seeking among the patients. In turn, we found some preliminary evidence that subjective valuation (rather than belief updating) may explain group differences in information seeking unrelated to delusions. Together, these results suggest that abnormalities in belief updating, characterized by stronger reliance on prior beliefs formed by incorporating information presented earlier in the inferential process, may be a core computational mechanism of delusional ideation in psychosis. Our results thus provide direct empirical support for an inferential mechanism that naturally captures the characteristic rigidity associated with delusional beliefs.

CYP-GUIDES ( Cy tochrome P sychotropic G enotyping U nder I nvestigation for De cision S upport) is a randomized controlled trial (RCT) of pharmacogenetic decision support in the psychotropic treatment of hospitalized patients with major depressive disorder or severe depression. Patients were treated according to their CYP2D6 functional status or empirically and compared for both their Length of Stay (LOS, primary outcome) at the hospital and Re-Admission Rate (RAR, secondary outcome) 30 days after discharge. The trial was conducted at the Institute of Living (Hartford Hospital, Hartford CT). CYP2D6 genotyping was implemented to infer the functional status of the CYP2D6 enzyme and classify it as sub-normal, normal or supra-normal. The electronic medical record (EMR) transmitted to the physician the indicated drug prescribing guidance. During the RCT, 1500 patients were recruited and 1459 genotyped for CYP2D6. A 1:2 randomization assigned 477 patients to standard therapy (Group S) and 982 to genetically-guided therapy (Group G). In Group S, standard empiric treatment was indicated for all patients. In Group G, medications primarily metabolized by the CYP2D6 enzyme were proscribed for patients with sub- or supra-normal CYP2D6 function. The clinical course, therapeutic guidance, and drug treatment for each patient are being published in this article and deposited in Mendeley Data. These data should be valuable to assess the impact of clinical decision support on utilization of psychiatric resources for treatment of severe depression requiring hospitalization.

Neuromelanin-sensitive MRI (NM-MRI) purports to detect the content of neuromelanin (NM), a product of dopamine metabolism that accumulates with age in dopamine neurons of the substantia nigra (SN). Interindividual variability in dopamine function may result in varying levels of NM accumulation in the SN; however, the ability of NM-MRI to measure dopamine function in nonneurodegenerative conditions has not been established. Here, we validated that NM-MRI signal intensity in postmortem midbrain specimens correlated with regional NM concentration even in the absence of neurodegeneration, a prerequisite for its use as a proxy for dopamine function. We then validated a voxelwise NM-MRI approach with sufficient anatomical sensitivity to resolve SN subregions. Using this approach and a multimodal dataset of molecular PET and fMRI data, we further showed the NM-MRI signal was related to both dopamine release in the dorsal striatum and resting blood flow within the SN. These results suggest that NM-MRI signal in the SN is a proxy for function of dopamine neurons in the nigrostriatal pathway. As a proof of concept for its clinical utility, we show that the NM-MRI signal correlated to severity of psychosis in schizophrenia and individuals at risk for schizophrenia, consistent with the well-established dysfunction of the nigrostriatal pathway in psychosis. Our results indicate that noninvasive NM-MRI is a promising tool that could have diverse research and clinical applications to investigate in vivo the role of dopamine in neuropsychiatric illness.

Earlier work in our laboratory demonstrated that naturally occurring reveromycin A (Rev A) causes apoptosis in osteoclasts without accompanying necrosis. Rev A death effects in both normal and diseased joint cells were investigated in this study. 10 □M Rev A did not cause apoptosis nor necrosis in monolayer chondrocytes, even at pH 6.8, a pH mimicking that of an inflamed joint. In contrast, at the acidic pH Rev A did induce significant apoptosis (four-fold increase at 48 hours of treatment, p

AIM: Variants of the MTHFR gene have been associated with a wide range of diseases. MATERIALS & METHODS: The present study analyzed data from clinical genotyping of MTHFR 677C>T and 1298A>C in 1405 patients in urban primary care settings. RESULTS: Striking differences in ethnogeographic frequencies of MTHFR polymorphisms were observed. African–Americans appear to be protected from MTHFR deficiency. Hispanics and Caucasians may be at elevated risk due to increased frequencies of 677C>T and 1298A>C, respectively. CONCLUSION: Individuals carrying mutations for both genes were rare and doubly homozygous mutants were absent, suggesting the TTcc is extremely rare in the greater population. The results suggest multilocus MTHFR genotyping may yield deeper insight into the ethnogeographic association between MTHFR variants and disease.

CYP-GUIDES (Cytochrome Psychotropic Genotyping Under Investigation for Decision Support) was a Randomized Controlled Trial comparing 2 outcomes in hospitalized patients with major depressive disorder treated according to the patient's CYP2D6 genotype and functional status versus standard psychotropic therapy. The primary outcome was hospital Length of Stay (LOS) and the secondary was Re-Admission Rate (RAR) 30 days after discharge. Methodology, total results and database of the trial have been published. Here we present a subanalysis that isolated 3 confounders to assess the impact of CYP2D6 therapeutic guidance on LOS: a single Electronic Medical Record, a minimum 3-day LOS, and CYP2D6 functional stratification of patients. CYP2D6 functional stratification enabled subgrouping patients and comparing outcomes according to CYP2D6 functionality within Group G and Group S. Subfunctional patients evidenced a 2-day shorter LOS in Group G compared to Group S. Drug administration for subfunctional patients in Group S evidenced a higher percentage of CYP2D6 substrate psychotropics being prescribed as well as a greater number of prescriptions than in functional patients. We conclude that there was an effect of pharmacogenetic clinical decision support that reduced LOS in patients with CYP2D6 subfunctional status and reduced prescribing of CYP2D6 substrate dependent drugs.

Findings from in vivo brain proton magnetic resonance spectroscopy (1H MRS) and preclinical studies have suggested region- and medication status-dependent increases in glutamate (Glu) levels and deficiencies in glutathione (GSH) levels in schizophrenia. N-acetylcysteine (NAC), a GSH synthesis precursor, has demonstrated modest clinical benefit in schizophrenia. The objective of this study was to examine the effects of acute administration of NAC on GSH and Glu levels measured with 1H MRS in 19 patients with schizophrenia and 20 healthy control subjects. Levels of GSH were acquired in dorsal anterior cingulate cortex (dACC), and those of Glu in dACC and medial prefrontal cortex (mPFC), at baseline and 60 min following acute oral administration of 2400 mg of NAC. No differences in the levels of GSH or Glu were found at baseline or following NAC administration between patients with schizophrenia and control subjects in either of the targeted brain regions. Future studies measuring GSH levels in brain regions previously found to exhibit glutamatergic abnormalities or using genetic polymorphisms, while controlling for the age and medication status of the cohorts, are warranted to better identify groups of patients more likely to respond to NAC and its mode of action and mechanisms.

The title compound, [Zn(C2H3O2)2(C12H13N3)]·2C2H4O2, consists of a five-coordinate trigonal–bipyramidal zinc complex (one N,N′,N′′-tridentate donor and two O-monodentate donors) and two acetic acid mol­ecules. The acetic acid mol­ecules hydrogen bond with the coordination complex. The coordination complex is located on a twofold axis that passes through the Zn atom and the secondary amine N atom is disordered across that axis.

Background: There is a growing demand by patients for easy electronic access to laboratory result data for use in personal health record systems (PHR-S) and for transfer to other health providers. The Blue Button Initiative is a public-private partnership offering a framework based on national standards to support patient access to electronic data. Objective: The aim of this project study was to architect an initial pilot implementation of the Blue Button framework for a commercial laboratory to facilitate patient access to electronic results. Methods: The proposed design architecture includes multiple application services, specifically an Encrypted Data Store, Client Access component, and Result Publishing service to accomplish these goals of the pilot project and meet the security and privacy requirements. Results: The resulting application components and programming interfaces accomplish the initial pilot goals and provide a base to expand the platform to offer support for mobile devices and additional interoperability options. Encryption and isolation of data have been used to safeguard the confidentiality, integrity and availability of protected health information (PHI) and allow for the use of standard cloud services to host external facing components. Conclusions: The Blue Button standards and framework provide a solid basis for facilitating electronic access to result data by patients and for meeting the requirements of View, Download, and Transmit (V/D/T) in Meaningful Use Stage 2 (MU-II). The Blue Button Framework can provide the functionality required for a Consumer Mediated Health Information Exchange which gives patients the ability to aggregate and control the use of their health information among providers. [iproc 2015;1(1):e7]