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Abstract Background A hallmark of Alzheimer’s disease is the presence of senile plaques in human brain primarily containing the amyloid peptides Aβ42 and Aβ40. Many drug discovery efforts have focused on decreasing the production of Aβ42 through γ-secretase inhibition. However, identification of γ-secretase inhibitors has also uncovered mechanism-based side effects. One approach to circumvent these side effects has been modulation of γ-secretase to shift Aβ production to favor shorter, less amyloidogenic peptides than Aβ42, without affecting the overall cleavage efficiency of the enzyme. This approach, frequently called γ-secretase modulation, appears more promising and has lead to the development of new therapeutic candidates for disease modification in Alzheimer’s disease. Results Here we describe EVP-0015962, a novel small molecule γ-secretase modulator. EVP-0015962 decreased Aβ42 in H4 cells (IC50 = 67 nM) and increased the shorter Aβ38 by 1.7 fold at the IC50 for lowering of Aβ42. AβTotal, as well as other carboxyl-terminal fragments of amyloid precursor protein, were not changed. EVP-0015962 did not cause the accumulation of other γ-secretase substrates, such as the Notch and ephrin A4 receptors, whereas a γ-secretase inhibitor reduced processing of both. A single oral dose of EVP-0015962 (30 mg/kg) decreased Aβ42 and did not alter AβTotal peptide levels in a dose-dependent manner in Tg2576 mouse brain at an age when overt Aβ deposition was not present. In Tg2576 mice, chronic treatment with EVP-0015962 (20 or 60 mg/kg/day in a food formulation) reduced Aβ aggregates, amyloid plaques, inflammatory markers, and cognitive deficits. Conclusions EVP-0015962 is orally bioavailable, detected in brain, and a potent, selective γ-secretase modulator in vitro and in vivo. Chronic treatment with EVP-0015962 was well tolerated in mice and lowered the production of Aβ42, attenuated memory deficits, and reduced Aβ plaque formation and inflammation in Tg2576 transgenic animals. In summary, these data suggest that γ-secretase modulation with EVP-0015962 represents a viable therapeutic alternative for disease modification in Alzheimer’s disease.

Objective: A confirmatory factor analysis (CFA) of the Adolescent Dissociative Experiences Scale (A-DES) that found a best-fitting three-factor model for a trauma-exposed sample was recently replicated; however, a post hoc bifactor CFA model fit the data better and identified a strong general factor. Only the general factor was associated with cumulative trauma exposure, but this association was small., Method: Structural equation modeling (SEM) and regression analyses were applied to the best-fitting three-factor bifactor model of dissociation found in the same sample of 1,157 treatment-seeking adolescents, most with high levels of trauma exposure, to further elucidate dissociation's construct validity and dimensionality., Results: The general factor was positively yet differentially associated with psychosocial outcomes. A dissociation by age interaction emerged for internalizing problems, demonstrating that the positive association was stronger for older participants. Also, an age of trauma exposure onset by dissociation interaction emerged predicting depression, such that later trauma onset produced a stronger association between dissociation and depression., Conclusions: Traumas occurring in later adolescence may confer greater risk of dissociation. Differential psychosocial outcomes also reinforce why approaching dissociation from a developmental psychopathology lens is important, enhancing the model's generalizability. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Objective: Research examining the factor structure of the Adolescent Dissociative Experiences Scale (A-DES) has yielded mixed findings. This study sought to further clarify the factor structure of the A-DES among youth with histories of exposure to multiple traumas and adversities., Method: We conducted a factor analysis of the A-DES using data from 1,157 treatment-seeking adolescents with histories of trauma exposure in order to expand understanding of dissociation's construct validity and provide the first attempt at post hoc analysis of trauma-impacted adolescents., Results: A bifactor CFA model fit the data best and identified a strong general factor, supporting a unidimensional latent structure. Only the general dissociation factor was associated with cumulative trauma exposure, operationalized as the number of different types of exposure endorsed on the Trauma History Profile (THP), but this association was small., Conclusions: The study findings point toward a unidimensional conceptualization of dissociation. A developmental psychopathology framework is recommended for future research, allowing a nuanced and integrated approach to understanding dissociation and increasing generalizability across adolescents. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Objective: Developmental trauma or chronic early childhood exposure to abuse and neglect by caregivers has been shown to have a long-lasting pervasive impact on mental and neural development, including problems with attention, impulse control, self-regulation, and executive functioning. Its long-term effects are arguably the costliest public health challenge in the United States. Children with developmental trauma rarely have a satisfactory response to currently available evidence-based psychotherapeutic and pharmacological treatments. Neurofeedback training (NFT) is a clinical application of brain computer interface technology, aiming to alter electrical brain activity associated with various mental dysfunctions. NFT has shown promise to improve posttraumatic stress disorder (PTSD) symptoms., Method: This randomized controlled study examined the effects of NFT on 37 children, aged 6-13 years with developmental trauma. Participants were randomly divided into active NFT ( n = 20) or treatment-as-usual control ( n = 17). Both groups underwent 4 assessments during equivalent timelines. The active group received 24 NFT sessions twice a week., Results: This pilot study demonstrated that 24 sessions of NFT significantly decreased PTSD symptoms, internalizing, externalizing, other behavioral and emotional symptoms, and significantly improved the executive functioning of children aged 6-13 years with severe histories of abuse and neglect who had not significantly benefited from any previous therapy., Conclusions: NFT offers the possibility to improve learning, enhance self-efficacy, and develop better social relationships in this hitherto largely treatment-resistant population. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Objective: This study is a follow-up to van der Kolk et al. (2014), a trial conducted through the Trauma Center at Justice Resource Institute, which demonstrated treatment efficacy and remains the only randomized controlled trial of trauma-sensitive yoga. The present process study extends the outcomes study by examining treatment moderators of the original trial., Method: Sixty-four women with childhood interpersonal trauma histories and posttraumatic stress disorder participated in the interventions: Trauma Center Trauma-Sensitive Yoga (TCTSY) versus active control (women's health education). Analyses explored if adult-onset interpersonal trauma and baseline psychological measures (clinician-rated and self-reported PTSD, dissociation, depression, psychological functioning) moderated PTSD changes., Results: Three of six measures had small effects in moderating the relationship between adult-onset interpersonal trauma and TCTSY efficacy, in which TCTSY was most efficacious for those with fewer adult-onset interpersonal traumas. Within this subgroup, various levels of all baseline measures except depression indicated that TCTSY was more effective in reducing PTSD than the active control condition., Conclusions: By delineating client characteristics most associated with PTSD improvements, practitioners may best target yoga interventions to increase effectiveness. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Introduction: Brain/Computer Interaction (BCI) devices are designed to alter neural signals and, thereby, mental activity. This study was a randomized, waitlist (TAU) controlled trial of a BCI, EEG neurofeedback training (NF), in patients with chronic PTSD to explore the capacity of NF to reduce PTSD symptoms and increase affect regulation capacities., Study Design: 52 individuals with chronic PTSD were randomized to either NF (n = 28) or waitlist (WL) (n = 24). They completed four evaluations, at baseline (T1), after week 6 (T2), at post-treatment (T3), and at one month follow up (T4). Assessment measures were:1. Traumatic Events Screening Inventory (T1); 2. the Clinician Administered PTSD Scale (CAPS; T1, T3, T4); 3. the Davidson Trauma Scale (DTS; T1-T4) and 4. the Inventory of Altered Self-Capacities (IASC; T1-T4). NF training occurred two times per week for 12 weeks and involved a sequential placement with T4 as the active site, P4 as the reference site., Results: Participants had experienced an average of 9.29 (SD = 2.90) different traumatic events. Post-treatment a significantly smaller proportion of NF (6/22, 27.3%) met criteria for PTSD than the WL condition (15/22, 68.2%), χ2 (n = 44, df = 1) = 7.38, p = .007. There was a significant treatment condition x time interaction (b = -10.45, t = -5.10, p< .001). Measures of tension reduction activities, affect dysregulation, and affect instability exhibited a significant Time x Condition interaction. The effect sizes of NF (d = -2.33 within, d = - 1.71 between groups) are comparable to those reported for the most effective evidence based treatments for PTSD., Discussion: Compared with the control group NF produced significant PTSD symptom improvement in individuals with chronic PTSD, as well as in affect regulation capacities. NF deserves further investigation for its potential to ameliorate PTSD and to improve affect regulation, and to clarify its mechanisms of action., Competing Interests: No competing interests

Child maltreatment is a serious public health concern, and its detrimental effects can be compounded by traumatic experiences associated with the child welfare (CW) system. Trauma-informed care (TIC) is a promising strategy for addressing traumatized children's needs, but research on the impact of TIC in CW is limited. This study examines initial findings of the Massachusetts Child Trauma Project, a statewide TIC initiative in the CW system and mental health network. After 1 year of implementation, Trauma-Informed Leadership Teams in CW offices emerged as key structures for TIC systems integration, and mental health providers' participation in evidence-based treatment (EBT) learning collaboratives was linked to improvements in trauma-informed individual and agency practices. After approximately 6 months of EBT treatment, children had fewer posttraumatic symptoms and behavior problems compared to baseline. Barriers to TIC that emerged included scarce resources for trauma-related work in the CW agency and few mental providers providing EBTs to young children. Future research might explore variations in TIC across service system components as well as the potential for differential effects across EBT models disseminated through TIC., (© The Author(s) 2015.)

Pharmacological activation of α7 nicotinic acetylcholine receptors (α7 nAChRs) may improve cognition in schizophrenia and Alzheimer's disease. The present studies describe an integrated pharmacological analysis of the effects of FRM-17874, an analogue of encenicline, on α7 nAChRs in vitro and in behavioral and neurophysiological assays relevant to cognitive function. FRM-17874 demonstrated high affinity binding to human α7 nAChRs, displacing [(3)H]-methyllacaconitine (Ki=4.3nM). In Xenopus laevis oocytes expressing human α7 nAChRs, FRM-17874 acted as an agonist, evoking inward currents with an EC50 of 0.42μM. Lower concentrations of FRM-17874 (0.01-3nM) elicited no detectable current, but primed receptors to respond to sub-maximal concentrations of acetylcholine. FRM-17874 improved novel object recognition in rats, and enhanced memory acquisition and reversal learning in the mouse water T-maze. Neurophysiological correlates of cognitive effects of drug treatment, such as synaptic transmission, long-term potentiation, and hippocampal theta oscillation were also evaluated. Modulation of synaptic transmission and plasticity was observed in rat hippocampal slices at concentrations of 3.2 and 5nM. FRM-17874 showed a dose-dependent facilitation of stimulation-induced hippocampal theta oscillation in mice and rats. The FRM-17874 unbound brain concentration-response relationship for increased theta oscillation power was similar in both species, exhibited a biphasic pattern peaking around 3nM, and overlapped with active doses and exposures observed in cognition assays. In summary, behavioral and neurophysiological assays indicate a bell-shaped effective concentration range and this report represents the first attempt to explain the concentration-response function of α7 nAChR-mediated pro-cognitive effects in terms of receptor pharmacology., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Two investigational compounds (FRM-1, (R)-7-fluoro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide and FRM-2, (R)-7-cyano-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide) resided in rat brain longer than in systemic circulation. In Caco-2 directional transport studies, they both showed good intrinsic passive permeability but differed significantly in efflux susceptibility (efflux ratio of <2 and ∼7, respectively), largely attributed to P-glycoprotein (P-gp). Capitalizing on these interesting properties, we investigated how cerebrospinal fluid (CSF) concentration (CCSF) would be shaped by unbound plasma concentration (Cu,p) and unbound brain concentration (Cu,b) in disequilibrium conditions and at steady state. Following subcutaneous administration, FRM-1CCSF largely followed Cu,p initially and leveled between Cu,p and Cu,b. However, it gradually approached Cu,b and became lower than, but parallel to Cu,b at the terminal phase. In contrast, FRM-2CCSF temporal profile mostly paralleled the Cu,p but was at a much lower level. Upon intravenous infusion to steady state, FRM-1CCSF and Cu,b were similar, accounting for 61% and 69% of the Cu,p, indicating a case of largely passive diffusion-governed brain penetration where CCSF served as a good surrogate for Cu,b. On the contrary, FRM-2CCSF and Cu,b were remarkably lower than Cu,p (17% and 8% of Cu,p, respectively), suggesting that FRM-2 brain penetration was severely impaired by P-gp-mediated efflux and CCSF underestimated this impact. A semi-physiologically based pharmacokinetic (PBPK) model was constructed that adequately described the temporal profiles of the compounds in the plasma, brain and CSF. Our work provided some insight into the relative importance of blood-brain barrier (BBB) and blood-CSF barrier (BCSFB) in modulating CCSF., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Most people in the United States and Canada with pediculosis will be treated with neurotoxic pediculicides containing pyrethrins or pyrethroids. Their widespread use led to significant resistance reported from various countries. Although treatment failures are frequently observed in Canada, the resistance frequency to pyrethroid pediculicide of human head lice (Pediculus humanus capitis) has not been determined., Objective: To determine the knockdown resistance (kdr) allele frequency in human head louse populations in Canada., Methods: Patients infested with Pediculus humanus capitis, aged 4 to 65 years, residents of Ontario, Quebec, and British Columbia, were participants. Head lice were collected by combing and picking the enrolled subjects' hair. Lice were analyzed by serial invasive signal amplification reaction (SISAR) for genotyping the T917I mutation of lice indicating permethrin resistance. The permethrin-resistant kdr allele (R allele) frequency could then be evaluated in the head lice collected in Canada., Results: Of the head louse populations analyzed, 133 of 137 (97.1%) had a resistant (R) allele frequency, whereas only 4 of 137 (2.9%) had a susceptible (S) allele frequency., Conclusions: The 97.1% resistant (R) allele frequency in head lice from Canada could explain the treatment failures encountered with pyrethrin and pyrethroid pediculicide treatments in Canadian populations infested with Pediculus humanus capitis as the latter will not be eliminated by those pediculicides.

Introduction: Anxiety disorders in adults involve aberrant processing of emotional information that is hypothesized to reflect perturbations in the amygdala. This study examines the relationship between face-emotion recognition and anxiety in a sample of children and adolescents participating in a brain-imaging study of amygdala structure and function., Methods: This study recruited 15 children and adolescents with ongoing anxiety disorders and 11 psychiatrically healthy comparisons group-matched on age, gender, and IQ. Face-emotion recognition was assessed using the Diagnostic Analysis of Nonverbal Accuracy Scale (DANVA)., Results: Children and adolescents with anxiety disorders exhibited significantly poorer performance on the face-emotion recognition task compared to healthy controls (z = 2.2; p < 0.05). This difference was found only for expressions posed by adults but not children., Discussion: Reduced accuracy on a face-emotion recognition test is consistent with perturbed amygdala function in pediatric anxiety disorders., Conclusion: As this study was conducted in a sample undergoing a neuroimaging investigation of amygdala integrity, future analyses will examine associations among amygdala function, clinical anxiety, and face-recognition abilities.