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Response to stress is dysregulated in psychosis (PSY). fMRI studies showed hyperactivity in hypothalamus (HYPO), hippocampus (HIPP), amygdala (AMYG), anterior cingulate (ACC), orbital and medial prefrontal (OFC; mPFC) cortices, with some studies reporting sex differences. We predicted abnormal steroid hormone levels in PSY would be associated with sex differences in hyperactivity in HYPO, AMYG, and HIPP, and hypoactivity in PFC and ACC, with more severe deficits in men. We studied 32 PSY cases (50.0% women) and 39 controls (43.6% women) using a novel visual stress challenge while collecting blood. PSY males showed BOLD hyperactivity across all hypothesized regions, including HYPO and ACC by FWE-correction. Females showed hyperactivity in HIPP and AMYG and hypoactivity in OFC and mPFC, the latter FWE-corrected. Interaction of group by sex was significant in mPFC (F = 7.00, p = 0.01), with PSY females exhibiting the lowest activity. Male hyperactivity in HYPO and ACC was significantly associated with hypercortisolemia post-stress challenge, and mPFC with low androgens. Steroid hormones and neural activity were dissociated in PSY women. Findings suggest disruptions in neural circuitry-hormone associations in response to stress are sex-dependent in psychosis, particularly in prefrontal cortex.

Five experiments examined whether overt repetition (i.e., saying a word aloud) during exposure is critical to the expressive learning of new words. When participants did not engage in overt repetition during exposure, they nevertheless exhibited clear expressive learning, both with and without an accompanying semantics, indicating that overt repetition is not critical to expressive word learning. In addition, learning without overt repetition did not differ from learning with overt repetition, suggesting that overt repetition confers no benefit for learning in this situation. These results are discussed in relation to previous studies, and it is suggested that benefits of repetition may accrue primarily in second language rather than in first language word learning.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jml.2004.12.002 Byline: Prahlad Gupta, John Lipinski, Brandon Abbs, Po-Han Lin Abstract: A growing body of research has emphasized the linkage between performance in immediate serial recall of lists, nonword repetition, and word learning. Recently, it has been reported that primacy and recency effects are obtained in repetition of individual syllables within nonwords (Gupta, in press). Five experiments examined whether such within-nonword primacy and recency effects are attributable to common sequencing mechanisms that are shared with immediate list recall. Experiments 1 and 2 indicated that the primacy and recency effects are not simply due to greater morphological salience at the beginnings/endings of nonwords, and that the serial position effects generalize to different stimuli and across a variety of stimulus lengths. Experiment 3 indicated that the primacy and recency effects are similar to those obtained in list recall. Experiments 4 and 5 examined alternative hypotheses for the observed serial position effects, concluding that the alternative hypotheses fail to account for the obtained pattern of results. These results provide support for the common sequencing mechanisms hypothesis. The implications of these results are discussed in terms of the relationship between list recall and nonword repetition, and in terms of broader issues in word learning. Author Affiliation: Department of Psychology ,University of Iowa, Iowa City, IA 52242, USA Article Note: (footnote) [star] We thank Gary Dell for helpful comments on this work, and Matthew Brown, Sara Even, Naveen Khetarpal, James Malicki, Byron Murphy, Sarah Oakley, Millisa Reynolds, Ellen Samuel, Kathleen Schnitker, Sierra Spies, and Linda Wood for assistance in conducting and transcribing experiments.

Understanding sex differences in stress regulation has important implications for understanding basic physiological differences in the male and female brain and their impact on vulnerability to sex differences in chronic medical disorders associated with stress response circuitry. In this functional magnetic resonance imaging study, we demonstrated that significant sex differences in brain activity in stress response circuitry were dependent on women's menstrual cycle phase. Twelve healthy Caucasian premenopausal women were compared to a group of healthy men from the same population, based on age, ethnicity, education, and right handedness. Subjects were scanned using negative valence/high arousal versus neutral visual stimuli that we demonstrated activated stress response circuitry [amygdala, hypothalamus, hippocampus, brainstem, orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), and anterior cingulate gyrus (ACG)].Womenwere scanned twice based on normal variation in menstrual cycle hormones [i.e., early follicular (EF) compared with late follicular-midcycle (LF/MC) menstrual phases]. Using SPM8b, there were few significant differences in blood oxygenation level-dependent (BOLD) signal changes inmencompared to EF women, except ventromedial nucleus (VMN), lateral hypothalamic area (LHA), left amygdala, and ACG. In contrast, men exhibited significantly greater BOLD signal changes compared to LF/MC women on bilateral ACG and OFC, mPFC, LHA, VMN, hippocampus, and periaqueductal gray, with largest effect sizes in mPFC and OFC. Findings suggest that sex differences in stress response circuitry are hormonally regulated via the impact of subcortical brain activity on the cortical control of arousal, and demonstrate that females have been endowed with a natural hormonal capacity to regulate the stress response that differs from males. [ABSTRACT FROM AUTHOR]

Background: Individuals with schizophrenia experience an inadequate response to antipsychotic (AP) treatment at a high rate, up to 70% in some cases (McEvoy et al. 2006). Possible reasons for this include subtherapeutic AP blood levels and medication ineffectiveness. Although patient self-report and clinician opinion are commonly used to identify non-adherence, they are unreliable. AP polypharmacy for inadequate response remains widespread despite a lack of supportive evidence. Few completed trials offer guidance on the optimal trial design and procedures to establish inadequate response at screening/baseline. Adequate treatment is defined as an AP taken at a therapeutic dose for a sufficient duration (Taylor et al. 2012). Confirming treatment stability and adherence, both prior to enrollment and during the trial, is necessary to ensure sufficient exposure to an AP prior to deeming a response inadequate and justifying augmentation. Measuring adherence during the trial is necessary to ensure correct interpretation of trial results. We present the trial design and adherence data from a recently completed Phase 3 clinical trial of an adjunctive therapy in inadequately responding patients with schizophrenia. The trial did not meet the primary endpoint (Bugarski-Kirola, et al. 2019). Methods: ENHANCE was a 6-week, randomized, double-blind study of adjunctive pimavanserin (PIM; a 5-HT2A inverse agonist) versus placebo to evaluate the treatment of schizophrenia in patients with an inadequate response to their prescribed AP (aripiprazole, olanzapine, risperidone, and others). During screening, patients provided documentation showing treatment stability for at least 8 weeks prior to screening, a blood sample was tested for adherence, and a telemedicine interview was completed with an independent clinician. After randomization, blood sampling occurred at Baseline, Week 1, Week 3, and Week 6 for pharmacokinetic (PK) assessments of the AP and adjunctive PIM. Results: ENHANCE screened 633 patients with 35 rescreens for a total of 668 screenings. Adherence to background AP was high for all patients screened as background AP levels were detected in 90.6% of patients. However, the most common reason for screen failure was still a failure to detect background AP (16.9% of all screen failures). Other common reasons for screen failure included lack of prescription stability/appropriate dosing, investigators determining the patient was inappropriate for the study, and withdrawal of consent, the latter of which often reflected the rigorous screening process required for the study. Proactively screen failing non-adherent patients led to higher levels of adherence at Baseline compared to screening with 94.9% of patients demonstrating adherence at Baseline. Moreover, this is a substantial improvement over the theoretical adherence rate of 84.5% had non-adherent patients been randomized. The high rate of adherence at Baseline for background AP was maintained at Weeks 1, 3 and 6. High adherence was also found for adjunctive PIM. 198 patients were randomized to the PIM treatment arm, 190 had a blood sample at Week 1 with 187 (98.4%) showing measurable levels of PIM, and 182 had a blood sample at Week 3 with 180 (98.9%) showing measurable levels of PIM. Patients leaving the study (either at Week 6 of treatment or as a result of early termination) showed a 96.8% adherence rate. Discussion: By employing rigorous screening procedures, including testing for AP treatment adherence, the ENHANCE study enrolled a representative sample of patients with a confirmed inadequate response to their current AP and achieved a high level of treatment adherence (both to patient’s AP treatment and study drug). [ABSTRACT FROM AUTHOR]