A computational neuroimaging study of reinforcement learning and goal-directed exploration in schizophrenia spectrum disorders.

BACKGROUND: Prior evidence indicates that negative symptom severity and cognitive deficits, in people with schizophrenia (PSZ), relate to measures of reward-seeking and loss-avoidance behavior (implicating the ventral striatum/VS), as well as uncertainty-driven exploration (reliant on rostrolateral prefrontal cortex/rlPFC). While neural correlates of reward-seeking and loss-avoidance have been examined in PSZ, neural correlates of uncertainty-driven exploration have not. Understanding neural correlates of uncertainty-driven exploration is an important next step that could reveal insights to how this mechanism of cognitive and negative symptoms manifest at a neural level. METHODS: We acquired fMRI data from 29 PSZ and 36 controls performing the Temporal Utility Integration decision-making task. Computational analyses estimated parameters corresponding to learning rates for both positive and negative reward prediction errors (RPEs) and the degree to which participates relied on representations of relative uncertainty. Trial-wise estimates of expected value, certainty, and RPEs were generated to model fMRI data. RESULTS: Behaviorally, PSZ demonstrated reduced reward-seeking behavior compared to controls, and negative symptoms were positively correlated with loss-avoidance behavior. This finding of a bias toward loss avoidance learning in PSZ is consistent with previous work. Surprisingly, neither behavioral measures of exploration nor neural correlates of uncertainty in the rlPFC differed significantly between groups. However, we showed that trial-wise estimates of relative uncertainty in the rlPFC distinguished participants who engaged in exploratory behavior from those who did not. rlPFC activation was positively associated with intellectual function. CONCLUSIONS: These results further elucidate the nature of reinforcement learning and decision-making in PSZ and healthy volunteers.

Technology-based communication among Hurricane Maria survivors in the United States: a trans-territorial lens.

PURPOSE: Rooted in a trans-territorial framework, the present study was designed to provide new evidence regarding the patterns of communication among Hurricane Maria survivors who migrated to the U.S. in the aftermath of the storm. METHODS: A total of 319 Hurricane Maria survivor adults ages 18 and older were recruited into the Adelante Boricua study between August 2020 and October 2021. Most participants had relocated to the U.S. between 2017 and 2018. We used latent profile analysis and multinomial regression to examine the relationship of technology-based communication with depressive symptoms, well-being, cultural connection, and migration stress. RESULTS: We identified a five-class solution, consisting of (1) moderate communication (32%), (2) disengaged (24%), (3) no social media (18%), (4) daily with family in Puerto Rico (6%), and (5) daily trans-territorial (13%) typologies. Participants in the disengaged class were more likely to report elevated depressive symptoms and limited English proficiency, lower prosocial behaviors, lower levels of religiosity, lower attendance at religious services in the U.S., and less engagement in social activities, compared to participants in the Moderate Communication class. CONCLUSION: Roughly one in four individuals in our sample reported very limited technology-based communication with friends/family in their sending and new-receiving communities. As technology and smartphones continue to become integrated into 21st-century life, it is vital that researchers explore how the tremendous potential for connectedness relates to trans-territorial crisis migrants' well-being and adaptation.

Motivational deficits in schizophrenia relate to abnormalities in cortical learning rate signals.

Individuals from across the psychosis spectrum display impairments in reinforcement learning. In some individuals, these deficits may result from aberrations in reward prediction error (RPE) signaling, conveyed by dopaminergic projections to the ventral striatum (VS). However, there is mounting evidence that VS RPE signals are relatively intact in medicated people with schizophrenia (PSZ). We hypothesized that, in PSZ, reinforcement learning deficits often are not related to RPE signaling per se but rather their impact on learning and behavior (i.e., learning rate modulation), due to dysfunction in anterior cingulate and dorsomedial prefrontal cortex (dmPFC). Twenty-six PSZ and 23 healthy volunteers completed a probabilistic reinforcement learning paradigm with occasional, sudden, shifts in contingencies. Using computational modeling, we found evidence of an impairment in trial-wise learning rate modulation (α) in PSZ before and after a reinforcement contingency shift, expressed most in PSZ with more severe motivational deficits. In a subsample of 22 PSZ and 22 healthy volunteers, we found little evidence for between-group differences in VS RPE and dmPFC learning rate signals, as measured with fMRI. However, a follow-up psychophysiological interaction analysis revealed decreased dmPFC-VS connectivity concurrent with learning rate modulation, most prominently in individuals with the most severe motivational deficits. These findings point to an impairment in learning rate modulation in PSZ, leading to a reduced ability to adjust task behavior in response to unexpected outcomes. At the level of the brain, learning rate modulation deficits may be associated with decreased involvement of the dmPFC within a greater RL network.

An audit of UK audiological practice in specialist paediatric oncology centres regarding hearing assessment of children at risk of ototoxicity due to chemotherapy.

OBJECTIVE: Platinum-based chemotherapy drugs are associated with substantial ototoxicity. The hearing of children treated with these drugs should be closely monitored. METHOD: A questionnaire was sent out to the 19 audiology departments associated with national paediatric cancer specialist centres in the UK looking at current practice in ototoxicity monitoring. RESULTS: Responses were received from 17 of 19 centres (89 per cent). All offered some form of audiometric monitoring service. Extended high-frequency testing (9-20 kHz) was only utilised by 7 services (29 per cent). A majority of respondents were reluctant to consider self-test devices in paediatric ototoxicity monitoring (n = 9; 53 per cent). Provision of long-term audiological follow up is sporadic with only 4 (23 per cent) respondents keeping all children with normal hearing under review once treatment is completed. CONCLUSION: While some good practice in paediatric ototoxicity was identified, opportunities exist to improve clinical practice and protocols, promote multidisciplinary team working and to utilise technologies such as extended high frequency and self-test audiometry.

Protein factor requirements of the Apaf-1 internal ribosome entry segment: roles of polypyrimidine tract binding protein and upstream of N-ras.

It has been reported previously that the 5' untranslated region of the mRNA encoding Apaf-1 (apoptotic protease-activating factor 1) has an internal ribosome entry site (IRES), whose activity varies widely among different cell types. Here it is shown that the Apaf-1 IRES is active in rabbit reticulocyte lysates, provided that the system is supplemented with polypyrimidine tract binding protein (PTB) and upstream of N-ras (unr), two cellular RNA binding proteins previously identified to be required for rhinovirus IRES activity. In UV cross-linking assays and electrophoretic mobility shift assays with individual recombinant proteins, the Apaf-1 IRES binds unr but not PTB; however, PTB binding occurs if unr is present. Over a range of different cell types there is a broad correlation between the activity of the Apaf-1 IRES and their content of PTB and unr. In cell lines deficient in these proteins, overexpression of PTB and unr stimulated Apaf-1 IRES function. This is the first example where an IRES in a cellular mRNA has been shown to be functionally dependent, both in vitro and in vivo, on specific cellular RNA binding proteins. Given the critical role of Apaf-1 in apoptosis, these results have important implications for the control of the apoptotic cascade.

Vibrational spectroscopic and ultrasound analysis for in-process characterization of high-density polyethylene/polypropylene blends during melt extrusion.

Spectroscopic techniques such as Raman, mid-infrared (MIR), and near-infrared (NIR) have become indispensable analytical tools for rapid chemical quality control and process monitoring. This paper presents the application of in-line Fourier transform near-infrared (FT-NIR) spectroscopy, Raman spectroscopy, and ultrasound transit time measurements for in-line monitoring of the composition of a series of high-density polyethylene (HDPE)/polypropylene (PP) blends during single-screw extrusion. Melt composition was determined by employing univariate analysis of the ultrasound transit time data and partial least squares (PLS) multivariate analysis of the data from both spectroscopic techniques. Each analytical technique was determined to be highly sensitive to changes in melt composition, allowing accurate prediction of blend content to within +/- 1% w/w (1sigma) during monitoring under fixed extrusion conditions. FT-NIR was determined to be the most sensitive of the three techniques to changes in melt composition. A four-factor PLS model of the NIR blend spectra allowed determination of melt content with a standard prediction error of +/- 0.30% w/w (1sigma). However, the NIR transmission probes employed for analysis were invasive into the melt stream, whereas the single probes adopted for Raman and ultrasound analysis were noninvasive, making these two techniques more versatile. All three measurement techniques were robust to the high temperatures and pressures experienced during melt extrusion, demonstrating each system's suitability for process monitoring and control.

Raman spectroscopic studies of the cure of dicyclopentadiene (DCPD).

The cure of polydicyclopentadiene conducted by ring-opening metathesis polymerisation in the presence of a Grubbs catalyst was studied using non-invasive Raman spectroscopy. The spectra of the monomer precursor and polymerised product were fully characterised and all stages of polymerisation monitored. Because of the monomer's high reactivity, the cure process is adaptable to reaction injection moulding and reactive rotational moulding. The viscosity of the dicyclopentadiene undergoes a rapid change at the beginning of the polymerisation process and it is critical that the induction time of the viscosity increase is determined and controlled for successful manufacturing. The results from this work show non-invasive Raman spectroscopic monitoring to be an effective method for monitoring the degree of cure, paving the way for possible implementation of the technique as a method of real-time analysis for control and optimisation during reactive processing. Agreement is shown between Raman measurements and ultrasonic time of flight data acquired during the initial induction period of the curing process.

Neuropeptidergic systems in plaques of Alzheimer's disease.

Polyclonal antibodies directed against substance P, somatostatin, neurotensin, cholecystokinin (CCK), leucine enkephalin, and vasoactive intestinal polypeptide (VIP) were employed to determine the immunoreactivities of neurites of senile plaques (SP) in Alzheimer's disease (AD). All of the antibodies labeled some neurites in some SP. The transmitter specificities of immunoreactive neurites tended to reflect the distribution of transmitter-associated fibers in normal tissue. This investigation also documented the presence of abnormal axons (as distinct from neurites within plaques) in the neuropil in brains of individuals with AD and in some aged controls. These findings suggest that a variety of transmitter systems are involved in the formation of neuropil abnormalities of SP. They also indicate that a greater number of neuronal systems are affected in AD than have been documented by neurochemical studies.

An improved method for the purification of retinal S-antigen using selective hydrophobic adsorption chromatography.

This paper describes the use of phenyl-Sepharose CL-4B as a solid-phase hydrophobic adsorbent in the purification of S-antigen from protein extracts of bovine, porcine and human retina. Chromatographic conditions were ascertained whereby the majority of contaminating proteins were bound to the adsorbent leaving S-antigen in the liquid phase. In combination with size fractionation on Ultrogel AcA, the method conveniently yielded porcine and bovine S-antigen preparations up to 100% purity. Immunogenicity of purified S-antigens was verified by induction of experimental autoimmune uveoretinitis in albino Lewis rats. The method is preparative in scale, fast in performance and yields S-antigen in high purity and antigenic potency.

Differential effect of Bordetella pertussis on experimental posterior uveitis in the black-hooded Lister rat.

The effect of an additional adjuvant, Bordetella pertussis, on the clinical and histopathologic features of experimental autoimmune uveitis in black-hooded Lister rats was investigated. Disease was induced by a single footpad injection of purified retinal S-antigen in Freund's complete adjuvant. In those animals that did not receive B Pertussis the clinical features were those of a retinal vasculitis with disc edema, periphlebitis, and deep retinal infiltrates. In contrast, animals that received B pertussis developed lesions in the pigment epithelium and choroid. Histopathologic studies disclosed focal photoreceptor necrosis associated with mononuclear cell infiltration in both groups of animals. However, in the group that did not receive B pertussis the disease was predominantly a retinitis associated with perivascular infiltration of retinal vessels, whereas in the group that did receive B pertussis the main feature was a focal choroiditis, with superficial retinal lesions being rarely observed. Retinal photoreceptors were the target tissue in both groups of rats, but the route by which they were damaged was altered from predominantly retinal to choroidal by the addition of Bordetella pertussis as an adjuvant. This change may be ascribed to the ability of B pertussis toxin to sensitize vascular endothelium to local mast cell products, these cells being plentiful around choroidal vessels but absent in the retinal circulation.

Maternal dietary choline availability alters mitosis, apoptosis and the localization of TOAD-64 protein in the developing fetal rat septum.

Maternal changes in dietary choline availability alter brain biochemistry and hippocampal development in the offspring resulting in lifelong behavioral changes in the offspring. In order to better understand the relationship between maternal diet, brain cytoarchitecture and behavior, we investigated the effects of choline availability on cell proliferation, apoptosis and differentiation in the fetal rat brain septum. Timed-pregnant rats on day E12 were fed AIN-76 diet with varying levels of dietary choline for 6 days. We found that choline deficiency (CD) significantly decreased the rate of mitosis in the progenitor neuroepithelium adjacent to the septum. In addition, we found an increased number of apoptotic cells in the septum of CD animals compared to controls (3.5+/-0.5 vs. 1.7+/-0.5 apoptotic cells per section; p<0.05). However, CD had no effect on apoptosis in the indusium griseum (IG), a region of cortex dorsal to the septum. Using an unbiased image analysis method and a monoclonal antibody we found a decreased expression of the TOAD-64 kDa protein, a marker of commitment to neuronal differentiation during fetal development, in the dorsal lateral septum of CD animals. CD also decreased the expression of TOAD-64 kDa protein in the IG and cortical plate adjacent to the septum. These results show that dietary choline availability during pregnancy alters the timing of mitosis, apoptosis and the early commitment to neuronal differentiation by progenitor cells in regions of the fetal brain septum, as well as hippocampus, two brain regions known to be associated with learning and memory.

Experimental posterior uveitis. I: A clinical, angiographic, and pathological study.

The clinical, angiographic, and histopathological features of experimental posterior uveitis in the black hooded Lister rat are described. This mild form of experimental allergic uveoretinitis (EAU) is induced by sensitisation with retinal S antigen in Freund's complete adjuvant, and the inflammation produced is confined to the posterior segment of the eye. This allows for the first time precise photographic and angiographic documentation of the evolution of clinical signs, because there is minimal clouding of the vitreous by inflammatory cells. Clinically the disease is characterised by the appearance of disc oedema and periphlebitis, followed by focal infiltrates in the deep retinal layers, with eventual atrophy of the pigment epithelium. Histologically, retinal vasculitis is associated with focal mononuclear cell infiltration and necrosis of the photoreceptor layers. This model closely resembles the clinical features of idiopathic retinal vasculitis seen in man.

Alcohol expectancies among adolescents with conduct disorder: prediction and mediation of drinking.

Among adolescents with conduct disorder, alcohol expectancies were examined for both predictive utility and mediation of other predictors of alcohol use (i.e., delinquency, family history, demographic and psychopathology variables). Data were collected from 260 adolescents with conduct disorder 11-18 years of age, who had been in either mental health residential facilities or community-based special education programs for adolescents with serious emotional disturbances. Zero-order correlations and structural path models assessed relationships between expectancies, alcohol use, and other predictors of alcohol use. Results indicated: (a) expectancies of enhanced social and cognitive behavior were significant (p < .05) univariate predictors of drinking, (b) among all of the selected predictors, expectancies of enhanced social behavior (i.e., Subscale 2 of the Alcohol Expectancy Questionnaire--Adolescent Form; AEQ-A) had the strongest association with alcohol use (r = .54) and mediated between 31% to 44% of the drinking variance associated with other significant predictors (p < .01). Results were discussed as supporting similar expectancy-drinking relationships among CD and nonclinical youth.

Modulation of motor cortex activity when observing rewarding and punishing actions.

Interpreting others' actions is essential for understanding the intentions and goals in social interactions. Activity in the motor cortex is evoked when we see another person performing actions, which can also be influenced by the intentions and context of the observed action. No study has directly explored the influence of reward and punishment on motor cortex activity when observing others' actions, which is likely to have substantial relevance in different social contexts. In this experiment, EEG was recorded while participants watched movie clips of a person performing actions that led to a monetary reward, loss or no change for the observer. Using the EEG mu rhythm as an index of motor resonance, our results demonstrate that observation of rewarding actions produce significantly greater motor cortex activity than punishing or neutral actions, with punishing actions producing greater activity than neutral ones. In addition, the dynamic change in the mu rhythm over sensorimotor cortex is modulated by reward and punishment, with punishing actions producing a prolonged suppression. These findings demonstrate that the associated reward value of an observed action may be crucial in determining the strength of the representation of the action in the observer's brain. Consequently, reward and punishment is likely to drive observational learning through changes in the action observation network, and may also influence how we interpret, understand, engage in and empathize with others' actions in social interaction.

Precoated femoral component in total hip arthroplasty. Results of 5- to 9-year followup.

One hundred nineteen consecutive primary hybrid total hip arthroplasties with a precoated femoral component were performed by one surgeon in 100 patients and followed up prospectively. Ninety-eight hips in 82 patients (mean age, 67 years) were evaluated clinically and radiographically at a mean of 6.5 years (range, 5-9 years). The hips were evaluated clinically using the Harris hip score, and radiographs were evaluated for femoral cement grade, loosening, and osteolysis. Ninety-five hips remained in place at the most recent followup. Two femoral components were revised for definite loosening, and one well fixed femoral component was removed because of late hematogenous infection. Excluding the three hips that were revised, the clinical result was excellent or good in 79 hips (83%), fair in 12 hips (13%), and poor in four hips (4%). All other femoral components were well fixed. There were defects of the cement mantles (C1 and C2) in 90 hips. No femoral component had a stem and cement radiolucent line. Focal femoral osteolysis was seen in only two hips. One acetabular component was removed at 5 years because of late hematogenous infection. One acetabular component had asymptomatic migration. The remaining 96 acetabular components were well fixed. Focal acetabular osteolysis was present in four hips. The mean linear polyethylene wear rate was 0.06 (+/- 0.05) mm per year. In contrast to other reports of early failure and osteolysis, the use of a precoated femoral component in this study did not adversely affect the fixation of hybrid total hip arthroplasty, with definite failure of only 2% (two of 98) of the femoral components.

Amyloidosis in Reiter's syndrome.

A patient with a 27-year-history of chronic relapsing Reiter's syndrome who developed secondary amyloidosis is described. While there are only 2 reports of this association in the English literature, additional cases are suggested in the light of our present concepts. The patient represents the only case of clinically apparent secondary amyloidosis among 158 patients with HLA B27 associated arthropathies currently followed at our institution. Our patient's amyloidosis was treated for nearly 1 year with colchicine without response.

Interorganellar crosstalk: new perspectives on signaling from the chloroplast to the nucleus.

Chlorophyll precursors, photosynthetic electron transport, and sugars have all been shown to be involved in signaling from the chloroplast to the nucleus, suggesting the presence of multiple signaling pathways of coordination between these two cellular compartments.