Sparse models for predicting psychosocial impairments in patients with PTSD: An empirical Bayes approach.

OBJECTIVE: Posttraumatic stress disorder (PTSD) is associated with psychosocial impairments, which represent a relevant focus for therapy. Previous results on the clinical predictors of these psychosocial impairments were inconsistent. The data analyzed in these contexts often suffer from a high number of correlated predictors and small sample sizes, entailing the risk of model overfitting. In Bayesian regression, the problem of overfitting can be mitigated by usage of specific zero-centered (regularizing) prior distributions. In this study, we used the 2 most common Bayesian regression models, the Bayesian Ridge and the Bayesian Lasso, to predict psychosocial impairments in 192 patients of a day clinic for the treatment of PTSD. METHOD: Predictions were based on specific dimensions of PTSD symptoms previously revealed by factor analyses, as well as posttraumatic cognitions, depressive symptoms, comorbid disorders, and demographics. The variance of the prior distribution was estimated through empirical Bayes (maximum marginal likelihood) and an approximation to the posterior distribution was obtained with stochastic variational inference and with a local approximation (Laplace approximation). RESULTS: Severe psychosocial impairments were mainly related to depressive symptoms and symptoms from the amnesia and numbing dimension of PTSD, while gender, posttraumatic cognitions, and reexperience and avoidance symptoms had no impact. As expected, the model coefficients were shrunken to zero when regularizing prior distributions were used, particularly for the Bayesian Lasso. CONCLUSION: Depressive and numbing symptoms are the main clinical correlates of psychosocial impairments in patients with PTSD. Usage of Bayesian and regularized regression can contribute to the generalizability and interpretability of research results. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Autobiographical Script-Driven Imagery Has No Detectable Effect on Emotion Regulation in Healthy Individuals.

INTRODUCTION: Emotion regulation (ER), the ability to actively modulate one's own emotion reactions, likely depends on the individual's current emotional state. Here, we investigated whether negative emotions induced by an interpersonal autobiographic script affect the neuronal processes underlying ER. METHODS: Twenty healthy participants were recruited and underwent functional magnetic resonance imaging (fMRI) during performance of distancing, a specific ER strategy, while viewing emotionally arousing pictures. Participants were instructed to either naturally experience ("permit" condition) or to actively downregulate ("regulate" condition) their emotional responses to the presented stimuli. Before each of the 4 runs in total, a neutral or negative autobiographical audio script was presented. The negative script comprised an emotionally negative event from childhood or adolescence that represented either emotional abuse or emotional neglect. The second event comprised an everyday neutral situation. We aimed at identifying the neural correlates of ER and their modulation by script-driven imagery. RESULTS: fMRI analyses testing for greater responses in the "regulate" than the "permit" condition replicated previously reported neural correlates of ER in the right dorsolateral prefrontal cortex and the right inferior parietal lobule. A significant ER effect was also observed in the left orbitofrontal cortex. In the amygdala, we found greater responses in the "permit" compared to the "regulate" condition. We did not observe a significant modulation of the ER effects in any of these regions by the negative emotional state induced by autobiographical scripts. Bayesian statistics confirmed the absence of such modulations by providing marginal evidence for null effects. DISCUSSION: While we replicated previously reported neural correlates of ER, we found no evidence for an effect of mood induction with individualized autobiographical scripts on the neural processes underlying ER in healthy participants.

Overly Strong Priors for Socially Meaningful Visual Signals Are Linked to Psychosis Proneness in Healthy Individuals.

According to the predictive coding theory of psychosis, hallucinations and delusions are explained by an overweighing of high-level prior expectations relative to sensory information that leads to false perceptions of meaningful signals. However, it is currently unclear whether the hypothesized overweighing of priors (1) represents a pervasive alteration that extends to the visual modality and (2) takes already effect at early automatic processing stages. Here, we addressed these questions by studying visual perception of socially meaningful stimuli in healthy individuals with varying degrees of psychosis proneness (n = 39). In a first task, we quantified participants' prior for detecting faces in visual noise using a Bayesian decision model. In a second task, we measured participants' prior for detecting direct gaze stimuli that were rendered invisible by continuous flash suppression. We found that the prior for detecting faces in noise correlated with hallucination proneness (r = 0.50, p = 0.001, Bayes factor 1/20.1) as well as delusion proneness (r = 0.46, p = 0.003, BF 1/9.4). The prior for detecting invisible direct gaze was significantly associated with hallucination proneness (r = 0.43, p = 0.009, BF 1/3.8) but not conclusively with delusion proneness (r = 0.30, p = 0.079, BF 1.7). Our results provide evidence for the idea that overly strong high-level priors for automatically detecting socially meaningful stimuli might constitute a processing alteration in psychosis.

Delusion Proneness is Linked to a Reduced Usage of Prior Beliefs in Perceptual Decisions.

Predictive coding theories state an aberrant weighting of prior beliefs and present sensory information as a core computational pathology in psychosis. Specifically, it has been proposed that the influence of prior beliefs which attenuate improbable sensory information is weakened, resulting in an overweighing of this potentially misleading information. However, it is currently unclear whether this alteration is specific to perceptual processes or whether it represents a more pervasive deficit that extends to cognitive processes. Here, we carried out 2 behavioral experiments that probed the usage of priors during perceptual and cognitive processes, respectively, in 123 healthy individuals with varying degrees of delusion proneness. In an audio-visual perceptual discrimination task, participants had to judge the global motion direction of random dot kinematograms. Prior beliefs were induced by auditory cues that probabilistically predicted the global motion direction of the dot kinematograms, allowing us to measure the impact of prior beliefs on perceptual decision making. A control experiment paralleled the design of the perceptual decision making task in the domain of cognitive decision making. By fitting the participants' responses with a probabilistic decision model, we quantified the impact of prior beliefs on participants' decisions in both tasks. With growing delusion proneness, we found a decreased impact of prior beliefs on perceptual but not on cognitive decision making. Our results show that delusion proneness is linked to a specifically reduced usage of prior beliefs in perceptual decisions, thereby empirically substantiating predictive coding theories of psychosis.

Correction: Psychotic Experiences and Overhasty Inferences Are Related to Maladaptive Learning.

[This corrects the article DOI: 10.1371/journal.pcbi.1005328.].

Psychotic Experiences and Overhasty Inferences Are Related to Maladaptive Learning.

Theoretical accounts suggest that an alteration in the brain's learning mechanisms might lead to overhasty inferences, resulting in psychotic symptoms. Here, we sought to elucidate the suggested link between maladaptive learning and psychosis. Ninety-eight healthy individuals with varying degrees of delusional ideation and hallucinatory experiences performed a probabilistic reasoning task that allowed us to quantify overhasty inferences. Replicating previous results, we found a relationship between psychotic experiences and overhasty inferences during probabilistic reasoning. Computational modelling revealed that the behavioral data was best explained by a novel computational learning model that formalizes the adaptiveness of learning by a non-linear distortion of prediction error processing, where an increased non-linearity implies a growing resilience against learning from surprising and thus unreliable information (large prediction errors). Most importantly, a decreased adaptiveness of learning predicted delusional ideation and hallucinatory experiences. Our current findings provide a formal description of the computational mechanisms underlying overhasty inferences, thereby empirically substantiating theories that link psychosis to maladaptive learning.

The sulfur oxygenase reductase from the mesophilic bacterium Halothiobacillus neapolitanus is a highly active thermozyme.

A biochemical, biophysical, and phylogenetic study of the sulfur oxygenase reductase (SOR) from the mesophilic gammaproteobacterium Halothiobacillus neapolitanus (HnSOR) was performed in order to determine the structural and biochemical properties of the enzyme. SOR proteins from 14 predominantly chemolithoautotrophic bacterial and archaeal species are currently available in public databases. Sequence alignment and phylogenetic analysis showed that they form a coherent protein family. The HnSOR purified from Escherichia coli after heterologous gene expression had a temperature range of activity of 10 to 99°C with an optimum at 80°C (42 U/mg protein). Sulfite, thiosulfate, and hydrogen sulfide were formed at various stoichiometries in a range between pH 5.4 and 11 (optimum pH 8.4). Circular dichroism (CD) spectroscopy and dynamic light scattering showed that the HnSOR adopts secondary and quaternary structures similar to those of the 24-subunit enzyme from the hyperthermophile Acidianus ambivalens (AaSOR). The melting point of the HnSOR was ≈20°C lower than that of the AaSOR, when analyzed with CD-monitored thermal unfolding. Homology modeling showed that the secondary structure elements of single subunits are conserved. Subtle changes in the pores of the outer shell and increased flexibility might contribute to activity at low temperature. We concluded that the thermostability was the result of a rigid protein core together with the stabilizing effect of the 24-subunit hollow sphere.

Substrate pathways and mechanisms of inhibition in the sulfur oxygenase reductase of acidianus ambivalens.

BACKGROUND: The sulfur oxygenase reductase (SOR) is the initial enzyme of the sulfur oxidation pathway in the thermoacidophilic Archaeon Acidianus ambivalens. The SOR catalyzes an oxygen-dependent sulfur disproportionation to H(2)S, sulfite and thiosulfate. The spherical, hollow, cytoplasmic enzyme is composed of 24 identical subunits with an active site pocket each comprising a mononuclear non-heme iron site and a cysteine persulfide. Substrate access and product exit occur via apolar chimney-like protrusions at the fourfold symmetry axes, via narrow polar pores at the threefold symmetry axes and via narrow apolar pores within in each subunit. In order to investigate the function of the pores we performed site-directed mutagenesis and inhibitor studies. RESULTS: Truncation of the chimney-like protrusions resulted in an up to sevenfold increase in specific enzyme activity compared to the wild type. Replacement of the salt bridge-forming Arg(99) residue by Ala at the threefold symmetry axes doubled the activity and introduced a bias toward reduced reaction products. Replacement of Met(296) and Met(297), which form the active site pore, lowered the specific activities by 25-55% with the exception of an M(296)V mutant. X-ray crystallography of SOR wild type crystals soaked with inhibitors showed that Hg(2+) and iodoacetamide (IAA) bind to cysteines within the active site, whereas Zn(2+) binds to a histidine in a side channel of the enzyme. The Zn(2+) inhibition was partially alleviated by mutation of the His residue. CONCLUSIONS: The expansion of the pores in the outer shell led to an increased enzyme activity while the integrity of the active site pore seems to be important. Hg(2+) and IAA block cysteines in the active site pocket, while Zn(2+) interferes over a distance, possibly by restriction of protein flexibility or substrate access or product exit.

Role of a novel disulfide bridge within the all-beta fold of soluble Rieske proteins.

Rieske proteins and Rieske ferredoxins are present in the three domains of life and are involved in a variety of cellular processes. Despite their functional diversity, these small Fe-S proteins contain a highly conserved all-beta fold, which harbors a [2Fe-2S] Rieske center. We have identified a novel subtype of Rieske ferredoxins present in hyperthermophilic archaea, in which a two-cysteine conserved SKTPCX((2-3))C motif is found at the C-terminus. We establish that in the Acidianus ambivalens representative, Rieske ferredoxin 2 (RFd2), these cysteines form a novel disulfide bond within the Rieske fold, which can be selectively broken under mild reducing conditions insufficient to reduce the [2Fe-2S] cluster or affect the secondary structure of the protein, as shown by visible circular dichroism, absorption, and attenuated total reflection Fourier transform IR spectroscopies. RFd2 presents all the EPR, visible absorption, and visible circular dichroism spectroscopic features of the [2Fe-2S] Rieske center. The cluster has a redox potential of +48 mV (25 degrees C and pH 7) and a pK (a) of 10.1 +/- 0.2. These shift to +77 mV and 8.9 +/- 0.3, respectively, upon reduction of the disulfide. RFd2 has a melting temperature near the boiling point of water (T(m) = 99 degrees C, pH 7.0), but it becomes destabilized upon disulfide reduction (DeltaT(m) = -9 degrees C, DeltaC(m) = -0.7 M guanidinium hydrochloride). This example illustrates how the incorporation of an additional structural element such as a disulfide bond in a highly conserved fold such as that of the Rieske domain may fine-tune the protein for a particular function or for increased stability.

Acidianus, Sulfolobus and Metallosphaera surface layers: structure, composition and gene expression.

The cell walls of Sulfolobales species consist of proteinaceous S-layers assembled from two polypeptides, SlaA and SlaB. We isolated the large S-layer protein of Acidianus ambivalens and both S-layer subunits of Sulfolobus solfataricus and Metallosphaera sedula, respectively. The slaAB genes, lying adjacently in the chromosomes, are constitutively transcribed as bicistronic operons in A. ambivalens and S. solfataricus. A smaller slaA transcript appeared in Northern hybridizations of A. ambivalens RNA. PCRs experiments showed that 80-85% of the transcripts stop at an oligo-T terminator downstream of slaA while 15-20% are read through to a second terminator downstream of slaB. The bicistronic operons including promoter and terminator regions are conserved in the Sulfolobales. While no SlaA homologue is found outside the Sulfolobales, SlaB is distantly similar to S-layer proteins of other Crenarchaeota, e.g. the Staphylothermus marinus tetrabrachion. Molecular modelling suggests SlaBs to be composed of 2-3 consecutive beta sandwich domains, a coiled-coil domain of 15-17 nm in length and a C-terminal transmembrane helix. Electron microscopy shows crystalline protein arrays with triangular and hexagonal pores. We propose that the mushroom-shaped 'unit cells' of the Sulfolobales' S-layers consist of three SlaBs anchoring the complex in the membrane and six SlaAs forming the detergent-resistant outer sacculus.