An Expanded Conceptual Framework for Understanding Irritability in Childhood: The Role of Cognitive Control Processes.

Children prone to irritability experience significant functional impairments and internalising and externalising problems. Contemporary models have sought to elucidate the underlying mechanisms in irritability, such as aberrant threat and reward biases to improve interventions. However, the cognitive control processes that underlie threat (e.g., attention towards threats) and reward (e.g., attention towards reward-related cues) biases and the factors which influence the differential activation of positive and negative valence systems and thus leading to maladaptive activation of cognitive control processes (i.e., proactive and reactive control) are unclear. Thus, we aim to integrate extant theoretical and empirical research to elucidate the cognitive control processes underlying threat and reward processing that contribute to irritability in middle childhood and provide a guiding framework for future research and treatment. We propose an expanded conceptual framework of irritability that includes broad intraindividual and environmental vulnerability factors and propose proximal 'setting' factors that activate the negative valence and positive valence systems and proactive and reactive cognitive control processes which underpin the expression and progression of irritability. We consider the implications of this expanded conceptualisation of irritability and provide suggestions for future research.

What is the cognitive footprint of insular glioma?

Cognitive impairment has a profound deleterious impact on long-term outcomes of glioma surgery. The human insula, a deep cortical structure covered by the operculum, plays a role in a wide range of cognitive functions including interceptive thoughts and salience processing. Both low-grade (LGG) and high-grade gliomas (HGG) involve the insula, representing up to 25% of LGG and 10% of HGG. Surgical series from the past 30 years support the role of primary cytoreductive surgery for insular glioma patients; however, reported cognitive outcomes are often limited to speech and language function. The breath of recent neuroscience literature demonstrates that the insula plays a broader role in cognition including interoceptive thoughts and salience processing. This article summarizes the vast functional role of the healthy human insula highlighting how this knowledge can be leveraged to improve the care of patients with insular gliomas.

Exploring latent clusters in pediatric OCD based on symptoms, severity, age, gender, and comorbidity.

Given diverse symptom expression and high rates of comorbid conditions, the present study explored underlying commonalities among OCD-affected children and adolescents to better conceptualize disorder presentation and associated features. Data from 830 OCD-affected participants presenting to OCD specialty centers was aggregated. Dependent mixture modeling was used to examine latent clusters based on their age- and gender adjusted symptom severity (as measured by the Children's Yale-Brown Obsessive-Compulsive Scale; CY-BOCS), symptom type (as measured by factor scores calculated from the CY-BOCS symptom checklist), and comorbid diagnoses (as assessed via diagnostic interviews). Fit statistics favored a four-cluster model with groups distinguished primarily by symptom expression and comorbidity type. Fit indices for 3-7 cluster models were only marginally different and characteristics of the clusters remained largely stable between solutions with small clusters of distinct presentations added in more complex models. Rather than identifying a single classification system, the findings support the utility of integrating dimensional, developmental, and transdiagnostic information in the conceptualization of OCD-affected children and adolescents. Identified clusters point to the centrality of contamination concerns to OCD, relationships between broader symptom expression and higher levels of comorbidity, and the potential for complex/neurodevelopmental presentations.

The expanding role of blood and tissue establishments in the development of advanced therapy medicinal products.

BACKGROUND AIMS: The relationship between blood establishments and advanced cellular therapies is evident in several European countries, with some involved in research and development and/or in manufacturing. The aim of the present study was to understand the advanced therapy medicinal product (ATMP) infrastructural, regulatory and logistic requirements needed for the Irish Blood Transfusion Service to support advanced therapeutics in Ireland. METHODS: An online survey consisting of 13 questions was distributed in a targeted manner to the identified ATMP stakeholders in Ireland, namely those working in industry, health care, regulatory agencies or education. Subject matter experts in the field were approached and interviewed to gain further insight into the relationship between blood and tissue establishments (BTEs) and ATMPs, to explore the advantages these institutions have in development and to highlight potential challenges for implementation. RESULTS: In total, 84.9% of survey respondents stated that BTEs have a role in the development of advanced therapeutics. Key BTE services identified as applicable to the ATMP sector from both surveys and interviews include the provision of starting materials for research and manufacturing, donor management, use of existing quality and traceability frameworks, product logistic strategies and Good Manufacturing Practice. Challenges for BTE expansion into the sector currently include high costs associated with ATMPs, lack of expertise in these therapies, limited therapeutic populations and no national ATMP strategic plan for Ireland. CONCLUSIONS: Blood establishments have services and expertise that can be extended into the advanced therapy sector. The existing knowledge and skill base of BTEs in Ireland should be leveraged to accelerate the development of ATMP strategies for industry and healthcare.

Subcallosal cingulate deep brain stimulation evokes two distinct cortical responses via differential white matter activation.

Subcallosal cingulate (SCC) deep brain stimulation (DBS) is an emerging therapy for refractory depression. Good clinical outcomes are associated with the activation of white matter adjacent to the SCC. This activation produces a signature cortical evoked potential (EP), but it is unclear which of the many pathways in the vicinity of SCC is responsible for driving this response. Individualized biophysical models were built to achieve selective engagement of two target bundles: either the forceps minor (FM) or cingulum bundle (CB). Unilateral 2 Hz stimulation was performed in seven patients with treatment-resistant depression who responded to SCC DBS, and EPs were recorded using 256-sensor scalp electroencephalography. Two distinct EPs were observed: a 120 ms symmetric response spanning both hemispheres and a 60 ms asymmetrical EP. Activation of FM correlated with the symmetrical EPs, while activation of CB was correlated with the asymmetrical EPs. These results support prior model predictions that these two pathways are predominantly activated by clinical SCC DBS and provide first evidence of a link between cortical EPs and selective fiber bundle activation.

Cortical signatures of sleep are altered following effective deep brain stimulation for depression.

Deep brain stimulation (DBS) of the subcallosal cingulate cortex (SCC) is an experimental therapy for treatment-resistant depression (TRD). Chronic SCC DBS leads to long-term changes in the electrophysiological dynamics measured from local field potential (LFP) during wakefulness, but it is unclear how it impacts sleep-related brain activity. This is a crucial gap in knowledge, given the link between depression and sleep disturbances, and an emerging interest in the interaction between DBS, sleep, and circadian rhythms. We therefore sought to characterize changes in electrophysiological markers of sleep associated with DBS treatment for depression. We analyzed key electrophysiological signatures of sleep-slow-wave activity (SWA, 0.5-4.5 Hz) and sleep spindles-in LFPs recorded from the SCC of 9 patients who responded to DBS for TRD. This allowed us to compare the electrophysiological changes before and after 24 weeks of therapeutically effective SCC DBS. SWA power was highly correlated between hemispheres, consistent with a global sleep state. Furthermore, SWA occurred earlier in the night after chronic DBS and had a more prominent peak. While we found no evidence for changes to slow-wave power or stability, we found an increase in the density of sleep spindles. Our results represent a first-of-its-kind report on long-term electrophysiological markers of sleep recorded from the SCC in patients with TRD, and provides evidence of earlier NREM sleep and increased sleep spindle activity following clinically effective DBS treatment. Future work is needed to establish the causal relationship between long-term DBS and the neural mechanisms underlying sleep.

Reaching Young People in Urban and Rural Communities with Mental Health and Wellbeing Support Within a Youth Sports Development Program: Integrating In-Person and Remote Modes of Service Delivery.

Embedding mental health and wellbeing programs within youth sports development programs can help provide more young people with mental health support. However, delivering such programs in multiple locations across metropolitan, regional, and rural areas requires novel solutions to overcome geographic and logistical barriers. We examined the delivery of an integrated system delivered within an Australian junior rugby league program. The program included online assessment and feedback about youth mental health, as well as connection with evidence-informed resources and referral sources via parent telephone and email support. There were four methods of delivering player workshops during training sessions: (a) In-person Delivery Only, (b) In-person + Remote Real-time (video-conferenced), (c) In-person + Remote Prerecorded (video-recorded), and (d) Remote Delivery Only (video-conferenced and/or video-recorded). In-person delivered player workshops were facilitated by local rugby league personnel. Remote delivered workshops were facilitated by psychologists from the mental health research team. Participants were 671 boys (12-15 years; M age = 13.35; SD = 0.35) in 21 metropolitan, regional and rural locations. Regardless of delivery condition, players with elevated anxiety, depression and behavioural problems reported significant declines in symptoms from pre- to post-program, and those within healthy ranges did not change from pre- to post-program. Player workshop enjoyment ratings were higher in the In-person + Remote Real-time condition and the Remote Delivery Only condition than the In-person Delivery Only condition. However, non-completion of the post-program assessment across all conditions was higher than in prior studies and a comparison group of players who did not complete the program was not included. Mental health benefits may be observed across in-person and remote modes of delivering mental health workshops within youth sports programs. However, the involvement of mental health personnel, whether in-person or remotely, and mixed delivery modes, may be important for young people's retention and satisfaction.

Extinction of negative conditioned stimulus valence in human fear conditioning.

Fear conditioning is a common experimental paradigm for modelling the development, and exposure-based treatment, of anxiety disorders. Measures of fear such as threat-expectancy, physiological arousal, and fear ratings typically extinguish, however feared stimuli may still be evaluated negatively (i.e. retain negative valence). This systematic review provides the first investigation of the relationship between fear conditioning methodology and extinction of negative stimulus valence. Principal findings were that type of CS (conditioned stimulus) and the CS-US pairing (i.e. specific combination of CS and unconditioned stimulus) predicted extinction outcome. Extinction of absolute negative CS valence was always achieved with shape CSs; often achieved with low fear-relevant animals as CSs, and less frequently achieved with faces as CSs - particularly neutral faces paired with a shock US. Modified extinction procedures typically achieved the same outcome as standard extinction procedures, except for partially-reinforced extinction, which was less effective than standard extinction, and positive imagery training, which was more effective than standard extinction. Further studies are warranted to evaluate the influence of fear conditioning methodology on extinction of absolute negative CS valence.

Daily use of digital technologies to feel better: Adolescents' digital emotion regulation, emotions, loneliness, and recovery, considering prior emotional problems.

INTRODUCTION: Adolescents report using digital technologies for emotion regulation (digital ER), with the aim of feeling better (i.e., improving emotions and reducing loneliness). In this 7-day diary study, we investigated associations of digital ER, emotions, and loneliness, and tested whether prior emotional problems moderated these associations. METHOD: Participants were 312 Australian adolescents (Mage = 13.91, SD = 1.52; 44% boys). Daily surveys measured digital ER; end-of-day happiness, sadness, worry, anger, and loneliness; and peak sadness, worry, and anger. End-of day emotions were subtracted from peak emotions to calculate emotion recovery for sadness, worry, and anger. Participants were randomly selected from two symptom strata (high/low) defined by depression and social anxiety measures collected before the diary. Data were analyzed using multilevel path modeling. Cross-level interactions tested whether symptom strata moderated associations. RESULTS: Digital ER was associated with more recovery from peak to end-of-day sadness and worry, but also with increased sadness, worry, anger, and loneliness by the next end-of-day. Higher end-of-day loneliness was associated with increased next-day digital ER. Prior emotional symptoms were not a significant moderator of daily digital ER and emotion associations. CONCLUSION: Adolescents who report more digital ER in a day show more recovery from the peak of negative emotion that day, but this recovery dissipates, with digital ER also associated with increased negative emotion and loneliness by the next day for all adolescents, regardless of prior symptom status. Lonelier adolescents use more digital ER by the next day, suggesting they need support to make social connections-online or offline.

Preliminary Effectiveness of a Brief School-Based HERO Intervention: Improving the Wellbeing of Final Year Adolescent Female Students.

Young people face multiple challenges, including appearance dissatisfaction, academic stressors, anxiety and depression. These challenges may increase during the final year of high school and may have become further exacerbated by the COVID-19 pandemic. This study examines the preliminary effectiveness of a brief, uncontrolled school-based intervention aimed at enhancing Psychological Capital (PsyCap), consisting of positive resources of hope, self-efficacy, resilience and optimism (HERO), and reducing mental health symptoms among female year 12 students (n = 95, Mage = 16.78, SD = 0.45). Outcomes on measures of HERO and secondary outcomes of flourishing, appearance dissatisfaction, anxiety and depression were measured at pre and post-intervention. In the overall cohort, no significant changes were found on the HERO outcomes or flourishing post-intervention, while symptoms of depression, anxiety and appearance dissatisfaction decreased significantly. For students with higher baseline anxiety, optimism and anxiety symptoms improved significantly at post-intervention. However, students with lower baseline anxiety experienced significant decreases in self-efficacy and optimism, as well as a significant increase in anxiety symptoms post-intervention. Baseline depression levels did not impact intervention outcomes. The findings, although mixed and limited by the lack of control group, suggest that a brief intervention grounded in PsyCap theory may improve student wellbeing under challenging circumstances.

Advances in Deep Brain Stimulation: From Mechanisms to Applications.

Deep brain stimulation (DBS) is an effective therapy for various neurologic and neuropsychiatric disorders, involving chronic implantation of electrodes into target brain regions for electrical stimulation delivery. Despite its safety and efficacy, DBS remains an underutilized therapy. Advances in the field of DBS, including in technology, mechanistic understanding, and applications have the potential to expand access and use of DBS, while also improving clinical outcomes. Developments in DBS technology, such as MRI compatibility and bidirectional DBS systems capable of sensing neural activity while providing therapeutic stimulation, have enabled advances in our understanding of DBS mechanisms and its application. In this review, we summarize recent work exploring DBS modulation of target networks. We also cover current work focusing on improved programming and the development of novel stimulation paradigms that go beyond current standards of DBS, many of which are enabled by sensing-enabled DBS systems and have the potential to expand access to DBS.

Using Nightly Sleep Guidelines to Address Links Between Adolescents' Self-Reported Weekly Sleep Patterns and Anxiety and Depression Symptoms.

Short and long nightly sleep durations are associated with anxiety and depression symptoms among adolescents. However, studies have not used recommended hours of nightly sleep or focused on sleep patterns across weekdays and weekends in examining links with anxiety and depression symptoms. The present study included 709 adolescents in Grade 11 (402 females; 307 males) who self-reported hours of sleep on weeknights and weekends and anxiety and depression symptoms. Using the recommended 8-10 h to define average nightly sleep for adolescents, sleep patterns across weekdays and weekends were categorised into seven classes: short stable, short increasing, average decreasing, average stable, average increasing, long decreasing, and long stable. Relative to average stable sleepers, short stable, short increasing, and long stable sleepers had significantly higher anxiety and depression. Adolescents require 8-10 h of sleep on weeknights, regardless of weekends, for optimal emotional wellbeing.

Strategies for supervising people with mental illnesses on probation caseloads: results from a nationwide study.

Probation officers are tasked with supervising the largest number of people living with mental illnesses in the criminal legal system, with an estimated 16-27% of individuals on probation identified as having a mental health condition. While academic research has recently focused on building the evidence base around the prototypical model of specialty mental health probation, less focus has been directed to the individual components of specialized mental health caseloads and other strategies agencies use to supervise people with mental illnesses. More specific information about these strategies would benefit probation agencies looking to implement or enhance supervision protocols for people with mental illnesses. This article describes the results from a nationwide study examining (1) probation agencies' mental health screening and identification methods; (2) characteristics of mental health caseloads, including eligibility criteria, officer selection, required training, and interfacing with service providers; and (3) other strategies agencies use to supervise people with mental illnesses beyond mental health caseloads. Strategies for identifying mental illnesses varied, with most agencies using risk needs assessments, self-report items asked during the intake process, or information from pre-sentencing reports. Less than a third of respondents reported using screening and assessment tools specific to mental health or having a system that tracks or "flags" mental illnesses. Results also showed wide variation in mental health training requirements for probation officers, as well as variation in the strategies used for supervising people with mental illnesses (e.g., mental health caseloads, embedded mental health services within probation, modified cognitive behavioral interventions). The wide variation in implementation of supervision strategies presents (1) an opportunity for agencies to select from a variety of strategies and tailor them to fit the needs of their local context and (2) a challenge in building the evidence base for a single strategy or set of strategies.

Cingulate dynamics track depression recovery with deep brain stimulation.

Deep brain stimulation (DBS) of the subcallosal cingulate (SCC) can provide long-term symptom relief for treatment-resistant depression (TRD)1. However, achieving stable recovery is unpredictable2, typically requiring trial-and-error stimulation adjustments due to individual recovery trajectories and subjective symptom reporting3. We currently lack objective brain-based biomarkers to guide clinical decisions by distinguishing natural transient mood fluctuations from situations requiring intervention. To address this gap, we used a new device enabling electrophysiology recording to deliver SCC DBS to ten TRD participants (ClinicalTrials.gov identifier NCT01984710). At the study endpoint of 24 weeks, 90% of participants demonstrated robust clinical response, and 70% achieved remission. Using SCC local field potentials available from six participants, we deployed an explainable artificial intelligence approach to identify SCC local field potential changes indicating the patient's current clinical state. This biomarker is distinct from transient stimulation effects, sensitive to therapeutic adjustments and accurate at capturing individual recovery states. Variable recovery trajectories are predicted by the degree of preoperative damage to the structural integrity and functional connectivity within the targeted white matter treatment network, and are matched by objective facial expression changes detected using data-driven video analysis. Our results demonstrate the utility of objective biomarkers in the management of personalized SCC DBS and provide new insight into the relationship between multifaceted (functional, anatomical and behavioural) features of TRD pathology, motivating further research into causes of variability in depression treatment.

A management model in blood, tissue and cell establishments to ensure rapid and sustainable patient access to advanced therapy medicinal products in Europe.

Blood, tissue and cell establishments (BTCs) stand out in the management of donor selection, procurement and processing of all types of substances of human origin (SoHO). In the last decades, the framework created around BTCs, including hospitals and national health system networks, and their links to research, development and innovation organizations and agencies have spurred their involvement in the study of groundbreaking advanced therapy medicinal products (ATMP). To further improve strategic synergies in the development of ATMPs, it will be required to promote intra- and inter-European collaborations by creating an international network involving BTCs and major stakeholders (i.e., research organizations, hospitals, universities, patient associations, public agencies). This vision is already shared with the European Blood Alliance, the association of non-profit blood establishments, with 26 member states throughout the European Union and European Free Trade Association states. Herein we present and analyze the "BTC for ATMP Development And Manufacture" (BADAM) model, an ethically responsible business model based on the values and missions of BTCs and their commitment to health equity, patient access and education (based on voluntary donation of SoHO to address unmet clinical needs, while contributing to training professionals and scientific literacy of our Society).

Catch the drift: Depressive symptoms track neural response during more efficient decision-making for negative self-referents.

Background: Adolescence is a time of heightened risk for developing depression and also a critical period for the development and integration of self-identity. Despite this, the relation between the neurophysiological correlates of self-referential processing and major depressive symptoms in youth is not well understood. Here, we leverage computational modeling of the self-referential encoding task (SRET) to identify behavioral moderators of the association between the posterior late positive potential (LPP), an event-related potential associated with emotion regulation, and youth self-reported symptoms of depression. Specifically, within a drift-diffusion framework, we evaluated whether the association between the posterior LPP and youth symptoms of major depression was moderated by drift rate, a parameter reflecting processing efficiency during self-evaluative decisions. Methods: A sample of 106 adolescents, aged 12 to 17 (53% male; Mage = 14.49, SD = 1.70), completed the SRET with concurrent high-density electroencephalography and self-report measures of depression and anxiety. Results: Findings indicated a significant moderation: for youth showing greater processing efficiency (drift rate) when responding to negative compared to positive words, larger posterior LPPs predicted greater depressive symptom severity. Limitations: We relied on a community sample and our study was cross-sectional in nature. Future longitudinal work with clinically depressed youth would be beneficial. Conclusions: Our results suggest a neurobehavioral model of adolescent depression wherein efficient processing of negative information co-occurs with increased demands on affective self-regulation. Our findings also have clinical relevance; youth's neurophysiological response (posterior LPP) and performance during the SRET may serve as a novel target for tracking treatment-related changes in one's self-identity.

Safety and feasibility of platelet transfusion through long catheters in the neonatal intensive care unit: an in vitro study.

OBJECTIVE: To assess the safety and feasibility of platelet transfusion through small-bore long lines used in the neonatal intensive care unit (NICU), including double-lumen umbilical venous catheters (UVCs) and 24 G and 28 G peripherally inserted central catheters (PICCs). DESIGN: Prospective in vitro controlled study. SETTING: Blood transfusion service laboratory. METHODS: In vitro platelet transfusions were set up as per NICU practice. Transfusion line pressure was monitored. Post-transfusion swirling, presence of aggregates, pH analysis and automated cell count in vitro activation response by flow cytometry assessing CD62P expression were assessed. MAIN OUTCOME MEASURES: All transfusions completed successfully. The rate of infusion was reduced in 5 of 16 transfusions through 28 G lines due to 'pressure high' alarms. There was no difference in swirling values or transfusion aggregate formation, CD62P expression levels, platelet count, platelet distribution width, mean platelet volume, plateletcrit or platelet to large cell ratio across transfusions post-transfusion. CONCLUSIONS: This study showed that in vitro platelet transfusion performed through 24 G and 28 G neonatal PICC lines and double-lumen UVCs is non-inferior to 24 G short cannulas, using outcome measures of platelet clumping, platelet activation and line occlusion. This suggests that where available these lines can be used if necessary for platelet transfusion.

The impact of donor biological variation on the quality and function of cold-stored platelets.

BACKGROUND AND OBJECTIVES: Room temperature-stored platelets (RTPs) maximize platelet viability but limit shelf life. The aims of this study were to investigate the impact of donor variability on cold-stored platelets (CSPs) and RTP, to determine whether RTP quality markers are appropriate for CSP. MATERIALS AND METHODS: Double platelet donations (n = 10) were collected from consented regular male donors stored in 100% plasma. A full blood count, donor age, weight, height and body mass index (BMI) were collected at the time of donation. Platelet donations were split equally into two bags, and assigned to non-agitated CSP or agitated RTP. The quality and function of platelets were assessed throughout the standard 7 days of storage and at expiry (day 8). Non-parametric statistical analyses were used to analyse results given the small sample size. RESULTS: As expected, there were significant differences between CSP and RTP throughout storage including a reduction in CSP concentration as well as a loss of swirling. Furthermore, a significant increase in CSP exhibiting activation and apoptotic markers was observed. Platelet concentrations were further impacted by donor BMI, and donors with the highest BMI (>29) had the lowest platelet concentration and activation response at the end of CSP storage. CONCLUSION: Platelet quality and functionality play a vital role in transfusion outcomes; however, blood components are inherently variable. This study demonstrated, for the first time, the specific impact of donor BMI on CSP quality and function and highlights the requirement for novel quality markers for assessing CSPs.

Treating sleep problems in young children: A randomised controlled trial of a group-based, parent-focused behavioural sleep intervention.

This study tested the efficacy of a 5 × 1.5 h/session, group-based, parent-focused, behavioural intervention (BI) targeting sleep problems in preschool children. Parents were randomised to either the BI (N = 62) or care as usual (CAU; N = 66) conditions. Outcomes included sleep, anxiety, behavioural problems, internalising and externalising symptoms, transition to school and academic achievement. Assessments were conducted at pre- and post-BI intervention (in the year prior to formal schooling), and then at follow-ups 1 and 2 in the first year of formal schooling. Relative to the CAU, the BI condition demonstrated significantly greater improvements in sleep, anxiety, behaviour problems and internalising and externalising symptoms from pre-to post-intervention. Improvements in sleep, anxiety, and internalising symptoms were maintained, while behaviour and externalising symptoms were further improved upon at school follow-up 2. For the BI group, improvements in sleep at post-intervention were found to mediate improvements in anxiety, internalising, and externalising symptoms, but not behaviour problems, at school follow-ups 1 and 2. There were no significant effects of condition on school transition or academic outcome measures. The results suggest that the BI is effective for sleep, anxiety, behaviour, internalising and externalising symptoms, but not for school transition or academic outcomes. ANZCTR NUMBER: ACTRN12618001161213.

Anxiety disorders in children and adolescents: A summary and overview of the literature.

Considerable work has advanced understanding of the nature, causes, management, and prevention of anxiety disorders in children and adolescents over the past 30 years. Prior to this time the primary focus was on school refusal and specific phobias. It is now recognised that children and adolescents experience the full gamut of anxiety disorders in very similar ways to adults and that anxiety disorders in the paediatric years can predict a lifelong mental-health struggle. Given the vast array of specific studies in this field, the current review summarises current knowledge about these high prevalence disorders, points to overarching limitations, and suggests potentially important future directions. Following a brief historical overview, the review summarises knowledge about demographic and epidemiological characteristics, distal and proximal risk factors, current treatment directions, and prevention. There is still a great deal to learn about the causes and treatments of child and adolescent anxiety disorders. By amalgamating our current knowledge, this review provides a window to the research directions that are likely to lead to future advances.