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Yann Quidé,1,2 Leonardo Tozzi,3 Mark Corcoran,4 Dara M Cannon,5 Maria R Dauvermann6,7 1School of Psychiatry, University of New South Wales (UNSW), Sydney, NSW, Australia; 2Neuroscience Research Australia, Randwick, NSW, Australia; 3Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA; 4School of Psychology, National University of Ireland Galway, Galway, Ireland; 5Centre for Neuroimaging & Cognitive Genomics (NICOG), Clinical Neuroimaging Laboratory, NCBES Galway Neuroscience Centre, School of Medicine, National University of Ireland Galway, Galway, Ireland; 6Department of Psychiatry, University of Cambridge, Cambridge, UK; 7McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USACorrespondence: Maria R DauvermannDepartment of Psychiatry, University of Cambridge, Clifford Allbutt Building, Cambridge Biomedical Campus Box 58, Cambridge CB2 0XY, UKTel +441223 465246Email md874@medschl.cam.ac.ukAbstract: Childhood trauma (CT) has been repeatedly linked to earlier onset and greater severity of bipolar disorder (BD) in adulthood. However, such knowledge is mostly based on retrospective and cross-sectional studies in adults with BD. The first objective of this selective review is to characterize the short-term effects of CT in the development of BD by focusing on studies in young people. The second objective is to describe the longer-term consequences of CT by considering studies with adult participants. This review first outlines the most prominent hypotheses linking CT exposure and the onset of BD. Then, it summarizes the psychological and biological risk factors implicated in the development of BD, followed by a discussion of original studies that investigated the role of CT in young people with early-onset BD, youths at increased risk of developing BD, or young people with BD with a focus on subclinical and clinical outcome measures. The review considers additional biological and psychological factors associated with a negative impact of CT on the long-term course of BD in later adulthood. Finally, we discuss how the integration of information of CT can improve ongoing early identification of BD and mitigate severe clinical expression in later adulthood.Keywords: bipolar disorder, childhood trauma, vulnerability, early onset, peripheral blood marker, brain

Rino Frisina,1 Irene Gius,1 Michele Palmieri,2 Alessandro Finzi,3 Luigi Tozzi,1 Barbara Parolini2 1Department of Ophthalmology of University of Padova, Padova, Italy; 2Eyecare Clinic, Brescia, Italy; 3Villa Erbosa Di Bologna, Bologna, Emilia-Romagna, ItalyCorrespondence: Rino FrisinaDepartment of Ophthalmology of University of Padova, Via Giustiniani n. 2, Padova 35128, ItalyTel +39 0498212110Fax +39 049 8755169Email frisinarino@gmail.comAbstract: Pathologic myopia (PM) is an ocular disorder characterized by a spherical equivalent (SE) of more than – 6.0 diopters (D) or by an axial length (AL) of more than 26.5 millimeters (mm). PM is associated with myopic maculopathy (MM). The ATN classification describes all the aspects of MM which regroups atrophic, tractional and neovascular consequences to the sclera, choroid and retina of highly myopic eyes. The advent of OCT allowed to define the ultrastructural characteristics of the tractional changes in MM, described by the term myopic traction maculopathy (MTM). They include foveoschisis/maculoschisis/retinoschisis (FS/MS/RS), retinal/foveal detachment (RD/FD), lamellar macular holes (LMH) and full-thickness macular holes (FTMH) with or without RD (MHRD). The MTM staging system (MSS) describes all foveal and retinal changes related to MTM and their natural history interpreting them as different stages of a single progressive disorder. The management of MTM can be just observation for the earliest cases with good vision or surgery for the severe stages with vision loss. There are two possible surgical approaches: ab externo, that acts on the alteration of the scleral shape and includes posterior scleral reinforcement and macular buckle. Ab interno, that targets the alteration of the foveal profile and consists in pars plana vitrectomy with removal of all the epiretinal tractions, maneuvers on the internal limiting membrane, and the use of intravitreal tamponade and laser. As they target two different sides of the same pathology, the two techniques have to be selected on the base of the MTM stage, single or combined.Keywords: pathological myopia, posterior staphyloma, retinal detachment, full thickness macular hole, macular buckle, pars plana vitrectomy, myopic traction maculopathy

Anxiety disorders are the most prevalent mental health conditions worldwide. Unfortunately, the understanding of the precise neurobiological mechanisms that underlie these disorders remains limited. Current diagnostic classifications, based on observable symptoms rather than underlying pathophysiology, do not capture the heterogeneity within and across anxiety disorders. Recent advances in functional neuroimaging have provided new insights into the neural circuits implicated in pathological anxiety, revealing dysfunctions that cut across traditional diagnostic boundaries. In this Review, we synthesize evidence that highlights abnormalities in neurobehavioural systems related to negative valence, positive valence, cognitive systems and social processes. We emphasize that pathological anxiety arises not only from heightened reactivity in acute threat ('fear') circuits but also from alterations in circuits that mediate distant (potential) and sustained threat, reward processing, cognitive control and social processing. We discuss how circuit vulnerabilities can lead to the emergence and maintenance of pathological anxiety. Once established, these neural abnormalities can be exacerbated by maladaptive behaviours that prevent extinction learning and perpetuate anxiety disorders. By delineating the specific neural mechanisms in each neurobiological system, we aim to contribute to a more comprehensive understanding of the neurobiology of anxiety disorders, potentially informing future research directions in this field., Competing Interests: Competing interests: L.M.W. declares US Patent Applications 10/034,645 and 15/820,338: ‘Systems and methods for detecting complex networks in MRI image data’. T.J.A. serves on the scientific advisory board of and has stock options with Mindbloom, and receives payment for editorial work from Elsevier. L.T. is employed by Ceribell Inc. The remaining authors declare no competing interests., (© 2024. Springer Nature Limited.)

Importance: Mental illnesses are a leading cause of disability globally, and functional disability is often in part caused by cognitive impairments across psychiatric disorders. However, studies have consistently reported seemingly opposite findings regarding the association between cognition and psychiatric symptoms., Objective: To determine if the association between general cognition and mental health symptoms diverges at different symptom severities in children., Design, Setting, and Participants: A total of 5175 children with complete data at 2 time points assessed 2 years apart (aged 9 to 11 years at the first assessment) from the ongoing Adolescent Brain and Cognitive Development (ABCD) study were evaluated for a general cognition factor and mental health symptoms from September 2016 to August 2020 at 21 sites across the US. Polynomial and generalized additive models afforded derivation of continuous associations between cognition and psychiatric symptoms across different ranges of symptom severity. Data were analyzed from December 2022 to April 2024., Main Outcomes and Measures: Aggregate cognitive test scores (general cognition) were primarily evaluated in relation to total and subscale-specific symptoms reported from the Child Behavioral Checklist., Results: The sample included 5175 children (2713 male [52.4%] and 2462 female [47.6%]; mean [SD] age, 10.9 [1.18] years). Previously reported mixed findings regarding the association between general cognition and symptoms may consist of several underlying, opposed associations that depend on the class and severity of symptoms. Linear models recovered differing associations between general cognition and mental health symptoms, depending on the range of symptom severities queried. Nonlinear models confirm that internalizing symptoms were significantly positively associated with cognition at low symptom burdens higher cognition = more symptoms) and significantly negatively associated with cognition at high symptom burdens., Conclusions and Relevance: The association between mental health symptoms and general cognition in this study was nonlinear. Internalizing symptoms were both positively and negatively associated with general cognition at a significant level, depending on the range of symptom severities queried in the analysis sample. These results appear to reconcile mixed findings in prior studies, which implicitly assume that symptom severity tracks linearly with cognitive ability across the entire spectrum of mental health. As the association between cognition and symptoms may be opposite in low vs high symptom severity samples, these results reveal the necessity of clinical enrichment in studies of cognitive impairment.

Although the lifetime burden due to major depressive disorder is increasing, we lack tools for selecting the most effective treatments for each patient. One-third to one-half of patients with major depressive disorder do not respond to treatment, and we lack strategies for selecting among available treatments or expediting access to new treatment options. This critical review concentrates on functional neuroimaging as a modality of measurement for precision psychiatry. We begin by summarizing the current landscape of how functional neuroimaging-derived circuit predictors can forecast treatment outcomes in depression. Then, we outline the opportunities and challenges in integrating circuit predictors into clinical practice. We highlight one standardized and reproducible approach for quantifying brain circuit function at an individual level, which could serve as a model for clinical translation. We conclude by evaluating the prospects and practicality of employing neuroimaging tools, such as the one that we propose, in routine clinical practice., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Mechanistically targeted behavioral interventions are a much-needed strategy for improving outcomes in depression, especially for vulnerable populations with comorbidities such as obesity. Such interventions may change behavior and outcome by changing underlying neural circuit function. However, it is unknown how these circuit-level modifications unfold over intervention and how individual differences in early circuit-level modifications may explain the heterogeneity of treatment effects. We addressed this need within a clinical trial of problem-solving therapy for participants with depression symptoms and comorbid obesity, focusing on the cognitive control circuit as a putative neural mechanism of action. Functional magnetic resonance imaging was applied to measure the cognitive control circuit activity at five time points over 24 months. Compared with participants who received usual care, those receiving problem-solving therapy showed that attenuations in cognitive control circuit activity were associated with enhanced problem-solving ability, which suggests that this circuit plays a key role in the mechanisms of problem-solving therapy. Attenuations in circuit activity were also associated with improved depression symptoms. Changes in cognitive control circuit activity at 2 months better predicted changes in problem-solving ability and depression symptoms at 6, 12, and 24 months, with predictive improvements ranging from 17.8 to 104.0%, exceeding baseline demographic and symptom characteristics. Our findings suggest that targeting the circuit mechanism of action could enhance the prediction of treatment outcomes, warranting future model refinement and improvement to pave the way for its clinical application.

There is an urgent need to derive quantitative measures based on coherent neurobiological dysfunctions or 'biotypes' to enable stratification of patients with depression and anxiety. We used task-free and task-evoked data from a standardized functional magnetic resonance imaging protocol conducted across multiple studies in patients with depression and anxiety when treatment free (n = 801) and after randomization to pharmacotherapy or behavioral therapy (n = 250). From these patients, we derived personalized and interpretable scores of brain circuit dysfunction grounded in a theoretical taxonomy. Participants were subdivided into six biotypes defined by distinct profiles of intrinsic task-free functional connectivity within the default mode, salience and frontoparietal attention circuits, and of activation and connectivity within frontal and subcortical regions elicited by emotional and cognitive tasks. The six biotypes showed consistency with our theoretical taxonomy and were distinguished by symptoms, behavioral performance on general and emotional cognitive computerized tests, and response to pharmacotherapy as well as behavioral therapy. Our results provide a new, theory-driven, clinically validated and interpretable quantitative method to parse the biological heterogeneity of depression and anxiety. Thus, they represent a promising approach to advance precision clinical care in psychiatry., (© 2024. The Author(s).)

The brain's default mode network (DMN) and the executive control network (ECN) switch engagement are influenced by the ventral attention network (VAN). Alterations in resting-state functional connectivity (RSFC) within this so-called triple network have been demonstrated in patients with major depressive disorder (MDD) or anxiety disorders (ADs). This study investigated alterations in the RSFC in patients with comorbid MDD and ADs to better understand the pathophysiology of this prevalent group of patients. Sixty-eight participants (52.9% male, mean age 35.3 years), consisting of 25 patients with comorbid MDD and ADs (MDD + AD), 20 patients with MDD only (MDD) and 23 healthy controls (HCs) were investigated clinically and with 3T resting-state fMRI. RSFC utilizing a seed-based approach within the three networks belonging to the triple network was compared between the groups. Compared with HC, MDD + AD showed significantly reduced RSFC between the ECN and the VAN, the DMN and the VAN and within the ECN. No differences could be found for the MDD group compared with both other groups. Furthermore, symptom severity and medication status did not affect RSFC values. The results of this study show a distinct set of alterations of RSFC for patients with comorbid MDD and AD compared with HCs. This set of dysfunctions might be related to less adequate switching between the DMN and the ECN as well as poorer functioning of the ECN. This might contribute to additional difficulties in engaging and utilizing consciously controlled emotional regulation strategies., (© 2024 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Significance: Spontaneous closure of an idiopathic full-thickness macular hole (FTMH) is a rare event. The underlying mechanisms are unclear because of the difficulty in detecting subtle structural changes even with serial imaging. Previous reports are largely optical coherence tomography (OCT) based, but multimodal imaging could highlight new information., Purpose: This study aimed to report the spontaneous closure of an idiopathic FTMH (iFTMH) and its recurrence and late closure documented by serial OCT integrated with multimodal imaging modalities and microperimetry (MP)., Case Report: A healthy 46-year-old man was referred to the Department of Ophthalmology of the University of Padova for an iFTMH in the right eye with preserved visual acuity. The patient was scheduled for monthly controls up to 12 months by an integrated assessment of OCT, angiography-OCT, short-wavelength fundus autofluorescence, and MP. Two months later, tracked OCT scans showed a closure of the hole with a residual lamellar macular hole. Sequential examinations revealed a discontinuation of photoreceptors (ellipsoid zone) and a recurrence of iFTMH, and 7 months later, iFTMH reclosed without any relevant changes up to 12 months. Foveal avascular zone area increased from the baseline reaching its maximum value when iFTMH recurred. Two hyper-fundus autofluorescence points were detected in the foveal area, one progressively decreased and one reached the most intense signal when iFTMH recurred. Retinal sensitivity decreased mostly in one hyper-fundus autofluorescence point when the ellipsoid zone line discontinued and reached the lowest value when iFTMH recurred, and increased mostly in the other points when iFTMH reclosed., Conclusions: Spontaneous iFTMH closure, as well as its recurrence and reclosure, is a rare event. By monitoring with multiple imaging modalities, MP and their overlaying elaboration can add new biomarkers with diagnostic and prognostic value., Competing Interests: Conflict of Interest Disclosure: None of the authors have reported a financial conflict of interest., (Copyright © 2023 American Academy of Optometry.)

Importance: Cognitive deficits in depression have been associated with poor functional capacity, frontal neural circuit dysfunction, and worse response to conventional antidepressants. However, it is not known whether these impairments combine together to identify a specific cognitive subgroup (or "biotype") of individuals with major depressive disorder (MDD), and the extent to which these impairments mediate antidepressant outcomes., Objective: To undertake a systematic test of the validity of a proposed cognitive biotype of MDD across neural circuit, symptom, social occupational function, and treatment outcome modalities., Design, Setting, and Participants: This secondary analysis of a randomized clinical trial implemented data-driven clustering in findings from the International Study to Predict Optimized Treatment in Depression, a pragmatic biomarker trial in which patients with MDD were randomized in a 1:1:1 ratio to antidepressant treatment with escitalopram, sertraline, or venlafaxine extended-release and assessed at baseline and 8 weeks on multimodal outcomes between December 1, 2008, and September 30, 2013. Eligible patients were medication-free outpatients with nonpsychotic MDD in at least the moderate range, and were recruited from 17 clinical and academic practices; a subset of these patients underwent functional magnetic resonance imaging. This prespecified secondary analysis was performed between June 10, 2022, and April 21, 2023., Main Outcomes and Measures: Pretreatment and posttreatment behavioral measures of cognitive performance across 9 domains, depression symptoms assessed using 2 standard depression scales, and psychosocial function assessed using the Social and Occupational Functioning Assessment Scale and World Health Organization Quality of Life scale were analyzed. Neural circuit function engaged during a cognitive control task was measured using functional magnetic resonance imaging., Results: A total of 1008 patients (571 [56.6%] female; mean [SD] age, 37.8 [12.6] years) participated in the overall trial and 96 patients participated in the imaging substudy (45 [46.7%] female; mean [SD] age, 34.5 [13.5] years). Cluster analysis identified what may be referred to as a cognitive biotype of 27% of depressed patients with prominent behavioral impairment in executive function and response inhibition domains of cognitive control. This biotype was characterized by a specific profile of pretreatment depressive symptoms, worse psychosocial functioning (d = -0.25; 95% CI, -0.39 to -0.11; P < .001), and reduced activation of the cognitive control circuit (right dorsolateral prefrontal cortex: d = -0.78; 95% CI, -1.28 to -0.27; P = .003). Remission was comparatively lower in the cognitive biotype positive subgroup (73 of 188 [38.8%] vs 250 of 524 [47.7%]; P = .04) and cognitive impairments persisted regardless of symptom change (executive function: ηp2 = 0.241; P < .001; response inhibition: ηp2 = 0.750; P < .001). The extent of symptom and functional change was specifically mediated by change in cognition but not the reverse., Conclusions and Relevance: Our findings suggest the presence of a cognitive biotype of depression with distinct neural correlates, and a functional clinical profile that responds poorly to standard antidepressants and instead may benefit from therapies specifically targeting cognitive dysfunction., Trial Registration: ClinicalTrials.gov Identifier: NCT00693849.

Canonical correlation analysis (CCA) is a technique for measuring the association between two multivariate data matrices. A regularized modification of canonical correlation analysis (RCCA) which imposes an ℓ 2 penalty on the CCA coefficients is widely used in applications with high-dimensional data. One limitation of such regularization is that it ignores any data structure, treating all the features equally, which can be ill-suited for some applications. In this article we introduce several approaches to regularizing CCA that take the underlying data structure into account. In particular, the proposed group regularized canonical correlation analysis (GRCCA) is useful when the variables are correlated in groups. We illustrate some computational strategies to avoid excessive computations with regularized CCA in high dimensions. We demonstrate the application of these methods in our motivating application from neuroscience, as well as in a small simulation example., Competing Interests: Declaration of conflicting interests The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

The pathophysiology of bipolar disorder (BD) remains mostly unclear. Yet, a valid biomarker is necessary to improve upon the early detection of this serious disorder. Patients with manifest BD display reduced volumes of the hippocampal subfields and amygdala nuclei. In this pre-registered analysis, we used structural MRI ( n = 271, 7 sites) to compare volumes of hippocampus, amygdala and their subfields/nuclei between help-seeking subjects divided into risk groups for BD as estimated by BPSS-P, BARS and EPI bipolar . We performed between-group comparisons using linear mixed effects models for all three risk assessment tools. Additionally, we aimed to differentiate the risk groups using a linear support vector machine. We found no significant volume differences between the risk groups for all limbic structures during the main analysis. However, the SVM could still classify subjects at risk according to BPSS-P criteria with a balanced accuracy of 66.90% (95% CI 59.2-74.6) for 10-fold cross-validation and 61.9% (95% CI 52.0-71.9) for leave-one-site-out. Structural alterations of the hippocampus and amygdala may not be as pronounced in young people at risk; nonetheless, machine learning can predict the estimated risk for BD above chance. This suggests that neural changes may not merely be a consequence of BD and may have prognostic clinical value.

Objectives: To evaluate the macular vascular flow in eyes with idiopathic macular pucker (Eye iMP ), pre and post pars plana vitrectomy with epiretinal and limiting membranes peeling, and to compare it with the vascular flow in the healthy fellow eyes (Eye fellow ), taken as physiological reference value., Methods: 40 eyes of 40 patients were recruited. Best-corrected visual acuity (BCVA) was evaluated. Spectral domain optical coherence tomography (SD-OCT) and OCT-angiography parameters were central foveal thickness (CFT), choroidal thickness (CT), foveal avascular zone (FAZ) area, vessel area density (VAD), vessel length fraction (VLF), vessel density index (VDI) of superficial capillary plexus (SCP) and deep vascular complex (DVC), choriocapillaris (CC) flow. Absolute and relative difference calculation was applied to evaluate macular vascular flow in Eye iMP adjusted for physiological changes detected in Eye fellow ., Follow-Up: 6 months., Results: BCVA improved (p = 0.003) in all cases following surgery. CFT reduced postoperatively (p = 0.0138). FAZ area was smaller in Eye iMP than Eye fellow (p = 0.0071) preoperatively and postoperatively it shrank further (p = 0.0027). After surgery, inverse correlation between FAZ area and BCVA was detected (r-0.683). VAD of SCP was pre- and post-operatively higher in Eye iMP than Eye fellow (baseline p = 0.0344, 6th month p = 0.0466). Relative difference of VDI of SCP (p = 0.0096) and CC flow (p = 0.0013) at 6 months reduced. DVC flow changed significantly only in Eye fellow . CT increased post-operatively in both Eyei MP (p = 0.0345) and Eye fellow (p = 0.00423), but relative difference did not change., Conclusions: Vascular flow indices monitoring demonstrated significant changes in both eyes: Eye iMP and Eye fellow . Relative difference of vascular flow provided objective estimate of changes due to iMP surgery taking into account physiological changes in Eye fellow ., (© 2022. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Surgical correction of traumatic aniridia aims to improve the quality of vision, compartmentalize the anterior and posterior chamber, and re-establish a satisfying cosmetic appearance. Various types of prosthetic iris devices (PIDs) are available, which differ in technical difficulty of implant and design: artificial iris (AI)-intraocular lens prosthesis, endocapsular capsular tension ring-based PID, and customized AI. The choice depends on the preexisting clinical condition after severe ocular trauma and on patient functional and cosmetic expectations. This systematic review of the literature compared anatomical and functional outcomes of various types of PIDs. Of 185 articles found in the literature, 70 fulfilled the eligibility criteria. 5 subgroups of PIDs were Ophtec, artificial iris from Ophtec BV, Morcher GmbH, HumanOptics AG, and other prosthesis. Both glare and aesthetic outcome improved postoperatively; in comparison with other PIDs, intraocular pressure rise was higher in the Morcher group (40%), whereas prosthesis dislocation was higher in the Ophtec group (39%)., (Copyright © 2023 Published by Wolters Kluwer on behalf of ASCRS and ESCRS.)

The oral cavity contains distinct microenvironments that serve as oral barriers, such as the non-shedding surface of the teeth (e.g., enamel), the epithelial mucosa and gingival tissue (attached gingiva) where microbial communities coexist. The interactions and balances between these communities are responsible for oral tissue homeostasis or dysbiosis, that ultimately dictate health or disease. Disruption of this equilibrium can lead to chronic inflammation and permanent tissue damage in the case of chronic periodontitis. There are currently no experimental tissue models able to mimic the structural, physical, and metabolic conditions present in the human oral gingival tissue to support the long-term investigation of host-pathogens imbalances. Herein, the authors report an in vitro 3D anatomical gingival tissue model, fabricated from silk biopolymer by casting a replica mold of an adult human mandibular gingiva to recreate a tooth-gum unit. The model is based on human primary cultures that recapitulate physiological tissue organization, as well as a native oxygen gradient within the gingival pocket to support human subgingival plaque microbiome with a physiologically relevant level of microbial diversity up to 24 h. The modulation of inflammatory markers in the presence of oral microbiome indicates the humanized functional response of this model and establishes a new set of tools to investigate host-pathogen imbalances in gingivitis and periodontal diseases., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Background: To evaluate the incidence and risk factors for cystoid macular edema (CME) and epiretinal membrane (ERM) development after surgery for primary rhegmatogenous retinal detachment (RRD)., Methods: Retrospective observational cohort study involving 62 consecutive patients with primary RRD who underwent RRD repair with either scleral buckling (SB) or pars plana vitrectomy (PPV). SB was used in young phakic patients without posterior vitreous detachment (PVD), high myopic patients, and RRD associated with either anterior or inferior retinal tears. PPV was preferred over SB in pseudophakic patients or those with media opacity and posterior breaks that precluded the SB approach. After surgery, the macular changes, including CME and ERM development, were evaluated 3 and 6 months postoperatively. Phacoemulsification and intraocular lens (IOL) implantation were performed in phakic patients where media opacity or lens bulging did not allow the surgeon to perform surgical maneuvers. The inner limiting membrane (ILM) peeling was randomly performed in the macula-off and the macula-on RRD "pending foveal detachment" subgroup., Results: Sixty-two eyes affected by RRD who underwent SB or PPV were enrolled. CME occurred in 33.3% of the PPV group regardless of the ERM formation. No CME cases were found in the SB group. Macula-off RRD increased the risk of CME by odds ratio (OR) = 4.3 times compared to macula-on RRD regardless of the surgical procedure (p = 0.04). Macula-off status increased the risk of CME of OR = 1.73 times compared to macula-on in the PPV subgroup (p = 0.4). Combined cataract surgery and PPV increased the risk of CME by OR = 3.3 times (p = 0.16) compared to PPV alone, and ILM peeling increased the risk of postoperative CME by OR = 1.8 times (p = 0.37). ERM occurred in 28% of patients who did not undergo ILM peeling, and 29.42% of those who underwent ILM peeling developed ERM (p = 0.6)., Conclusions: The risk of postoperative CME was higher in patients with macula-off than in macula-on RRD and in those with macula-off RRD who underwent PPV. The SB would be advisable in patients with RRD sparing the macula. Furthermore, despite having several advantages, the combined phacoemulsification plus IOL implantation and PPV highly increased the risk of postoperative CME., (© 2023. The Author(s).)

Objectives: Major Depression (MDD) and anxiety disorders are stress-related disorders that share pathophysiological mechanisms. There is evidence for alterations of glutamate-glutamine, N-acetylaspartate (NAA) and GABA in the anterior cingulate cortex (ACC), a stress-sensitive region affected by hypothalamic-pituitary-adrenal axis (HPA). The aim was to investigate metabolic alterations in the ACC and whether hair cortisol, current stress or early life adversity predict them., Methods: We investigated 22 patients with MDD and comorbid anxiety disorder and 23 healthy controls. Proton magnetic resonance spectroscopy was performed with voxels placed in pregenual (pg) and dorsal (d) ACC in 3 T. Analysis of hair cortisol was performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS)., Results: The N-acetylaspartate/Creatin ratio (NAA/Cr) was reduced in patients in both pgACC ( p  = .040) and dACC ( p  = .016). A significant interactive effect of diagnosis and cortisol on both pg-NAA/Cr (F = 5.00, p  = .033) and d-NAA/Cr (F = 7.86, p  = .009) was detected, whereby in controls cortisol was positively correlated with d-NAA/Cr (r = 0.61, p  = .004)., Conclusions: Our results suggest a relationship between NAA metabolism in ACC and HPA axis activity as represented by long-term cortisol output.

The development of fast, non-destructive, and green methods with adequate sensitivity for saffron authentication has important implications in the quality control of the entire production chain of this precious spice. In this context, the highly suitable sensitivity of a spectroscopic method coupled with chemometrics was verified. A total number of 334 samples were analyzed using attenuated-total-reflectance Fourier-transform infrared (ATR-FTIR) spectroscopy; the collected spectra were processed by partial-least-squares discriminant analysis (PLS-DA) to evaluate the feasibility of this study for the discrimination between compliant saffron (fresh samples produced in 2020) and saffron samples adulterated with non-fresh stigmas produced in 2018 and 2016. PLS-DA was able to classify the saffron samples in accordance with the aging time and to discriminate fresh samples from the samples adulterated with non-fresh (legally expired) stigmas, achieving 100% of both sensitivity and specificity in external prediction. Moreover, PLS regression was able to predict the adulteration level with sufficient accuracy (the root-mean-square error of prediction was approximately 3-5%). In summary, ATR-FTIR and chemometrics can be employed to highlight the illegal blending of fresh saffron with unsold stocks of expired saffron, which may be a common fraudulent practice not yet considered in the scientific literature., Competing Interests: The authors declare no conflict of interest.

Purpose: Outcomes of pneumatic retinopexy (PnR) using surgical microscope, wide-angle viewing system, and chandelier endoilluminator (microscope-assisted pneumatic retinopexy) for primary rhegmatogenous retinal detachment (RRD)., Methods: Retrospective study. 43 consecutive eyes with RRD undergoing microscope-assisted PnR surgery (MAPR) were analysed. Inclusion criteria comprehend phakic eyes with single retinal break or a group of breaks in detached retina in the same quadrant above 8- and 4-o'clock meridians. Follow-up was at least 6 months., Results: Of the 43 eyes, a total of 25 (58%) presented preoperatively a single retinal break, 15 (35%) had two retinal breaks in the same quadrant and 3 (7%) presented three or more retinal breaks in the same quadrant. Other retinal breaks not observed preoperatively were discovered intraoperatively in 12 eyes (28%). In 9 (21%) the missed retinal breaks were in the same quadrant as the main diagnosed break(s), while 3 (7%) had missed retinal breaks in a different one. These 3 eyes as no longer adhering to the PnR indication criteria switched intraoperatively to other surgical procedures and were excluded in the reattachment rate results. The total primary reattachment rate with MAPR was achieved in 37 eyes (92.5%). No significant BCVA changes were observed postoperatively., Conclusion: MAPR is an effective and safe surgical option, it allows to work with both hands free and provides an adequate visualization of the retina during the procedure minimizing the risk of missed retinal breaks potentially leading to surgical failure.

Purpose: To analyse morpho-functional foveal changes in eyes with lamellar macular hole (LMH) by an integrated assessment of short-wavelength fundus autofluorescence (SW-FAF) and microperimetry (SW-FAF/microperimetry integrated assessment) before and after treatment with a technique of double-inverted flaps of epiretinal proliferation (EP) and internal limiting membrane (ILM)., Methods: Clinical and tomographic parameters were best-corrected visual acuity (BCVA), LMH size, central retinal thickness (CRT) and outer retinal layer integrity. SW-FAF/microperimetry integrated assessment allowed to analyse retinal sensitivity (RS) and FAF status of the fovea by an overlay of RS map on SW-FAF image. Follow-up was at baseline, 1, 3, 6 and 12 postoperative months., Results: Forty pseudophakic eyes. Hyper-FAF area was associated with larger LMH size (p = 0.0073) and inversely correlated with CRT (p = 0.021). Lower preoperative RS was observed in hyper-FAF than normo-FAF areas (p = 0.0117). External limiting membrane (ELM) defect was associated with worse BCVA (p = 0.0004). After surgery, BCVA improved (p = 0.001) and it was related to ELM recovery (p = 0.00483), hyper-FAF area decreased (p = 0.001), and RS increased (p = 0.440). Hyper-FAF points that normalized their FAF were associated with higher RS improvement compared to unchanged points., Conclusion: Short-wavelength fundus autofluorescence/microperimetry integrated assessment provides important information on the entity of damage of LMH and on postoperative recovery. Double-inverted EP and ILM flap technique is safe and effective for LMH treatment., (© 2021 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

This review aims to collect the proposed surgical techniques for treating full thickness macular hole (FTMH) refractory to pars plana vitrectomy and internal limiting membrane (ILM) peeling and to analyse and compare anatomical and functional outcomes in order to evaluate their efficacy. The articles were grouped according to the surgical techniques used. Refractory FTMH closure rate and best-corrected visual acuity (BCVA) gain were the two analysed parameters. Thirty-six articles were selected. Ten surgical technique subgroups were defined: autologous platelet concentrate (APC); lens capsular flap transplantation (LCFT); autologous free ILM flap transplantation (free ILM flap); enlargement of ILM peeling, macular hole hydrodissection (MHH), autologous retinal graft (ARG), silicon oil (SO), human amniotic membrane (hAM), perifoveal relaxing retinotomy, arcuate temporal retinotomy. Refractory FTMH closure rate was similar among subgroups, not significant heterogeneity emerged (p = 0.176). BCVA gain showed a significant dependence on surgical technique (p < 0.0001), significant heterogeneity among subgroups emerged (p < 0.0001). Three sets of surgical technique subgroups with a homogeneous BCVA gain were defined: high BCVA gain (hAM); intermediate BCVA gain (APC, ARG, LCFT, MHH, SO); low BCVA gain (free ILM flap, enlargement of peeling, arcuate temporal retinotomy). In terms of visual recovery, the most efficient technique for treating refractory FTMH is hAM, lens capsular flap and APC that allow to obtain better functional outcomes than free ILM flap. MHH, ARG, perifoveal relaxing and arcuate temporal retinotomy require complex and unjustified surgical manoeuvres in view of the surgical alternatives with overlapping anatomical and functional results., (© 2020. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Background: Several studies in major depressive disorder (MDD) have found inflammation, especially C-reactive protein (CRP), to be consistently associated with MDD and network dysfunction. The aim was to investigate whether CRP is linked to a distinct set of resting-state functional connectivity (RSFC) alterations., Methods: For this reason, we investigated the effects of diagnosis and elevated blood plasma CRP levels on the RSFC in 63 participants (40 females, mean age 31.4 years) of which were 27 patients with a primary diagnosis of MDD and 36 healthy control-subjects (HC), utilizing a seed-based approach within five well-established RSFC networks obtained using fMRI., Results: Of the ten network pairs examined, five showed increased between-network RSFC-values unambiguously connected either to a diagnosis of MDD or elevated CRP levels. For elevated CRP levels, increased RSFC between DMN and AN was found. Patients showed increased RSFC within DMN areas and between the DMN and ECN and VAN, ECN and AN and AN and DAN., Conclusions: The results of this study show dysregulated neural circuits specifically connected to elevated plasma CRP levels and independent of other alterations of RSFC in MDD. This dysfunction in neural circuits might in turn result in a certain immune-inflammatory subtype of MDD., (Copyright © 2022. Published by Elsevier B.V.)

In this paper we provide an overview of the rationale, methods, and preliminary results of the four Connectome Studies Related to Human Disease investigating mood and anxiety disorders. The first study, "Dimensional connectomics of anxious misery" (HCP-DAM), characterizes brain-symptom relations of a transdiagnostic sample of anxious misery disorders. The second study, "Human connectome Project for disordered emotional states" (HCP-DES), tests a hypothesis-driven model of brain circuit dysfunction in a sample of untreated young adults with symptoms of depression and anxiety. The third study, "Perturbation of the treatment resistant depression connectome by fast-acting therapies" (HCP-MDD), quantifies alterations of the structural and functional connectome as a result of three fast-acting interventions: electroconvulsive therapy, serial ketamine therapy, and total sleep deprivation. Finally, the fourth study, "Connectomes related to anxiety and depression in adolescents" (HCP-ADA), investigates developmental trajectories of subtypes of anxiety and depression in adolescence. The four projects use comparable and standardized Human Connectome Project magnetic resonance imaging (MRI) protocols, including structural MRI, diffusion-weighted MRI, and both task and resting state functional MRI. All four projects also conducted comprehensive and convergent clinical and neuropsychological assessments, including (but not limited to) demographic information, clinical diagnoses, symptoms of mood and anxiety disorders, negative and positive affect, cognitive function, and exposure to early life stress. The first round of analyses conducted in the four projects offered novel methods to investigate relations between functional connectomes and self-reports in large datasets, identified new functional correlates of symptoms of mood and anxiety disorders, characterized the trajectory of connectome-symptom profiles over time, and quantified the impact of novel treatments on aberrant connectivity. Taken together, the data obtained and reported by the four Connectome Studies Related to Human Disease investigating mood and anxiety disorders describe a rich constellation of convergent biological, clinical, and behavioral phenotypes that span the peak ages for the onset of emotional disorders. These data are being prepared for open sharing with the scientific community following screens for quality by the Connectome Coordinating Facility (CCF). The CCF also plans to release data from all projects that have been pre-processed using identical state-of-the-art pipelines. The resultant dataset will give researchers the opportunity to pool complementary data across the four projects to study circuit dysfunctions that may underlie mood and anxiety disorders, to map cohesive relations among circuits and symptoms, and to probe how these relations change as a function of age and acute interventions. This large and combined dataset may also be ideal for using data-driven analytic approaches to inform neurobiological targets for future clinical trials and interventions focused on clinical or behavioral outcomes., Competing Interests: Declarations of Competing Interest The Authors have no conflicts of interest to declare., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Although the COVID-19 pandemic has been shown to worsen anxiety and depression symptoms, we do not understand which behavioral and neural factors may mitigate this impact. To address this gap, we assessed whether adaptive and maladaptive coping strategies affect symptom trajectory during the pandemic. We also examined whether pre-pandemic integrity of brain regions implicated in depression and anxiety affect pandemic symptoms., Methods: In a naturalistic sample of 169 adults (66.9% female; age 19-74 years) spanning psychiatric diagnoses and subclinical symptoms, we assessed anhedonia, tension, and anxious arousal symptoms using validated components (21-item Depression, Anxiety, and Stress Scale), coping strategies (Brief-Coping Orientation to Problems Experienced), and gray matter volume (amygdala) and cortical thickness (hippocampus, insula, anterior cingulate cortex) from magnetic resonance imaging T1-weighted scans. We conducted general linear mixed-effects models to test preregistered hypotheses that 1) maladaptive coping pre-pandemic and 2) lower structural integrity pre-pandemic would predict more severe pandemic symptoms; and 3) coping would interact with neural structure to predict pandemic symptoms., Results: Greater use of maladaptive coping strategies was associated with more severe anxious arousal symptoms during the pandemic ( p  = .011, false discovery rate-corrected p [ p FDR ] = .035), specifically less self-distraction ( p  = .014, p FDR  = .042) and greater self-blame ( p  = .002, p FDR  = .012). Reduced insula thickness pre-pandemic predicted more severe anxious arousal symptoms ( p  = .001, p FDR  = .027). Self-distraction interacted with amygdala volume to predict anhedonia symptoms ( p  = .005, p FDR  = .020)., Conclusions: Maladaptive coping strategies and structural variation in brain regions may influence clinical symptoms during a prolonged stressful event (e.g., COVID-19 pandemic). Future studies that identify behavioral and neural factors implicated in responses to global health crises are warranted for fostering resilience., (© 2021 The Authors.)

Traumatic brain injury (TBI) is a leading cause of death and disability with no specific effective therapy, in part because disease driving mechanisms remain to be elucidated. Receptor interacting protein kinases (RIPKs) are serine/threonine kinases that assemble multi-molecular complexes that induce apoptosis, necroptosis, inflammasome and nuclear factor kappa B activation. Prior studies using pharmacological inhibitors implicated necroptosis in the pathogenesis of TBI and stroke, but these studies cannot be used to conclusively demonstrate a role for necroptosis because of the possibility of off target effects. Using a model of cerebral contusion and RIPK3 and mixed lineage kinase like knockout (MLKL -/- ) mice, we found evidence for activation of RIPK3 and MLKL and assembly of a RIPK1-RIPK3-MLKL necrosome complex in pericontusional brain tissue. Phosphorylated forms of RIPK3 and MLKL were detected in endothelium, CD11b + immune cells, and neurons, and RIPK3 was upregulated and activated in three-dimensional human endothelial cell cultures subjected to CCI. RIPK3 -/- and MLKL -/- mice had reduced blood-brain barrier damage at 24 h (p < 0.05), but no differences in neuronal death (6 h, p = ns in CA1, CA3 and DG), brain edema (24 h, p = ns), or lesion size (4 weeks, p = ns) after CCI. RIPK3 -/- , but not MLKL -/- mice, were protected against postinjury motor and cognitive deficits at 1-4 weeks (RIPK3 -/- vs WT: p < 0.05 for group in wire grip, Morris water maze hidden platform trials, p < 0.05 for novel object recognition test, p < 0.01 for rotarod test). RIPK3 -/- mice had reduced infiltrating leukocytes (p < 0.05 vs WT in CD11b + cells, microglia and macrophages), HMGB1 release and interleukin-1 beta activation at 24-48 h (p < 0.01) after CCI. Our data indicate that RIPK3 contributes to functional outcome after cerebral contusion by mechanisms involving inflammation but independent of necroptosis., (© 2021. The Author(s).)

The goal of our study was to use functional connectivity to map brain function to self-reports of negative emotion. In a large dataset of healthy individuals derived from the Human Connectome Project (N = 652), first we quantified functional connectivity during a negative face-matching task to isolate patterns induced by emotional stimuli. Then, we did the same in a complementary task-free resting state condition. To identify the relationship between functional connectivity in these two conditions and self-reports of negative emotion, we introduce group regularized canonical correlation analysis (GRCCA), a novel algorithm extending canonical correlations analysis to model the shared common properties of functional connectivity within established brain networks. To minimize overfitting, we optimized the regularization parameters of GRCCA using cross-validation and tested the significance of our results in a held-out portion of the data set using permutations. GRCCA consistently outperformed plain regularized canonical correlation analysis. The only canonical correlation that generalized to the held-out test set was based on resting state data (r = 0.175, permutation test p = 0.021). This canonical correlation loaded primarily on Anger-aggression. It showed high loadings in the cingulate, orbitofrontal, superior parietal, auditory and visual cortices, as well as in the insula. Subcortically, we observed high loadings in the globus pallidus. Regarding brain networks, it loaded primarily on the primary visual, orbito-affective and ventral multimodal networks. Here, we present the first neuroimaging application of GRCCA, a novel algorithm for regularized canonical correlation analyses that takes into account grouping of the variables during the regularization scheme. Using GRCCA, we demonstrate that functional connections involving the visual, orbito-affective and multimodal networks are promising targets for investigating functional correlates of subjective anger and aggression. Crucially, our approach and findings also highlight the need of cross-validation, regularization and testing on held out data for correlational neuroimaging studies to avoid inflated effects., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2021. Published by Elsevier Inc.)