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The University of Oxford, Department of Psychiatry is working with partners to develop and lead The Young People’s Campaign for the Lancet Commission on Global Mental Health and Sustainable Development
Thalamic deep brain stimulation for central poststroke pain syndrome: an international multicenter study.
OBJECTIVE: The effectiveness and optimal stimulation site of deep brain stimulation (DBS) for central poststroke pain (CPSP) remain elusive. The objective of this retrospective international multicenter study was to assess clinical as well as neuroimaging-based predictors of long-term outcomes after DBS for CPSP. METHODS: The authors analyzed patient-based clinical and neuroimaging data of previously published and unpublished cohorts from 6 international DBS centers. DBS leads were reconstructed and normalized. A stimulation map was constructed on the basis of individual stimulation settings and associated outcomes. Furthermore, the authors projected the individual segmented stroke lesions and volumes of tissue activated (VTAs) of the stimulating electrode onto a normalized human connectome to obtain the connectivity profiles of the individual lesions and VTAs. RESULTS: The authors analyzed the data of 54 patients, of whom 15 were excluded from the final analysis due to a lack of imaging data. Among the remaining 39 patients from 6 different cohorts, the authors found 14 (35.9%) responders who were defined by pain relief of at least 50% at 12-month follow-up. Stimulation mapping identified areas in the posterior limb of the internal capsule, the sensorimotor thalamus, and the medial and intralaminar thalamus as effective for pain reduction. Baseline characteristics did not differ between responders and nonresponders. The stimulation sites of the responders showed significantly reduced structural connectivity to the sensory areas of the cerebral cortex compared to nonresponders. CONCLUSIONS: This comprehensive, multicenter analysis corroborates the efficacy of DBS in treating CPSP for a relevant number of patients. The posterior limb of the internal capsule and the sensorimotor thalamus emerged as potential stimulation sweet spots. The difference in structural connectivity between responders and nonresponders may constitute a biomarker of effective stimulation that can help guide surgical planning in future well-designed prospective trials.
1H, 13C and 15N resonance assignments for the acetyltransferase domain of the kinetoplastid kinetochore protein KKT23 from Trypanosoma brucei.
KKT23 is a kinetoplastid-specific kinetochore protein that has a C-terminal GCN5-related histone acetyltransferase domain that acetylates the C-terminal tail of histone H2A. Here, we present the 1H, 13C and 15N resonance assignments for the C-terminal region of KKT23 (KKT23125-348) from Trypanosoma brucei in complex with known cofactors for acetyltransferases, acetyl coenzyme A and coenzyme A. These assignments provide the starting point for detailed investigation of the structure, dynamics and interactions of KKT23 in solution.
Dreaming of Better Treatments: Advances in Drug Development for Sleep Medicine and Chronotherapy.
Throughout history, the development of new sleep medicines has been driven by progress in our understanding of the mechanisms underlying sleep. Ancient civilisations used their understanding of the sedative nature of natural herbs and compounds to induce sleep. The discovery of barbiturates and bromides heralded a new era of synthetic sleep medicine in the 19th century. This was followed by the development of benzodiazepines that were used to inhibit signalling throughout the brain by promoting gamma-amino butyric acid release and thereby produce loss of consciousness. As our understanding of sleep has deepened, newer therapies have more specifically targeted the wake-inducing neurotransmitter orexin with fewer side effects. Given the newly highlighted role of kinases in sleep/wake regulation, we predict that the next breakthroughs in sleep medicine will likely target these kinases. Given the fundamental role that sleep plays in maintaining brain health through processes such as glymphatic clearance, sleep medicine has therapeutic potential beyond just sleep. Recent evidence suggests that sleep disruptions directly contribute to the build-up of pathological neuronal proteins in neurodegenerative disorders. Therefore, sleep medicine could improve prognosis in disorders such as these. Great attention must be paid to the mechanism of action of each sleep medicine, however, as sleep medicines which do not fully mimic sleep could actually worsen disease progression.
Smartphone-based Monitoring and cognition Modification Against Recurrence of Depression (SMARD): An RCT of Memory Bias Modification Training vs. Cognitive Control Training vs. Attention Bias Modification Training in remitted recurrently depressed patients with 1.5 year follow-up.
BACKGROUND: Major Depressive Disorder (MDD) has a 50-80% recurrence rate highlighting the urgent need for more efficient recurrence prevention programs. Currently, recurrences are often identified too late, while existing preventive strategies may not sufficiently address ethio-patho-physiological mechanisms for recurrence. Negative memory bias (the tendency to better remember negative than positive events), negative attention bias (selective attention favoring mood-congruent information), and cognitive control deficits are important factors involved in the onset, maintenance, and recurrence of depressive episodes. METHODS: Here we describe the protocol for the Smartphone-based Monitoring and cognition Modification Against Recurrence of Depression (SMARD) study, aiming to investigate different forms of cognitive training programs administered via smartphones, in order to develop a second-generation recurrence prevention program. In addition, we will gather Experience Sampling Method (ESM) assessments during a 6-day period, and during the follow-up period we will obtain behavioral data on (social) activities with BEHAPP, a smartphone-based Mobile Passive Monitoring application for remote behavioral monitoring to identify behavioral changes indicative of an imminent depressive episode. In a randomized controlled trial, SMARD will compare the effects of a smartphone-based Memory Bias Modification Training (MBT), Cognitive Control Training (CCT), and Attention Bias Modification Training (ABT) versus cognitive domain-specific (active-) sham trainings in 120 remitted MDD-patients with recurrent-MDD. Over the course of three weeks, participants receive multiple daily training sessions. Thereafter, participants will be followed up for 1.5 years with 3-monthly interviews to assess recurrences. DISCUSSION: The SMARD study aims to 1. assess the effects of the cognitive training programs versus their training-specific (active-) sham conditions on changes in memory, cognitive control dysfunction and attention; 2. relate training effects to neural networks previously identified in (recurrence of) MDD (therefore we obtain functional Magnetic Resonance Imaging ((f)MRI) scans before and after the training in a subset of participants); 3. link baseline and change in memory, cognitive control, attention and neural functioning, and ESM data to prospective recurrences; 4. examine whether passive smartphone-use monitoring can be used for prediction of recurrences. TRIAL REGISTRATION: NL-OMON26184 and NL-OMON27513. Registered 12 August 2021-Retrospectively registered, https://onderzoekmetmensen.nl/en/trial/26184 en https://onderzoekmetmensen.nl/en/trial/27513 .
Smelling x as y? On (the impossibility of) multistable perception in the chemical senses.
Multistable percepts are intriguing phenomena whereby an ambiguous sensory input can be perceived in one of several qualitatively different ways. In such cases, people can switch their attention to perceive the stimulus in either way, though they typically cannot maintain both interpretations in awareness simultaneously. The abundance of evidence demonstrating multistable perception in the visual and auditory modalities can be contrasted with the scarcity, if not absence, of studies reporting similar phenomena in the chemical senses (primarily olfaction and gustation), prompting an intriguing question about this apparent qualitative difference between the senses. This paper seeks to address this question by first briefly reviewing multistable perceptual phenomena in vision and audition to underscore their defining features. We then assess the limited body of research that has occasionally linked multistability to the chemical senses. While a few studies suggest loose analogies between olfactory perception and visual or auditory multistability, no compelling evidence exists for such phenomena in taste. We argue that this absence is unlikely to be explained by any single factor. Rather, it appears to stem from a confluence of constraints, including the lack of spatio-temporal structure and intrinsic dimensionality in chemosensory stimuli, as well as their distinct evolutionary functions and cognitive framing. Together, these factors may help to explain why multistable perceptual experiences seem not to emerge in the chemical senses.
Poster Session: Characteristic differences in eye movements in people with Parkinson's disease.
Parkinson's disease is a neurodegenerative condition that impairs motor control, including oculomotor function. This study focuses on identifying characteristic differences in eye movements between people with Parkinson's diseases and healthy controls across four different tasks. Two static tasks, a fixation task and a tumbling E task, were measured using an adaptive optics scanning laser ophthalmoscope (AOSLO) to capture fixational eye movements with high spatial and temporal resolution. Two moving target tasks, guided saccade and smooth pursuit, were measured using the EyeLink 1000 Plus to study large-scale eye movements. Three participants with Parkinson's disease and three healthy control performed these tasks. In the fixation task, the participant fixated on a static target for 5s, and in the tumbling E task, an 'E' near the acuity limit was presented in different orientations for 0.7s. The guided saccade task required the participant to quickly shift their gaze between locations separated by 11ᵒ, while the smooth pursuit task involved tracking a smoothly moving target at two different speeds: 10ᵒ/s and 20ᵒ/s. Both moving target tasks were performed in horizontal and vertical directions. Oculomotor parameters such as saccade amplitude, saccade velocity, saccadic delay, saccadic rate, and intersaccadic intervals were extracted from the eye movement trace. Here we report the differences in these parameters between healthy controls and participants with Parkinson's disease.
The compulsive eating paradigm: can psychedelics help in treating obesity?
Obesity is a multifactorial disorder involving a behavioural aetiology in subsets of patients that traditional therapeutic approaches have failed to address. Drawing parallels with addiction, the rewarding aspects of a chronic energy-dense diet can compromise dopaminergic reward circuits, eventually causing individuals to become habitually responsive to food-related stimuli despite adverse health consequences. The maladaptive prediction of reward and motivational salience that becomes associated with food-related stimuli can exert top-down influence on perception and attention, promoting compulsive eating behaviour. Emerging research suggests that psychedelics, e.g., psilocybin and LSD, induce non-ordinary mental states where the influence of such behaviours could potentially be reduced and modified. Based on current evidence, mechanisms have been proposed which suggest that psychedelics might relax the top-down influence of high-level predictions encoded within neuronal hierarchies and sensitise them to bottom-up information flow. Additionally, psychedelics are thought to open a window of psychological flexibility, allowing people to potentially become open to new cognitive and behavioural strategies that can be offered via assisted psychotherapy. Therefore, psychedelics-assisted psychotherapy may encourage beneficial changes to eating behaviour, in those with maladaptive eating habits. While promising in theory, new research is needed to assess the potential efficacy of psychedelics-assisted psychotherapy in treating compulsive eating behaviour.
Origin, evolution, and success of pbla, the gonococcal beta-lactamase plasmid, and implications for public health.
Neisseria gonorrhoeae is a leading cause of sexually transmitted infection (STI) and a priority AMR pathogen. Two narrow host range plasmids, pbla and pConj, have contributed to ending penicillin and tetracycline therapy, respectively, and undermine current prevention strategies including doxycycline post-exposure prophylaxis (Doxy-PEP). Here, we investigated the origin and evolution of the beta-lactamase plasmid, pbla. We demonstrate that pbla was likely acquired by the gonococcus from Haemophilus ducreyi, and describe the subsequent evolutionary pathways taken by the three major pbla variants. We show that the ability of pConj to spread pbla promotes their co-occurrence in the gonococcal population and the spread of pbla. Changes that mitigate fitness costs of pbla and the emergence of TEM beta-lactamases that confer increased resistance have contributed to the success of pbla. In particular, TEM-135, which has arisen in certain pbla variants, increases resistance to beta-lactams and only requires one amino acid change to become an extended spectrum beta-lactamase (ESBL). The evolution of pbla underscores the threat of plasmid-mediated resistance to current therapeutic and preventive strategies against gonococcal infection. Given the close relationship between pbla and pConj, widespread use of Doxy-PEP is likely to promote spread of both plasmids, strains which carry pConj and are resistant against third generation cephalosporins, and the emergence of plasmid-mediated ESBL in the gonococcus, with significant public health consequences.
Clinical and cost-effectiveness of lithium versus quetiapine augmentation for treatment-resistant depression in adults: LQD a pragmatic randomised controlled trial.
BACKGROUND: Lithium and several atypical antipsychotics are the recommended first-line augmentation options for treatment-resistant depression; however, few studies have compared them directly, and none for longer than 8 weeks. Consequently, there is little evidence-based guidance for clinicians when choosing an augmentation option for patients with treatment-resistant depression. OBJECTIVES: This trial examined whether it is more clinically and cost-effective to prescribe lithium or quetiapine augmentation therapy for patients with treatment-resistant depression over 12 months. DESIGN: This was a parallel group, multicentre, pragmatic, open-label superiority trial comparing the clinical and cost-effectiveness of lithium versus quetiapine augmentation of antidepressant medication in treatment-resistant depression. Participants were randomised 1 : 1 at baseline to the decision to prescribe either lithium or quetiapine. SETTING: Six National Health Service trusts in England. PARTICIPANTS: Eligible participants were aged ≥ 18 years, met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for major depressive disorder, scored ≥ 14 on the 17-item Hamilton Depression Rating Scale and whose depression had had an inadequate response to at least two therapeutic antidepressant treatment trials in the current episode, with a current antidepressant treatment at or above the therapeutic dose for ≥ 6 weeks. Patients with a history of psychosis or bipolar disorder were excluded. Patients were judged suitable for either treatment. INTERVENTIONS: After randomisation, pre-prescribing safety checks were undertaken as per standard care and trial clinicians decided whether to proceed with prescribing the allocated medication. Trial clinicians received recommendations for titration and dosing in line with current clinical guidelines; however, dosing regimens could be altered according to tolerability and response. Participants were followed up using weekly self-report questionnaires and 8-, 26- and 52-week research visits. MAIN OUTCOME MEASURES: The co-primary outcome measures were depressive symptom severity over 52 weeks, measured weekly using the self-rated Quick Inventory of Depressive Symptomatology, and time to all-cause treatment discontinuation of the trial medication. Economic analyses compared costs between the two treatment arms over 52 weeks, from a National Health Service and Personal Social Services perspective, and a societal perspective. RESULTS: Two hundred and twelve participants were randomised, 107 to quetiapine and 105 to lithium. The quetiapine arm showed a significantly greater reduction in depressive symptoms than the lithium arm over 52 weeks (quetiapine vs. lithium area under the differences curve = -68.36, 95% confidence interval: -129.95 to -6.76, p = 0.0296). Median days to discontinuation did not significantly differ between the two arms (quetiapine = 365.0, interquartile range = 57.0-365.0, lithium = 212.0, interquartile range = 21.0-365.0), p = 0.1196. Quetiapine was more cost effective than lithium. Thirty-two serious adverse events were recorded, only one of which was deemed possibly related to the intervention (lithium). LIMITATIONS: The trial was unblinded, therefore expectancies regarding the trial medications may have influenced the results. Further, there was substantial missing data for some of the secondary outcome measures. CONCLUSIONS: As well as being more cost-effective, quetiapine may be a more clinically effective augmentation option for treatment-resistant depression. FUTURE WORK: Examining predictors of treatment response, including clinical, sociodemographic and biological factors, will help establish whether there are additional factors to consider when choosing an augmentation treatment for treatment-resistant depression. TRIAL REGISTRATION: This trial is registered as ISRCTN16387615. FUNDING: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/222/02) and is published in full in Health Technology Assessment; Vol. 29, No. 12. See the NIHR Funding and Awards website for further award information.
Correction: Evaluating the generalisability of region-naïve machine learning algorithms for the identification of epilepsy in low-resource settings.
[This corrects the article DOI: 10.1371/journal.pdig.0000491.].
The DESTINIES Study: an online Delphi study to build international consensus on the medical conditions and procedures that confer immunosuppression and their respective COVID-19 risk profiles
Background: The lack of international consensus on defining and categorising immunosuppression has undermined disease surveillance and patient care, particularly during the COVID-19 pandemic. To address this, a global expert panel was recruited to join the eDElphi STudy to fully defiINe and COVID-risk stratify ImmunosupprESsion (DESTINIES) and develop a COVID risk-stratified digital phenotype for ‘adult immunosuppression’ (the DESTINIES phenotype). Methods: Panellists were presented with all medical diagnoses and procedures cited in prevailing immunosuppressed definitions; they evaluated their appropriateness for the DESTINIES phenotype and their risks for severe COVID-19 outcomes through anonymous online questionnaires and discussion. Panel agreement with a series of clinical statements were also assessed; statements incorporated longstanding disputes, including variables that could reverse immunosuppression. Each round of data collection informed and refined a draft phenotype until final ratification. This study was active between May and September 2024. Findings: Sixty-four experts from four continents and 12 international agencies completed two rounds of consensus questionnaire, a discussion group and ratifying vote. Panellists identified candidates posing higher (e.g. Transplantation, Primary Immunodeficiency) and lower COVID-19 risk (e.g. Anorexia nervosa, Cerebral spinal fluid leak) but disagreed on the categorisation of others (e.g. Asplenia, Immune-mediated Inflammatory Disease). Consensus was reached on ten clinical statements, notably removing Drug-managed HIV and Cancer remission from consideration as immunosuppressed. The DESTINIES phenotype was ratified with near unanimous support (94%) for implementation in surveillance. Interpretation: Pending validation, the DESTINIES phenotype provides a clinically meaningful, internationally ratified and digitally practical method for identifying and COVID-19 risk-stratifying adult immunosuppressed patients in healthcare data. Funding: This work was funded by the UK Medical Research Council and EMIS Health.
Cadê o Kauê? Co-design and acceptability testing of a chat-story aimed at enhancing youth participation in the promotion of mental health in Brazil.
BACKGROUND: Adolescent mental health is vital for public health, yet many interventions fail to recognise adolescents as proactive community contributors. This paper discusses the co-design and acceptability testing of a chat-story intervention to enhance Brazilian adolescents' participation in the promotion of mental health in their peer communities. We specifically highlight the iterative process of co-creating this intervention with community stakeholders. METHODS: The co-design was led by researchers, a youth collaborative group, and health-tech experts. Part 1 included quantitative (n = 1,768) and qualitative (n = 46) studies with Brazilian adolescents aged 15-18 for priority-setting. Part 2 involved co-creation and technical production, with input from youth advisors (n = 24), school staff (n = 11), and policy experts (n = 3). In Part 3, the chat-story was user tested (n = 32). Parts 4 and 5 assessed acceptability through a qualitative study in schools (n = 138) and initial efficacy during an online campaign (n = 795). RESULTS: Participants aspired to support their peers' mental health in schools, both one-to-one and collectively, but felt unprepared. This informed the chat-story's goal of enhancing peer support and collective action skills. Themes identified during Part 1, such as prejudice and academic pressure, were woven into the narrative to raise awareness of the social determinants of mental health, drawing from real-life stories. In the final story, players search for their missing best friend at school, uncovering his anxiety struggles and practicing skills such as empathic listening and partnership building. A manual for teachers was collaboratively designed for use within school settings, supplementing direct-to-user online applications. Acceptability testing showed participants found the tool authentic and user-friendly. Online users perceived the tool as preparing and motivating them to offer peer support and engage in collective action. CONCLUSIONS: The immersive co-creation model, enriched by input from key stakeholders, yielded a relevant and well-received intervention for Brazilian adolescents. Co-designed creative tools like chat-stories hold promise as digital mental health tools, fostering awareness, critical reflection, and inspiring adolescents to drive positive social change.
Redefining respiratory sinus arrhythmia as respiratory heart rate variability: an international Expert Recommendation for terminological clarity.
The variation of heart rate in phase with breathing, known as 'respiratory sinus arrhythmia' (RSA), is a physiological phenomenon present in all air-breathing vertebrates. RSA arises from the interaction of several physiological mechanisms but is primarily mediated by rhythmic changes in cardiac parasympathetic (vagal) activity, increasing heart rate during inspiration and decreasing heart rate during expiration. RSA amplitude is an indicator of autonomic and cardiac health; RSA is diminished or absent in common pathological conditions such as chronic heart failure and hypertension. In this Expert Recommendation, we argue that the term 'RSA', although historically important, is semantically inaccurate and carries misleading pathological connotations, contributing to misunderstanding and misinterpretation of the origin and the physiological importance of the phenomenon. We propose replacing 'RSA' with the term 'respiratory heart rate variability' (RespHRV), which avoids pathological connotations and emphasizes the specific respiratory contribution to heart rate variability. We clarify that RespHRV encompasses respiratory-related heart rate variations in both the low-frequency and high-frequency bands traditionally defined in heart rate variability analysis, and that its amplitude should not be misconstrued as a measure of vagal tone. Adopting the proposed term 'RespHRV' is expected to unify understanding and stimulate further experimental and clinical research into the physiological mechanisms and functional importance of this phenomenon.