Changes in responses of the amygdala and hippocampus during fear conditioning are associated with persecutory beliefs.

The persecutory delusion is the most common symptom of psychosis, yet its underlying neurobiological mechanisms are poorly understood. Prior studies have suggested that abnormalities in medial temporal lobe-dependent associative learning may contribute to this symptom. In the current study, this hypothesis was tested in a non-clinical sample of young adults without histories of psychiatric treatment (n = 64), who underwent classical Pavlovian fear conditioning while fMRI data were collected. During the fear conditioning procedure, participants viewed images of faces which were paired (the CS+) or not paired (the CS-) with an aversive stimulus (a mild electrical shock). Fear conditioning-related neural responses were measured in two medial temporal lobe regions, the amygdala and hippocampus, and in other closely connected brain regions of the salience and default networks. The participants without persecutory beliefs (n = 43) showed greater responses to the CS- compared to the CS+ in the right amygdala and hippocampus, while the participants with persecutory beliefs (n = 21) failed to exhibit this response. These between-group differences were not accounted for by symptoms of depression, anxiety or a psychosis risk syndrome. However, the severity of subclinical psychotic symptoms overall was correlated with the level of this aberrant response in the amygdala (p = .013) and hippocampus (p = .033). Thus, these findings provide evidence for a disruption of medial temporal lobe-dependent associative learning in young people with subclinical psychotic symptoms, specifically persecutory thinking.

The impact of early intervention for first episode psychosis on cognitive functioning.

IMPORTANCE: Impaired cognitive functioning is a core characteristic of schizophrenia, present from the onset of the illness and relatively stable thereafter. Despite evidence supporting the impact of early intervention services (EIS) on improving symptoms and functioning in first episode psychosis (FEP), controlled research has not examined its impact on cognitive functioning. OBJECTIVE: To evaluate the longitudinal course of cognitive functioning in FEP patients participating in a large, controlled study comparing EIS with usual services. METHODS: A total of 404 persons ages 15-40 years old with non-affective FEP participated in the Recovery After Initial Schizophrenia-Early Treatment Program. A cluster randomized controlled trial was conducted with 34 community mental health treatment centers across the U.S. randomized to provide either an EIS program (NAVIGATE) or usual Community Care (CC) to FEP patients for 2 years. Cognitive functioning was assessed with the Brief Assessment of Cognition in Schizophrenia (BACS) at baseline and 1- and 2-years later. RESULTS: Older participants (≥20 years old) in both treatment groups improved on all BACS tests. Younger participants (15-19) in NAVIGATE improved significantly more on Digit Sequencing (working memory) than those in CC, whereas both groups improved on most of the other BACS tests. Improvements in cognitive functioning occurred mostly over the first year and were correlated with reductions in symptom severity. DISCUSSION: EIS do not improve cognitive functioning more than usual care for older FEP patients but may improve working memory in younger FEP patients. Interventions targeting cognition may be required to enhance cognitive functioning in most FEP patients.

Uncovering and mitigating bias in large, automated MRI analyses of brain development.

Large, population-based MRI studies of adolescents promise transformational insights into neurodevelopment and mental illness risk 1,2. However, MRI studies of youth are especially susceptible to motion and other artifacts 3,4. These artifacts may go undetected by automated quality control (QC) methods that are preferred in high-throughput imaging studies, 5 and can potentially introduce non-random noise into clinical association analyses. Here we demonstrate bias in structural MRI analyses of children due to inclusion of lower quality images, as identified through rigorous visual quality control of 11,263 T1 MRI scans obtained at age 9-10 through the Adolescent Brain Cognitive Development (ABCD) Study6. Compared to the best-rated images (44.9% of the sample), lower-quality images generally associated with decreased cortical thickness and increased cortical surface area measures (Cohen's d 0.14-2.84). Variable image quality led to counterintuitive patterns in analyses that associated structural MRI and clinical measures, as inclusion of lower-quality scans altered apparent effect sizes in ways that increased risk for both false positives and negatives. Quality-related biases were partially mitigated by controlling for surface hole number, an automated index of topological complexity that differentiated lower-quality scans with good specificity at Baseline (0.81-0.93) and in 1,000 Year 2 scans (0.88-1.00). However, even among the highest-rated images, subtle topological errors occurred during image preprocessing, and their correction through manual edits significantly and reproducibly changed thickness measurements across much of the cortex (d 0.15-0.92). These findings demonstrate that inadequate QC of youth structural MRI scans can undermine advantages of large sample size to detect meaningful associations.

Feeling rushed? Perceived time pressure impacts executive function and stress.

Executive function (EF) is critical to everyday life, but it can be undermined by adverse psychological states like stress and negative affect. For example, inadequate time to perform a task is a common stressor that can disrupt EF. Although the impact of actual time pressure on EF has been established, little is known about how self-generated, perceived time pressure (PTP) affects EF in the absence of objective time limits. We chose Eriksen's Flanker task as an index of cognitive inhibition, a key component of EF, and we varied the interval between successive trials, the inter-trial interval (ITI), to proxy PTP. This manipulation strongly impacted task performance: shrinking the ITI to increase PTP diminished cognitive inhibition and increased both stress and negative affect. Subsequently lengthening the ITI to decrease PTP reversed nearly all of these effects, except stress, which persisted. Multilevel linear regression modeling revealed that ITI and stress predicted inhibition, and exploratory mediation modeling suggested that stress mediates the relationship between ITI and inhibition. These findings validate perceived time pressure as an empirical stressor and demonstrate EF's sensitivity to changes in PTP.

Perceptual timing precision with vibrotactile, auditory, and multisensory stimuli.

The growing use of vibrotactile signaling devices makes it important to understand the perceptual limits on vibrotactile information processing. To promote that understanding, we carried out a pair of experiments on vibrotactile, auditory, and bimodal (synchronous vibrotactile and auditory) temporal acuity. On each trial, subjects experienced a set of isochronous, standard intervals (400 ms each), followed by one interval of variable duration (400 ± 1-80 ms). Intervals were demarcated by short vibrotactile, auditory, or bimodal pulses. Subjects categorized the timing of the last interval by describing the final pulse as either "early" or "late" relative to its predecessors. In Experiment 1, each trial contained three isochronous standard intervals, followed by an interval of variable length. In Experiment 2, the number of isochronous standard intervals per trial varied, from one to four. Psychometric modeling revealed that vibrotactile stimulation produced poorer temporal discrimination than either auditory or bimodal stimulation. Moreover, auditory signals dominated bimodal sensitivity, and inter-individual differences in temporal discriminability were reduced with bimodal stimulation. Additionally, varying the number of isochronous intervals in a trial failed to improve temporal sensitivity in either modality, suggesting that memory played a key role in judgments of interval duration.

Complex clinical management of group A Streptococcal pelvic inflammatory disease after bilateral tubal ligation in a small community hospital.

A 43-year-old woman with a history of bilateral tubal ligation and bilateral ovarian cysts presented to our hospital with progressively worsening right lower quadrant pain and abdominal distension. Her exam findings of vaginal discharge and cervical motion tenderness, in combination with her marked leucocytosis, were suggestive of pelvic inflammatory disease (PID). PCR for Chlamydia trachomatis and Neisseria gonorrhoeae was negative, however, our patient's blood cultures grew group A Streptococcus This exceptionally severe presentation of PID, in combination with uncommon laboratory findings, led to complex multidisciplinary clinical decision making guided by extensive literature review. Here, we present a rare case of group A Streptococcus PID after bilateral tubal ligation, and highlight the role of a family medicine primary team in the medical and surgical management of a complex case at a community hospital.

Feeling the Beat (and Seeing It, Too): Vibrotactile, Visual, and Bimodal Rate Discrimination.

Beats are among the basic units of perceptual experience. Produced by regular, intermittent stimulation, beats are most commonly associated with audition, but the experience of a beat can result from stimulation in other modalities as well. We studied the robustness of visual, vibrotactile, and bimodal signals as sources of beat perception. Subjects attempted to discriminate between pulse trains delivered at 3 Hz or at 6 Hz. To investigate signal robustness, we intentionally degraded signals on two-thirds of the trials using temporal-domain noise. On these trials, inter-pulse intervals (IPIs) were stochastic, perturbed independently from the nominal IPI by random samples from zero-mean Gaussian distributions with different variances. These perturbations produced directional changes in the IPIs, which either increased or decreased the likelihood of confusing the two pulse rates. In addition to affording an assay of signal robustness, this paradigm made it possible to gauge how subjects' judgments were influenced by successive IPIs. Logistic regression revealed a strong primacy effect: subjects' decisions were disproportionately influenced by a trial's initial IPIs. Response times and parameter estimates from drift-diffusion modeling showed that information accumulates more rapidly with bimodal stimulation than with either unimodal stimulus alone. Analysis of error rates within each condition suggested consistently optimal decision making, even with increased IPI variability. Finally, beat information delivered by vibrotactile signals proved just as robust as information conveyed by visual signals, confirming vibrotactile stimulation's potential as a communication channel.

Impact of population-specific dental development on age estimation using dental atlases.

OBJECTIVES: The steady development and subsequent eruption of the dentition is particularly useful for the estimation of age in juveniles. There are few studies that examine and test methods on a population-diverse sample. Our goal is to test the Ubelaker () and London Atlas (2010) dental charts on a sample representing several different population backgrounds to infer if refinement for population-specific standards should be developed. MATERIALS AND METHODS: The first and second authors examined panoramic radiographs of 335 individuals from the James K. Economides Orthodontic Collection blind to chronological age, sex, and ancestry and scored using both dental atlases. RESULTS: The age of Native Americans and African Americans was generally overestimated, suggesting faster rates of development. European Americans and New Mexico Hispanics, while not always showing the highest success rates, generally were closer to the correct age than other ancestry groups. The overall success rate for Ubelaker () was 80.00% for both observers, while the London Atlas was significantly lower at approximately 21.79-23.28%. Accuracy rates did not differ significantly between ancestry groups, though patterns were evident regarding under- or over-estimation of age. DISCUSSION: The present study demonstrates that incorrect age estimations were typically still within 1.5 years of the actual age. Ubelaker () had higher rates of success due to broader age ranges. The results suggest that though accuracy rates did not significantly differ, different developmental rates may affect age estimates and population-specific standards should be considered for known-ancestry individuals, while aging standards constructed from a diverse sample should be utilized for unknown-ancestry cases.

Qualitative Assessment of Clerkship Students' Perspectives of the Topics of Pain and Addiction in their Preclinical Curriculum.

OBJECTIVE: A majority of physicians feel poorly trained in the treatment of chronic pain and addiction. As such, it is critical that medical students receive appropriate education in both pain management and addiction. The purpose of this study was to assess the pre-clinical curriculum in pain medicine and addiction from the perspective of students after they had completed their pre-clinical training and to assess what they perceived as the strengths and weaknesses of their training. METHODS: The authors conducted focused interviews among clinical medical students who had completed at least 6 months of clerkships. The interviews targeted the students' retrospective opinions about the pre-clinical curriculum and their preparedness for clinical encounters with either pain or addiction-related issues during their rotations. Coders thematically analyzed the de-identified interview transcripts, with consensus reached through discussion and code modification. RESULTS: Themes that emerged through the focused interviews included: fragmented curricular structure (and insufficient time) for pain and addiction medicine, not enough specific treatment strategies for pain or addiction, especially for complex clinical scenarios, and lack of a trained work-force to provide guidance in the management of pain and addiction. CONCLUSION: This study demonstrated the feasibility of gathering student perspectives to inform changes to improve the pre-clinical curriculum in pain and addiction medicine. Students identified multiple areas for improvement at the pre-clerkship level, which have informed updates to the curriculum. More research is needed to determine if curricular changes based on student feedback lead to improved learning outcomes.

Taphonomic Analysis of Rodentia and Lagomorpha Bone Gnawing Based Upon Incisor Size.

Rodent and lagomorph species have a worldwide distribution and have the potential to alter remains from forensic cases by gnawing soft tissue and bones and through dispersal. The present research compiled metric data on the incisors widths of all rodent and lagomorph species whose ranges include Massachusetts, U.S.A., to compare their sizes to gnawing damage found on 17 cases of human remains from the Office of the Chief Medical Examiner, Boston, MA. Data on gnawing maximum striation widths also were collected from live laboratory, zoo, and wild specimens. Gnawing damage on the forensic cases could be attributed only to a particular size class of rodent or lagomorph, and identification to a particular species based on gnawing damage alone may be possible only in relatively rare cases. Multiple species examined here have broad distribution ranges, so their taphonomic alterations may impact bones from forensic cases throughout large portions of North America.

Comparison of the accuracy and precision of pharmacokinetic equations to predict free meropenem concentrations in critically ill patients.

Population pharmacokinetic analyses can be applied to predict optimized dosages for individual patients. The aim of this study was to compare the prediction performance of the published population pharmacokinetic models for meropenem in critically ill patients. We coded the published population pharmacokinetic models with covariate relationships into dosing software to predict unbound meropenem concentrations measured in a separate cohort of critically ill patients. The agreements between the observed and predicted concentrations were evaluated with Bland-Altman plots. The absolute and relative bias and precision of the models were determined. The clinical implications of the results were evaluated according to whether dose adjustments were required from the predictions to achieve a meropenem concentration of >2 mg/liter throughout the dosing interval. A total of 157 free meropenem concentrations from 56 patients were analyzed. Eight published population pharmacokinetic models were compared. The models showed an absolute bias in predicting the unbound meropenem concentrations from a mean percent difference (95% confidence interval [CI]) of -108.5% (-119.9% to -97.3%) to 19.9% (7.3% to 32.7%), while absolute precision ranged from -249.1% (-263.4% to -234.8%) to 31.9% (17.6% to 46.2%) and -178.9% (-196.9% to -160.9%) to 175.0% (157.0% to 193.0%). A dose change was required in 44% to 64% of the concentration results. Seven of the eight equations evaluated underpredicted free meropenem concentrations. In conclusion, the overall accuracy of these models supports their inclusion in dosing software and application for individualizing meropenem doses in critically ill patients to increase the likelihood of achievement of optimal antibiotic exposures.

Spatial context learning survives interference from working memory load.

The human visual system is constantly confronted with an overwhelming amount of information, only a subset of which can be processed in complete detail. Attention and implicit learning are two important mechanisms that optimize vision. This study addressed the relationship between these two mechanisms. Specifically we asked, Is implicit learning of spatial context affected by the amount of working memory load devoted to an irrelevant task? We tested observers in visual search tasks where search displays occasionally repeated. Observers became faster when searching repeated displays than unrepeated ones, showing contextual cuing. We found that the size of contextual cuing was unaffected by whether observers learned repeated displays under unitary attention or when their attention was divided using working memory manipulations. These results held when working memory was loaded by colors, dot patterns, individual dot locations, or multiple potential targets. We conclude that spatial context learning is robust to interference from manipulations that limit the availability of attention and working memory.

Structural and semantic constraints on the resolution of pronouns and reflexives.

We present four experiments on the interpretation of pronouns and reflexives in picture noun phrases with and without possessors (e.g. Andrew's picture of him/himself, the picture of him/himself). The experiments (two off-line studies and two visual-world eye-tracking experiments) investigate how syntactic and semantic factors guide the interpretation of pronouns and reflexives and how different kinds of information are integrated during real-time reference resolution. The results show that the interpretation of pronouns and reflexives in picture NP constructions is sensitive not only to purely structural information, as is commonly assumed in syntactically-oriented theories of anaphor resolution, but also to semantic information (see Kuno, S. (1987). Functional syntax: Anaphora, discourse and empathy. Chicago: University of Chicago Press; Tenny, C. (2003). Short distance pronouns in representational noun phrases and a grammar of sentience. Ms.). Moreover, the results show that pronouns and reflexives differ in the degree of sensitivity they exhibit to different kinds of information. This finding indicates that the form-specific multiple-constraints approach (see Brown-Schmidt, S., Byron, D. K., & Tanenhaus, M. K. (2005). Beyond salience: Interpretation of personal and demonstrative pronouns. Journal of Memory and Language, 53, 292-313; Kaiser, E. (2003). The quest for a referent: A crosslinguistic look at reference resolution. Ph.D. dissertation. University of Pennsylvania, Philadelphia, PA; Kaiser, E. (2005). When salience is not enough: Pronouns, demonstratives and the quest for an antecedent. In: Laury, R. (Ed.), Minimal reference in Finnic: The use and interpretation of pronouns and zero in Finnish and Estonian discourse (pp. 135-162). Helsinki, Finland: Suomalaisen Kirjallisuuden Seura; Kaiser, E., & Trueswell, J. (2008). Interpreting pronouns and demonstratives in Finnish: Evidence for a form-specific approach to reference resolution. Language and Cognitive Processes, 23(5), 709-748), which states that referential forms can exhibit asymmetrical sensitivities to the different constraints guiding reference resolution, also applies in the within-sentence domain.

Orienting attention in visual working memory reduces interference from memory probes.

Given a changing visual environment, and the limited capacity of visual working memory (VWM), the contents of VWM must be in constant flux. Using a change detection task, the authors show that VWM is subject to obligatory updating in the face of new information. Change detection performance is enhanced when the item that may change is retrospectively cued 1 s after memory encoding and 0.5 s before testing. The retro-cue benefit cannot be explained by memory decay or by a reduction in interference from other items held in VWM. Rather, orienting attention to a single memory item makes VWM more resistant to interference from the test probe. The authors conclude that the content of VWM is volatile unless it receives focused attention, and that the standard change detection task underestimates VWM capacity.

Processing reflexives and pronouns in picture noun phrase.

Binding theory (e.g., Chomsky, 1981) has played a central role in both syntactic theory and models of language processing. Its constraints are designed to predict that the referential domains of pronouns and reflexives are nonoverlapping, that is, are complementary; these constraints are also thought to play a role in online reference resolution. The predictions of binding theory and its role in sentence processing were tested in four experiments that monitored participants' eye movements as they followed spoken instructions to have a doll touch a picture belonging to another doll. The instructions used pronouns and reflexives embedded in picture noun phrases (PNPs) containing possessor phrases (e.g., Pick up Ken. Have Ken touch Harry's picture of himself). Although the interpretations assigned to pronouns were generally consistent with binding theory, reflexives were frequently assigned interpretations that violated binding theory. In addition, the timing and pattern of eye movements were inconsistent with models of language processing that assume that binding theory acts as an early filter to restrict the referential domain. The interpretations assigned to reflexives in PNPs with possessors suggest that they are binding-theory-exempt logophors, a conclusion that unifies the treatment of reflexives in PNPs.

Assignment of reference to reflexives and pronouns in picture noun phrases: evidence from eye movements.

Most structural Binding Theories predict a complementary distribution between reflexives and pronouns in picture noun phrases containing possessors (e.g. "Ken's picture of himself/him"). In two head-mounted eye-tracking experiments, listeners frequently violated Binding Theory predictions for reflexives, often interpreting the reflexives as taking an antecedent outside of the binding domain, and violating complementarity assumptions. Moreover, the pattern and timing of the eye movements showed Binding Theory violations for reflexives during the earliest moments of reference resolution. The results demonstrate that either binding constraints must be reformulated to decouple pronouns and reflexives or all reflexives in picture noun phrases must be treated as logophors, and thus exempt from structural Binding Theory.