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Optical coherence tomography with voxel-based morphometry: a new tool to unveil focal retinal neurodegeneration in multiple sclerosis
AbstractNeurodegeneration is the main contributor to disability accumulation in multiple sclerosis. Previous studies in neuro-ophthalmology have revealed that neurodegeneration in multiple sclerosis also affects the neuro-retina. Optical coherence tomography has been used to measure thinning of retinal layers, which correlates with several other markers for axonal/neuronal loss in multiple sclerosis. However, the existing analytical tools have limitations in terms of sensitivity and do not provide topographical information. In this study, we aim to evaluate whether voxel-based morphometry can increase sensitivity in detecting neuroaxonal degeneration in the retina and offer topographical information. A total of 131 people with multiple sclerosis (41 clinically isolated syndrome, 53 relapsing-remitting and 37 progressive multiple sclerosis) and 50 healthy subjects were included. Only eyes with normal global peripapillary retinal nerve fibre layer thickness and no history of optic neuritis were considered. Voxel-based morphometry and voxel-wise statistical comparisons were performed on the following: (i) patients at different disease stages and 2) patients who experienced the first demyelination attack without subclinical optic neuritis, assessed by visual evoked potentials. Standard parameters failed to discern any differences; however, voxel-based morphometry–optical coherence tomography successfully detected focal macular atrophy of retinal nerve fibre layer and ganglion cell/inner plexiform layer, along with thickening of inner nuclear layer in patients who experienced the first demyelination attack (disease duration = 4.2 months). Notably, the atrophy pattern of the ganglion cell/inner plexiform layer was comparable across disease phenotypes. In contrast, the retinal nerve fibre layer atrophy spread from the optic nerve head to the fovea as the disease evolved towards the progressive phase. Furthermore, for patients who experienced the first neurological episode, the severity of retinal nerve fibre layer atrophy at entry could predict a second attack. Our results demonstrate that voxel-based morphometry–optical coherence tomography exhibits greater sensitivity than standard parameters in detecting focal retinal atrophy, even at clinical presentation, in eyes with no history of optic neuritis and with normal latency of visual evoked potentials. Thinning of the ganglion cell/inner plexiform layer primarily concentrated in nasal perifovea in all disease phenotypes, indicating selective vulnerability of retinal ganglion cells and their perifoveal axons. Conversely, the degree of retinal nerve fibre layer thinning seems to be related to the clinical course of multiple sclerosis. The findings suggest bidirectional neurodegeneration in the visual pathway. Voxel-based morphometry–optical coherence tomography shows potential as a valuable tool for monitoring neurodegeneration on a patient level and evaluating the efficacy of novel neuroprotective treatments.
Anatomy of the superior hypogastric plexus and its relevance to anterior lumbar interbody fusion
OBJECTIVE Retrograde ejaculation (RE) is a known complication of anterior lumbar interbody fusion (ALIF) and results from injury to the superior hypogastric plexus (SHP) during intervertebral disc exposure. Yet, there has been no recommendation for SHP mobilization. Thus, the aim of this study was to describe the anatomy of the SHP and vessels at the L5–S1 level, and to evaluate the possibility of SHP mobilization and its retraction to the side. METHODS Twelve formaldehyde-embalmed cadavers (6 female and 6 male; mean age 65.5 years [range 60–77 years]) were dissected. Distances from the SHP and middle sacral vessels to the midline were measured at the L5–S1 level. The relationship of the great vessel bifurcations and common iliac vessels to the SHP were noted. The extent of lateral retraction of the SHP following mobilization was measured in relation to the midline. Moreover, the positions of the SHP and middle sacral vessels relative to the midline at the L5–S1 level were determined. RESULTS The SHP formed below the aortic bifurcation and was present at the L5–S1 level in all cases. The SHP overlaid the midline with a left-sided shift. There were 4 cases (33.3%) in which lateral retraction was not achievable because the plexus divided into hypogastric nerves at the L5–S1 level or was too wide for safe mobilization. In the remaining cases, retraction on the left side was achievable up to 15.3 mm from the midline, while retraction to the right side was limited to 5.3 mm from the midline. The types of SHP morphological arrangement included single cord (41.7%), plexiform (41.7%), and fiber (16.6%). CONCLUSIONS Based on the more extensive left-sided shift of the SHP at the L5–S1 level and frequent presence of the third left splanchnic lumbar nerve, attempting retraction to the left side is recommended. If it is not feasible, the SHP should be split at the midline, with both components mobilized laterally.
Multimodal gradients unify local and global cortical organization.
Functional specialization of brain areas and subregions, as well as their integration into large-scale networks, are key principles in neuroscience. Consolidating both local and global perspectives on cortical organization, however, remains challenging. Here, we present an approach to integrate inter- and intra-areal similarities of microstructure, structural connectivity, and functional interactions. Using high-field in-vivo 7 tesla (7 T) Magnetic Resonance Imaging (MRI) data and a probabilistic post-mortem atlas of cortical cytoarchitecture, we derive multimodal gradients that capture cortex-wide organization. Inter-areal similarities follow a canonical sensory-fugal gradient, linking cortical integration with functional diversity across tasks. However, intra-areal heterogeneity does not follow this pattern, with greater variability in association cortices. Findings are replicated in an independent 7 T dataset and a 100-subject 3 tesla (3 T) cohort. These results highlight a robust coupling between local arealization and global cortical motifs, advancing our understanding of how specialization and integration shape human brain function.
Approval of retinal gene therapies in the US and Europe based on visual acuity and microperimetry
Introduction: Gene therapy is an emerging technology for the treatment of inherited retinal diseases. Whilst the development of delivery vectors and genotyping is progressing at speed, outcome measures used for regulatory approval are slow to change and hinder progress at clinical trial stage. Traditional measures of visual function such as best corrected visual acuity (BCVA) and low luminance visual acuity (LLVA) may only be useful across a very short window and in late stages of disease. They are unsuitable measures for early- to mid- stage disease where foveal function, and so letter reading, is primarily unaffected. In such cases, microperimetry is an accurate and repeatable measure of retinal function of the whole of the macular region. Areas covered: This article provides evidence-based guidance on criteria for microperimetry outcome measures, drawing on experience from long-term clinical trials in RPGR-related retinitis pigmentosa. Expert opinion: Microperimetry provides a sensitive and repeatable measure of retinal function, with mean sensitivity across the macula or central 16-point region offering a more reliable metric than single-point requirements recommended by the FDA. A 2.5 dB gain in mean sensitivity is equivalent to a 13-letter increase in low-luminance ETDRS representing a clinically significant change and aligning closely with regulatory standards.
Treatment Selection and Prioritization for the EJS ACT-PD MAMS Trial Platform.
BACKGROUND: There are currently no disease-modifying therapies (DMTs) registered for Parkinson's disease (PD). The Edmond J. Safra Accelerating Clinical Trials in Parkinson Disease (EJS ACT-PD) initiative will expedite clinical assessment of putative DMTs through a multi-arm multistage (MAMS) trial, testing several treatments against a common placebo arm and replacing unsuccessful therapies early. OBJECTIVE: The objective of this study was to describe the treatment selection process for the EJS ACT-PD clinical trial platform. METHODS: A Treatment Selection Working Group (TSWG) identified compounds using complementary strategies, such as literature search, related initiatives (Cure Parkinson's International Linked Clinical Trials [iLCT] initiative), and expert suggestions. Compounds were classified into five mechanistic subgroups (mitochondrial, lysosomal, protein, inflammation, "other"). "Go/No-Go" criteria and a scoring system covering preclinical, pharmacological, and clinical evidence were devised. Experts scored the candidates for quantitative rankings. Dossiers adapted from iLCT documents were produced for the top-ranked compounds and in turn prioritized by the TSWG. Practical and logistical considerations from the Steering Committee (SC) guided the final decision. Patient and Public Involvement and Engagement representatives provided feedback throughout the process. RESULTS: A total of 293 interventions were identified, 52 of which passed the "Go/No-Go" criteria and were scored. Dossiers of the 14 top-ranked compounds were submitted to the SC. Telmisartan, terazosin, and ursodeoxycholic acid were selected as the initial interventions. CONCLUSIONS: Drug selection in DMT PD MAMS trials requires consideration of scientific and practical issues. We present a robust system that can inform similar initiatives. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Prevalence Rates of Frequent Dream Recall and Nightmares by Age, Gender and Sleep Duration in 16 Countries.
The present study aimed to describe the prevalence rates of frequent (i.e., at least weekly) dream recall and nightmares with consideration for differences in age, gender and sleep duration in 16 countries using equivalent assessment methods. The study sample included 15,854 participants (69.9% women) aged 18-99 years (M = 42.39, SD = 16.43) collected by the International COVID-19 Sleep Study collaboration, which used a unified online survey to collect data from May to November 2021 across 16 countries. Participants provided demographic information as well as self-reported estimates of their dream recall and nightmare frequency and sleep duration in 2021 and retrospectively for 2019. Frequent dream recall occurred in 54.0% of participants in 2021 and 51.1% in 2019. Frequent nightmares were reported by 11.0% of participants in 2021 and 6.9% in 2019. Ad hoc regression models found dream recall and sleep duration to have a linear relation, whereas nightmare frequency demonstrated a quadratic relation to sleep duration. Frequent dream recall and nightmare prevalence rates are reported for each of the 16 study countries by age, gender and sleep duration. This is the first multi-continent study to estimate frequent dream recall and nightmare prevalence, which both provides updated prevalence rates during the COVID-19 pandemic as well as extends existing knowledge to previously never studied countries.
Sleep During Pandemic Times: Summary of Findings and Future Outlook Through the Lens of the International COVID Sleep Study (ICOSS).
To study the impact of the COVID-19 pandemic on sleep and circadian rhythms-two fundamental pillars for health-the collaboration International COVID-19 Sleep Study (ICOSS) was established. The present overview comprehensively discusses the findings from this collaboration. Involving sleep researchers across the globe, ICOSS used a harmonised questionnaire to cover changes in sleep and sleep disorders, as well as physical and mental health. Two survey waves were conducted, one in 2020 and another one in 2021. In ICOSS-1, a total of 26,539 people from 14 countries across four continents (Europe, Asia, North and South America) participated. In ICOSS-2, two more countries joined ICOSS, and 15,813 people participated. The focus in ICOSS-2 was on Long COVID. Participants accessed the widely disseminated online surveys in their native language. In the 20 papers published so far, the surveys have uncovered several novel findings, including how the pandemic impacted sleep patterns, the prevalence of sleep disorders, chronotype-based differences and sleep-immune system interactions. To the best of our knowledge, there is no other large-scale multinational study targeting the general population investigating the role of sleep and sleep disorders alongside a variety of psychological, biological, social and economic factors during the recent COVID-19 pandemic.
CMV serostatus is associated with improved survival and delayed toxicity onset following anti-PD-1 checkpoint blockade
Abstract Cytomegalovirus (CMV) is a globally endemic latent herpes virus that profoundly impacts T cell immunity. We investigated the oncological consequences of CMV infection across 341 prospectively recruited patients receiving immune checkpoint blockade (ICB) for melanoma. CMV+ patients with metastatic melanoma (MM) have higher lymphocyte counts, reduced neutrophil to lymphocyte ratio and divergent CD8+ T cell gene expression. Combination anti-CTLA-4/anti-PD-1 ICB, but not single-agent anti-PD-1 ICB, induces cytotoxicity and CMV-associated gene expression in CD8+ T cells from CMV− patients. Correspondingly, overall survival was independent of CMV serostatus in combination anti-CTLA-4/anti-PD-1 ICB recipients (CMV+ hazard ratio for death: 1.02, P = 0.92), whereas CMV+ single-agent anti-PD-1 ICB recipients had improved overall survival (CMV+ hazard ratio for death: 0.37, P < 0.01), a finding also seen in CMV+ adjuvant single-agent anti-PD-1 ICB recipients (CMV+ hazard ratio for recurrence: 0.19, P = 0.03). We identify TBX21, encoding T-bet, as a transcriptional driver of CMV-associated CD8+ T cell gene expression, finding that TBX21 expression is predictive of overall survival (hazard ratio: 0.62, P = 0.026). CMV+ patients unexpectedly show reduced cumulative incidence of grade 3+ immune-related adverse events at 6 months (0.30 versus 0.52, P = 2.2 × 10−5), with lower incidence of colitis (P = 7.8 × 10−4) and pneumonitis (P = 0.028), an effect replicated in non-melanoma ICB recipients (n = 58, P = 0.044). Finally, we find reduced CMV seropositivity rates in patients with MM compared with UK Biobank controls (odds ratio: 0.52, P = 1.8 × 10−4), indicating CMV seropositivity may protect against MM. Specifically, patients with BRAF-mutated MM are less likely to be CMV+ (odds ratio = 2.2, P = 0.0054), while CMV− patients present 9 yr earlier with BRAF wild-type MM (P = 1.3 × 10−4). This work reveals an interaction between CMV infection, MM development according to BRAF status and response to ICB, while demonstrating CMV infection is protective against severe ICB immune-related adverse events, highlighting the potential importance of previous infection history and chronic immune activation in MM development and immunotherapy outcomes.
On brain stimulation in epilepsy.
Brain stimulation has, for many decades, been considered as a potential solution for the unmet needs of the many people living with drug-resistant epilepsy. Clinically, there are several different approaches in use, including vagus nerve stimulation, deep brain stimulation of the thalamus, and responsive neurostimulation. Across populations of patients, all deliver reductions in seizure load and sudden unexpected death in epilepsy risk, yet do so variably, and the improvements seem incremental rather than transformative. In contrast, within the field of experimental neuroscience, the transformational impact of optogenetic stimulation is evident; by providing a means to control subsets of neurons in isolation, it has revolutionized our ability to dissect out the functional relations within neuronal microcircuits. It is worth asking, therefore, how preclinical optogenetics research could advance clinical practice in epilepsy? Here, we review the state of the clinical field, and the recent progress in preclinical animal research. We report various breakthrough results, including the development of new models of seizure initiation, its use for seizure prediction, and for fast, closed-loop control of pathological brain rhythms, and what these experiments tell us about epileptic pathophysiology. Finally, we consider how these preclinical research advances may be translated into clinical practice.
The convergence of neuromodulation and brain–computer interfaces
Neuromodulation and brain–computer interfaces are rapidly evolving fields with distinct origins but with the shared goal of improving the lives of people with neurological and psychiatric disorders or injuries. Their increasing technological overlap provides new opportunities for collaborative work and rapid progress in neurotechnology.
Editor's Choice - Effect of Carotid Endarterectomy on 20 Year Incidence of Recorded Dementia: A Randomised Trial.
OBJECTIVE: Stroke and carotid atherosclerosis are associated with dementia. Carotid endarterectomy (CEA) reduces stroke risk, although its effect on later dementia is uncertain. Participants in the Asymptomatic Carotid Surgery Trial (ACST-1), randomly allocated to immediate vs. deferral of CEA (i.e., no intervention unless or until triggered by ipsilateral transient ischaemic attack or stroke), were followed, to study effects on dementia. METHODS: From 1993 to 2003, ACST-1 included 3 120 participants with asymptomatic tight carotid stenosis. All UK and Swedish patients (n = 1 601; 796 immediate vs. 805 deferral) were followed with trial records, national electronic health record linkage, and (UK only) by post and telephone. Cumulative incidence and competing risk analyses were used to measure the effects of risk factors and CEA on dementia risk. Intention to treat analyses yielded hazard ratios (HRs; immediate vs. deferral) of dementia. RESULTS: The median follow up was 19.4 years (interquartile range 16.9 - 21.7). Dementia was recorded in 107 immediate CEA patients and 115 allocated delayed surgery; 1 290 patients died (1 091 [538 vs. 536] before any dementia diagnosis). Dementia incidence rose with age and with female sex (men: 8.3% aged < 70 years at trial entry vs. 15.1% aged ≥ 70; women: 15.1% aged < 70 years at trial entry vs. 22.4% aged ≥ 70 years) and was higher in those with pre-existing cerebral infarction (silent or with prior symptoms; 20.2% vs. 13.6%). Dementia risk was similar in both randomised groups: 6.7% vs. 6.6% at 10 years and 14.3% vs. 15.5% at 20 years, respectively. The dementia HR was 0.98 (95% confidence interval [CI] 0.75 - 1.28; p = .89), with no heterogeneity in the neutral effect of immediate CEA on dementia related to age, carotid stenosis, blood pressure, diabetes, country of residence, or medical treatments at trial entry (heterogeneity values p > .05). CONCLUSION: CEA was not associated with significant reductions in the long term hazards of dementia, but the CI did not exclude a proportional benefit or hazard of about 25%.