Telomere biology and its maintenance in schizophrenia spectrum disorders: Exploring links to cognition.

OBJECTIVE: Contemporary research suggests reduced telomere length in schizophrenia spectrum disorders (SZ) compared to age-adjusted non-affected individuals. However, the role of telomere maintenance and telomere repair in SZ is poorly understood as well as the involvement of telomere biology in cognitive abnormalities in SZ. METHODS: The study consisted of 758 participants (SZ [n = 357] and healthy controls, HC [n = 401]) collected as part of the Norwegian TOP study. Participants were assessed with standardized neuropsychological tests measuring five cognitive domains. Leucocyte telomere length (TL) was measured via blood and determined by quantitative real-time Polymerase Chain Reaction (qPCR) providing a telomere to single copy ratio (T/S ratio), used to estimate the mean telomere length. Telomerase activity was assessed by the expression levels of the Telomerase Reverse Transcriptase (TERT) and Telomerase RNA Component (TERC) genes. To assess telomere maintenance and telomere repair we calculated the telomerase expression to TL ratio (TERT/TL and TERC/TL respectively). RESULTS: Patients had reduced TERT (F = 5.03, p = 0.03), but not TERC expression (F = 1.04, p = 0.31), and higher TERT/TL (F = 6.68, p = 0.01) and TERC/TL (F = 6.71, p = 0.01), adjusted for age, sex, and ethnicity. No statistically significant association was observed between any of the telomere biology markers and the cognitive domains (p > 0.05). CONCLUSION: Our study shows changes in TERT expression and telomere maintenance and telomere repair in SZ compared HC. However, the role of telomere biology in the mechanism underlying cognitive impairment in psychosis seems limited.

Use of a Suction-Monopolar Stimulator for Continuous Neurophysiology Monitoring During Endonasal Resection of a Cavernous Sinus Schwannoma: 2-Dimensional Operative Video.

Cavernous sinus schwannomas are exceptionally rare tumors.1,2 Although these tumors commonly originate from the trigeminal nerve, instances involving the oculomotor, abducens, trochlear nerves, and the carotid plexus have also been documented.2-7 In this operative video, we showcase a 44-year-old man with a medical history of acromegaly and schwannomatosis who presented with retro orbital pain and a growing cystic lesion in the left cavernous sinus. Genetic testing ruled out neurofibromatosis types 1 and 2. An endonasal resection was recommended considering the left side and extradural location of the lesion.8 The tumor was excised through an endonasal transpterygoid approach using 2 suctions, one of which was equipped with an electrode tip for continuous monitoring of extraocular nerves during the resection process. Imaging postoperatively demonstrated near-total resection. Institutional review board approval was not required; the patient agreed to undergo the procedure and to have his operative video published.

Use of a Monopolar Stimulator to Preserve the Frontotemporal Branches of the Facial Nerve During a Pterional Approach: 2-Dimensional Operative Video.

Preservation of the frontotemporal branches of the facial nerve is essential to obtain good cosmetic outcomes after anterolateral cranial base approaches.1,2 Since the description of the interfacial dissection, most nerve injuries are due to retraction of the nerve fibers and not direct transection.3-5 In this video, we showcase the use of a monopolar stimulator to guide the placement of hook retractors and assess no undue retraction is applied to the nerve fibers during a pterional craniotomy. This simple tool can help in preserving frontalis function after anterolateral skull base craniotomies. Institutional review board approval was not required; the patient consented to the procedure and to the publication of his/her image.

The interplay of oxytocin and sex hormones.

The neuropeptide oxytocin has historically been associated with reproduction and maternal behavior. However, more recent research has uncovered that oxytocin has a much wider range of roles in physiology and behavior. Despite the excitement surrounding potential therapeutical applications of intranasally administered oxytocin, the results of these intervention studies have been inconsistent. Various reasons for these mixed results have been proposed, which tend to focus on methodological issues, such as study design. While methodological issues are certainly important, emerging evidence suggests that the interaction between oxytocin and sex hormones may also account for these varied findings. To better understand the purpose and function of the interaction of oxytocin with sex hormones, with a focus on estrogens, progesterone, and testosterone, we conducted a comprehensive thematic review via four perspectives: evolutionary, developmental, mechanistic, and survival. Altogether, this synergistic approach highlights the critical function of sex hormone activity for accomplishing the diverse roles of oxytocin via the modulation of oxytocin release and oxytocin receptor activity, which is also likely to contribute to the heterogeneity of outcomes after oxytocin administration.

Calcified Meningiomas Demonstrate Equivocal Grade, Proliferation, and Immediate Surgical Outcomes.

BACKGROUND/OBJECTIVE: Meningioma calcification is thought to predict reduced growth potential and aggression. However, historical studies have primarily focused on correlating calcification in small meningiomas (diameter less than 2.5 cm) rather than analyzing characteristics of calcified meningiomas across all sizes. In this study, we investigate the pathologic and clinical implications of meningioma calcification. METHODS: We utilized a historical database of 342 consecutive newly diagnosed intracranial meningiomas with preoperative computed tomography and magnetic resonance imaging scans treated at a single institution from 2005 to 2019. We correlated the presence of calcification with patient demographics, grade, Mindbomb Homolog-1 index, location, volume, Simpson grade, and recurrence using both univariate and multivariate generalized linear models. RESULTS: On univariate analysis, no single variable correlated with tumor calcification. Notably, neither tumor 2021 World Health Organization grade (P = 0.91) nor Mindbomb Homolog-1 index (P = 0.62) predicted calcification. After accounting for demographic characteristics and tumor volume and location, there was no significant association between 2021 World Health Organization grade (P = 0.52) and Mindbomb Homolog-1 index (P = 0.54) and calcification. Calcification had no influence on resection grade (P = 0.59) or recurrence (P = 0.80). CONCLUSIONS: In this series, calcified meningiomas exhibited similar 2021 World Health Organization tumor grading distribution, proliferation indexes, and immediate surgical outcomes compared to their noncalcified counterparts. These findings question the historical role of using meningioma calcification as an independent guide to their management.

Balanced bidirectional optogenetics reveals the causal impact of cortical temporal dynamics in sensory perception.

Whether the fast temporal dynamics of neural activity in brain circuits causally drive perception and cognition remains one of most longstanding unresolved questions in neuroscience 1-6 . While some theories posit a 'timing code' in which dynamics on the millisecond timescale is central to brain function, others instead argue that mean firing rates over more extended periods (a 'rate code') carry most of the relevant information. Existing tools, such as optogenetics, can be used to alter temporal structure of neural dynamics 7 , but they invariably change mean firing rates, leaving the interpretation of such experiments ambiguous. Here we developed and validated a new approach based on balanced, bidirectional optogenetics that can alter temporal structure of neural dynamics while mitigating effects on mean activity. Using this new approach, we found that selectively altering cortical temporal dynamics substantially reduced performance in a sensory perceptual task. These results demonstrate that endogenous temporal dynamics in the cortex are causally required for perception and behavior. More generally, this new bidirectional optogenetic approach should be broadly useful for disentangling the causal impact of different timescales of neural dynamics on behavior.

The effects of oxytocin administration on social and routinized behaviors in autism: A preregistered systematic review and meta-analysis.

Oxytocin administration has demonstrated considerable promise for providing individualized support for autistic people. However, studies evaluating the effects of oxytocin administration on autistic characteristics have yielded inconsistent results. This systematic review and meta-analysis investigates the effect of oxytocin administration on social and routinized behaviors in autism using recently developed methods to accurately assess the potential impact of effect size dependency and publication bias. Our frequentist meta-analysis yielded a significant summary effect size estimate for the impact of oxytocin administration on social outcomes in autism (d = 0.22, p < 0.001). The summary effect size estimate for routinized behavior outcomes was not statistically significant (d = 0.14, p = 0.22), with a follow up test indicating that the effect size estimate was not either statistically equivalent (Z = -1.06, p = 0.2), assuming a smallest effect size of interest of 0.25. Frequentist and Bayesian assessments for publication bias, as well as results from Robust Bayesian meta-analysis of oxytocin effects on social outcomes in autism, indicated that summary effect sizes might be inflated due to publication bias. Future studies should aim to reduce bias by preregistering analysis plans and to increase precision with larger sample sizes.

An evolutionary timeline of the oxytocin signaling pathway.

Oxytocin is a neuropeptide associated with both psychological and somatic processes like parturition and social bonding. Although oxytocin homologs have been identified in many species, the evolutionary timeline of the entire oxytocin signaling gene pathway has yet to be described. Using protein sequence similarity searches, microsynteny, and phylostratigraphy, we assigned the genes supporting the oxytocin pathway to different phylostrata based on when we found they likely arose in evolution. We show that the majority (64%) of genes in the pathway are 'modern'. Most of the modern genes evolved around the emergence of vertebrates or jawed vertebrates (540 - 530 million years ago, 'mya'), including OXTR, OXT and CD38. Of those, 45% were under positive selection at some point during vertebrate evolution. We also found that 18% of the genes in the oxytocin pathway are 'ancient', meaning their emergence dates back to cellular organisms and opisthokonta (3500-1100 mya). The remaining genes (18%) that evolved after ancient and before modern genes were classified as 'medium-aged'. Functional analyses revealed that, in humans, medium-aged oxytocin pathway genes are highly expressed in contractile organs, while modern genes in the oxytocin pathway are primarily expressed in the brain and muscle tissue.

Redefining effect size interpretations for psychotherapy RCTs in depression.

INTRODUCTION: Effect sizes are often used to interpret the magnitude of a result and in power calculations when planning research studies. However, as effect size interpretations are context-dependent, Jacob Cohen's suggested guidelines for what represents a small, medium, and large effect are unlikely to be suitable for a diverse range of research populations and interventions. Our objective here is to determine empirically-derived effect size thresholds associated with psychotherapy randomized controlled trials (RCTs) in depression by calculating the effect size distribution. METHODS: We extracted effect sizes from 366 RCTs provided by the systematic review of Cuijpers and colleagues (2020) on psychotherapy for depressive disorders across all age groups. The 50th percentile effect size, as this represents a medium effect size, and the 25th (small) and 75th (large) percentile effect sizes were calculated to determine empirically-derived effect size thresholds. RESULTS: After adjusting for publication bias, 0.27, 0.53, and 0.86 represent small, medium, and large effect sizes, respectively, for psychotherapy treatment for depressive disorders. DISCUSSION: The effect size distribution for psychotherapy treatment of depression indicates that observed effect size thresholds are larger than Cohen's suggested effect size thresholds (0.2, 0.5, and 0.8). These results have implications for the interpretation of study effects and the planning of future studies via power analyses, which often use effect size thresholds.

Robust fault reconstruction using sliding mode observers with nonlinear nominal systems.

This paper is concerned with fault reconstruction based on sliding mode observers; its contribution is twofold: on the one hand, it develops a novel sliding mode observer whose nominal system is nonlinear, thus relaxing former limitations on the subject, namely, rank restrictions, linear outputs, and conservative bounds; on the other hand, based on the referred sliding mode observer, a novel robust fault reconstruction scheme is constructed which can solve a variety of problems that former methodologies cannot treat. Nonlinearities are cast as convex expressions, which enables obtaining design conditions in the form of linear matrix inequalities. Examples are provided to compare the proposal with former methodologies, thus highlighting the contributions.

[Neonatal hypoglycemia: glucose gel efficacy in the treatment of early hypoglycemia in newborns with risk factors. Randomized clinical trial]. / Hipoglucemia neonatal: eficacia de la glucosa gel en el tratamiento de la hipoglucemia precoz en recién nacidos con factores de riesgo. Ensayo clínico aleatorizado.

Hypoglycemia is the most frequent metabolic disorder in newborns; the administration of 40% glu cose gel in the oral mucosa could be as effective in its correction as the administration of formula milk, not interfering with breastfeeding. OBJECTIVE: To evaluate the efficacy of 40% glucose gel com pared with formula milk in the treatment of early asymptomatic hypoglycemia in newborns with risk factors. PATIENTS AND METHOD: Randomized clinical trial, non-inferiority, conducted in a private hos pital. Newborns attended in rooming-in with the following risk factors were included: late preterm, large and small for gestational age at term, and children of diabetic mothers. In the presence of hy poglycemia, one group received 40% glucose gel (A) in the oral mucosa and another group received formula milk (B). Therapeutic failure was considered as persistence or repetition of hypoglycemia in the first 48h of life. RESULTS: 866 NBs with risk factors were registered over 36 month; 278 (32.1 %) presented hypoglycemia; 105 NBs in group A and 115 in group B completed the study. 75 (71 %) NBs in group A and 104 (90,4 %) in group B achieved hypoglycemia correction. After analyzing the trends obtained, it was decided to discontinue the study. CONCLUSIONS: The administration of 40% glucose gel was not equivalent to the administration of formula milk in the treatment of early asymptomatic hypoglycemia in newborns with risk factors.

Enhancing precision in human neuroscience.

Human neuroscience has always been pushing the boundary of what is measurable. During the last decade, concerns about statistical power and replicability - in science in general, but also specifically in human neuroscience - have fueled an extensive debate. One important insight from this discourse is the need for larger samples, which naturally increases statistical power. An alternative is to increase the precision of measurements, which is the focus of this review. This option is often overlooked, even though statistical power benefits from increasing precision as much as from increasing sample size. Nonetheless, precision has always been at the heart of good scientific practice in human neuroscience, with researchers relying on lab traditions or rules of thumb to ensure sufficient precision for their studies. In this review, we encourage a more systematic approach to precision. We start by introducing measurement precision and its importance for well-powered studies in human neuroscience. Then, determinants for precision in a range of neuroscientific methods (MRI, M/EEG, EDA, Eye-Tracking, and Endocrinology) are elaborated. We end by discussing how a more systematic evaluation of precision and the application of respective insights can lead to an increase in reproducibility in human neuroscience.

All-optical recreation of naturalistic neural activity with a multifunctional transgenic reporter mouse.

Determining which features of the neural code drive behavior requires the ability to simultaneously read out and write in neural activity patterns with high precision across many neurons. All-optical systems that combine two-photon calcium imaging and targeted photostimulation enable the activation of specific, functionally defined groups of neurons. However, these techniques are unable to test how patterns of activity across a population contribute to computation because of an inability to both read and write cell-specific firing rates. To overcome this challenge, we make two advances: first, we introduce a genetic line of mice for Cre-dependent co-expression of a calcium indicator and a potent soma-targeted microbial opsin. Second, using this line, we develop a method for read-out and write-in of precise population vectors of neural activity by calibrating the photostimulation to each cell. These advances offer a powerful and convenient platform for investigating the neural codes of computation and behavior.

Telomere length and verbal learning in bipolar disorders.

INTRODUCTION: Recent studies indicate accelerated ageing processes, shorter telomere length and poorer cognitive functioning in patients with bipolar disorder. The neurobiology underlying cognitive function in bipolar disorder is yet to be established. We anticipated that accelerated ageing as indicated by shortened telomere length, would be associated with reduced cognitive performance in bipolar disorder, particularly for ageing sensitive functions such as memory and learning. METHODS: The study consisted of 647 participants (bipolar disorder [n = 246] and healthy controls [n = 401]). All participants underwent a standardized neuropsychological test battery, including working memory, executive functioning, processing speed, verbal learning, and verbal memory. Leucocyte telomere length was measured via blood and determined by quantitative real-time Polymerase Chain Reaction (qPCR) providing a telomere to single copy ratio (T/S ratio). The T/S ratio was used as an estimate of the mean telomere length of each participant. All analyses were adjusted for medication, Daily Defined Dose (DDD), chronological age, sex, and ethnicity. RESULTS: Patients had shorter telomere lengths than healthy controls (Cohen's d = 0.11, p = 0.01). Within patients', a positive association was observed for verbal learning and telomere length (ß = 0.14, p = 0.025), along with a trend for verbal memory and telomere length (ß = 0.11, p = 0.07). No other associations were observed for telomere length and cognitive functioning in the patient or the control group (p > 0.1). CONCLUSION: Our study may suggest poorer brain health in bipolar disorder as indexed by shorter telomere length and reduced learning correlates. However, the role of telomere length on cognitive functioning in bipolar disorder seems limited.

Nasal oxytocin administration does not influence eye gaze or perceived relationship of male volunteers with physicians in a simulated online consultation: a randomized, placebo-controlled trial.

The patient-physician relationship is a critical determinant of patient health outcomes. Verbal and non-verbal communication, such as eye gaze, are vital aspects of this bond. Neurobiological studies indicate that oxytocin may serve as a link between increased eye gaze and social bonding. Therefore, oxytocin signaling could serve as a key factor influencing eye gaze as well as the patient-physician relationship. We aimed to test the effects of oxytocin on gaze to the eyes of the physician and the patient-physician relationship by conducting a randomized placebo-controlled crossover trial in healthy volunteers with intranasally administered oxytocin (with a previously effective single dose of 24 IU, EudraCT number 2018-004081-34). The eye gaze of 68 male volunteers was studied using eye tracking during a simulated video call consultation with a physician, who provided information about vaccination against the human papillomavirus. Relationship outcomes, including trust, satisfaction, and perceived physician communication style, were measured using questionnaires and corrected for possible confounds (social anxiety and attachment orientation). Additional secondary outcome measures for the effect of oxytocin were recall of information and pupil diameter and exploratory outcomes included mood and anxiety measures. Oxytocin did not affect the eye-tracking parameters of volunteers' gaze toward the eyes of the physician. Moreover, oxytocin did not affect the parameters of bonding between volunteers and the physician nor other secondary and exploratory outcomes in this setting. Bayesian hypothesis testing provided evidence for the absence of effects. These results contradict the notion that oxytocin affects eye gaze patterns or bonding.

Dissociating instructive from permissive roles of brain circuits with reversible neural activity manipulations.

Neuroscientists rely on targeted perturbations and lesions to causally map functions in the brain1. Yet, since the brain is highly interconnected, manipulation of one area can impact behavior through indirect effects on many other brain regions, complicating the interpretation of such results2,3. On the other hand, the often-observed recovery of behavior performance after lesion can cast doubt on whether the lesioned area was ever directly involved4,5. Recent studies have highlighted how the results of acute and irreversible inactivation can directly conflict4-6, making it unclear whether a brain area is instructive or merely permissive in a specific brain function. To overcome this challenge, we developed a three-stage optogenetic approach which leverages the ability to precisely control the temporal period of regional inactivation with either brief or sustained illumination. Using a visual detection task, we found that acute optogenetic inactivation of the primary visual cortex (V1) suppressed task performance if cortical inactivation was intermittent across trials within each behavioral session. However, when we inactivated V1 for entire behavioral sessions, animals quickly recovered performance in just one to two days. Most importantly, after returning these recovered animals to intermittent cortical inactivation, they quickly reverted to failing on optogenetic inactivation trials. These data support a revised model where the cortex is the default circuit that instructs perceptual performance in basic sensory tasks. More generally, this novel, temporally controllable optogenetic perturbation paradigm can be broadly applied to brain circuits and specific cell types to assess whether they are instructive or merely permissive in a brain function or behavior.

Brain-based gene expression of putative risk genes for anorexia nervosa.

The etiology of anorexia nervosa (AN) remains elusive. Recent genome-wide association studies identified the first genes liked to AN which reached genome-wide significance, although our understanding of how these genes confer risk remains preliminary. Here, we leverage the Allen Human Brain Atlas to characterize the spatially distributed gene expression patterns of genes linked to AN in the non-disordered human brain, developing whole-brain maps of AN gene expression. We found that genes associated with AN are most expressed in the brain, relative to all other body tissue types, and demonstrate gene-specific expression patterns which extend to cerebellar, temporal and basal ganglia structures in particular. fMRI meta-analyses reveal that AN gene expression maps correspond with functional brain activity involved in processing and anticipating appetitive and aversive cues. Findings offer novel insights around putative mechanisms through which genes associated with AN may confer risk.

Heart rate monitoring to detect acute pain in non-verbal patients: a study protocol for a randomized controlled clinical trial.

BACKGROUND: Autism entails reduced communicative abilities. Approximately 30% of individuals with autism have intellectual disability (ID). Some people with autism and ID are virtually non-communicative and unable to notify their caregivers when they are in pain. In a pilot study, we showed that heart rate (HR) monitoring may identify painful situations in this patient group, as HR increases in acutely painful situations. OBJECTIVES: This study aims to generate knowledge to reduce the number of painful episodes in non-communicative patients' everyday lives. We will 1) assess the effectiveness of HR as a tool for identifying potentially painful care procedures, 2) test the effect of HR-informed changes in potentially painful care procedures on biomarkers of pain, and 3) assess how six weeks of communication through HR affects the quality of communication between patient and caregiver. METHODS: We will recruit 38 non-communicative patients with autism and ID residing in care homes. ASSESSMENTS: HR is measured continuously to identify acutely painful situations. HR variability and pain-related cytokines (MCP-1, IL-1RA, IL-8, TGFß1, and IL-17) are collected as measures of long-term pain. Caregivers will be asked to what degree they observe pain in their patients and how well they believe they understand their patient's expressions of emotion and pain. Pre-intervention: HR is measured 8 h/day over 2 weeks to identify potentially painful situations across four settings: physiotherapy, cast use, lifting, and personal hygiene. INTERVENTION: Changes in procedures for identified painful situations are in the form of changes in 1) physiotherapy techniques, 2) preparations for putting on casts, 3) lifting techniques or 4) personal hygiene procedures. DESIGN: Nineteen patients will start intervention in week 3 while 19 patients will continue data collection for another 2 weeks before procedure changes are introduced. This is done to distinguish between specific effects of changes in procedures and non-specific effects, such as caregivers increased attention. DISCUSSION: This study will advance the field of wearable physiological sensor use in patient care. TRIAL REGISTRATION: Registered prospectively at ClinicalTrials.gov (NCT05738278).

The problems with systematic reviews: a living systematic review.

OBJECTIVES: Systematic reviews and meta-analyses are proliferating as they are an important building block to inform evidence-based guidelines and decision-making. Enforcement of best practice in clinical trials is firmly on the research agenda of good clinical practice, but there is less clarity as to how evidence syntheses that combine these studies can be influenced by bad practice. Our aim was to conduct a living systematic review of articles that highlight flaws in published systematic reviews to formally document and understand these problems. STUDY DESIGN AND SETTING: We conducted a comprehensive assessment of all literature examining problems, which relate to published systematic reviews. RESULTS: The first iteration of our living systematic review (https://systematicreviewlution.com/) has found 485 articles documenting 67 discrete problems relating to the conduct and reporting of systematic reviews which can potentially jeopardize their reliability or validity. CONCLUSION: Many hundreds of articles highlight that there are many flaws in the conduct, methods, and reporting of published systematic reviews, despite the existence and frequent application of guidelines. Considering the pivotal role that systematic reviews have in medical decision-making due to having apparently transparent, objective, and replicable processes, a failure to appreciate and regulate problems with these highly cited research designs is a threat to credible science.