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Abstract Objective This study evaluates the performance of the novel MRI sequence stimulus‐induced rotary saturation (SIRS) to map responses to interictal epileptic activity in the human cortex. Spin‐lock pulses have been applied to indirectly detect neuronal activity through magnetic field perturbations. Following initial reports about the feasibility of the method in humans and animals with epilepsy, we aimed to investigate the diagnostic yield of spin‐lock MR pulses in comparison with scalp‐EEG in first seizure patients. Methods We employed a novel method for measurements of neuronal activity through the detection of a resonant oscillating field, stimulus‐induced rotary saturation contrast (SIRS) at spin‐lock frequencies of 120 and 240 Hz acquired at a single 3T MRI system. Within a prospective observational study, we conducted SIRS experiments in 55 patients within 7 days after a suspected first unprovoked epileptic seizure and 61 healthy control subjects. In this study, we report on the analysis of data from a single 3T MRI system, encompassing 35 first seizure patients and 31 controls. Results The SIRS method was applicable in all patients and healthy controls at frequencies of 120 and 240 Hz. We did not observe any significant age‐ or sex‐related differences. Specificity of SIRS at 120 Hz was 90.3% and 93.5% at 240 Hz. Sensitivity was 17.1% at 120 Hz and 40.0% at 240 Hz. Significance SIRS targets neuronal oscillating magnetic fields in patients with epilepsy. The coupling of presaturated spins to epilepsy‐related magnetic field perturbations may serve as a—at this stage experimental—diagnostic test in first seizure patients to complement EEG findings as a standard screening test. Plain Language Summary Routine diagnostic tests carry several limitations when applied after a suspected first seizure. SIRS is a noninvasive MRI method to enable time‐sensitive diagnosis of image correlates of epileptic activity with increased sensitivity compared to routine EEG.

Childhood trauma (CT) often co-occurs with alcohol use disorder (AUD) and is associated with poor treatment outcome. We could demonstrated that patients with AUD and a history of childhood trauma showed reduced structural connectivity of the amygdala. Here, we additionally aimed to investigate fronto-limbic functional connectivity (FC) in patients with AUD with (AUD-CT) and without (AUD-noCT) CT. Based on findings in CT, we hypothesized reduced FC of the amygdala with the prefrontal cortex in AUD-CT and worse treatment outcome compared to AUD-noCT.Resting state fMRI scans were acquired in abstinent inpatients with AUD and healthy controls (HCs). We compared bilateral amygdala FC between AUD-CT (n = 21), AUD-noCT (n = 22), and HC (n = 27) using seed-based connectivity (SBC) and region-of-interest to region-of-interest (ROI-ROI) analysis. Sociodemographic and alcohol-specific variables (percent days abstinent, PDA) were assessed at treatment admission and three-month follow-up. The Childhood Trauma Questionnaire (CTQ) assessed trauma severity. SBC analysis revealed that AUD-CT showed increased FC of the left and right amygdala with the medial prefrontal cortex and left paracingulate gyrus compared to HC. AUD-CT showed increased ROI-ROI FC of the left with the right amygdala and the right amygdala with the medial prefrontal cortex. Moreover, AUD-CT exhibited a greater reduction of PDA at three-month follow-up compared to AUD-noCT.Increased FC of the amygdala, the medial prefrontal cortex, and paracingulate gyrus in AUD-CT might be a compensatory adaption to the reduced structural connectivity of the amygdala. Those specific alterations of FC in AUD-CT may represent a distinguishable neurobiological subtype of AUD, possibly underlying the complex clinical picture and worse treatment outcome.

Background: Numerous studies show that electroconvulsive therapy (ECT) induces hippocampal neuroplasticity, but findings are inconsistent regarding its clinical relevance. This study aims to investigate ECT-induced plasticity of anterior and posterior hippocampi using mathematical complexity measures in neuroimaging, namely Higuchi's fractal dimension (HFD) for fMRI time series and the fractal dimension of cortical morphology (FD-CM). Furthermore, we explore the potential of these complexity measures to predict ECT treatment response. Methods: Twenty patients with a current depressive episode (16 with major depressive disorder and 4 with bipolar disorder) underwent MRI-scans before and after an ECT-series. Twenty healthy controls matched for age and sex were also scanned twice for comparison purposes. Resting-state fMRI data were processed, and HFD was computed for anterior and posterior hippocampi. Group-by-time effects for HFD in anterior and posterior hippocampi were calculated and correlations between HFD changes and improvement in depression severity were examined. For FD-CM analyses, we preprocessed structural MRI with CAT12′s surface-based methods. We explored group-by-time effects for FD-CM and the predictive value of baseline HFD and FD-CM for treatment outcome. Results: Patients exhibited a significant increase in bilateral hippocampal HFD from baseline to follow-up scans. Right anterior hippocampal HFD increase was associated with reductions in depression severity. We found no group differences and group-by-time effects in FD-CM. After applying a whole-brain regression analysis, we found that baseline FD-CM in the left temporal pole predicted reduction of overall depression severity after ECT. Baseline hippocampal HFD did not predict treatment outcome. Conclusion: This study suggests that HFD and FD-CM are promising imaging markers to investigate ECT-induced neuroplasticity associated with treatment response.

Abstract Measles virus (MV) vaccine strains have shown significant preclinical antitumor activity against glioblastoma (GBM), the most lethal glioma histology. In this first in human trial (NCT00390299), a carcinoembryonic antigen-expressing oncolytic measles virus derivative (MV-CEA), was administered in recurrent GBM patients either at the resection cavity (Group A), or, intratumorally on day 1, followed by a second dose administered in the resection cavity after tumor resection on day 5 (Group B). A total of 22 patients received study treatment, 9 in Group A and 13 in Group B. Primary endpoint was safety and toxicity: treatment was well tolerated with no dose-limiting toxicity being observed up to the maximum feasible dose (2×107 TCID50). Median OS, a secondary endpoint, was 11.6 mo and one year survival was 45.5% comparing favorably with contemporary controls. Other secondary endpoints included assessment of viremia, MV replication and shedding, humoral and cellular immune response to the injected virus. A 22 interferon stimulated gene (ISG) diagonal linear discriminate analysis (DLDA) classification algorithm in a post-hoc analysis was found to be inversely (R = −0.6, p = 0.04) correlated with viral replication and tumor microenvironment remodeling including proinflammatory changes and CD8 + T cell infiltration in post treatment samples. This data supports that oncolytic MV derivatives warrant further clinical investigation and that an ISG-based DLDA algorithm can provide the basis for treatment personalization.

Abstract Background Migration is a phenomenon worldwide, with older migrants, particularly those with fewer socioeconomic resources, having an increased risk of developing adverse cognitive and health outcomes and social isolation. Therefore, it is of utmost importance to validate interventions that promote healthy aging in this population. Previous studies have shown a positive impact of mindfulness based-stress reduction (MBSR) on outcomes such as cognition and sleep. However, only a few studies verified its potential in older adults, especially with vulnerable populations such as migrants. This article presents the protocol of the MEDITAGING study, which is the first to investigate the MBSR effects in migrants aged ≥55 in comparison to a health promotion program. Methods MEDITAGING is a two-arm randomized, double-blinded, controlled study, which will include older Portuguese-speaking migrants (n = 90). Participants are randomized to the MBSR or a health promotion program. Both interventions are conducted in groups over a total of 8 weeks, incorporating weekly meetings, an additional 4-hour class, and extra at-home tasks. The health promotion program has the same structure as the MBSR but comprises different activities related to dementia prevention, healthy habits, cognitive stimulation, sleeping, nutrition, watercolor painting, and physical activity. The assessment of executive functioning, physiological stress measures, self-reported questionnaires, and qualitative interviews are conducted at baseline, after 8 weeks (post-intervention), and at a follow-up session (from one to 3 months thereafter). Analyzes will be conducted using a modified intention-to-treat approach (all participants with at least 3 days of participation in the group-sessions and one post-intervention observation). Discussion This study will test effects of a mindfulness-based intervention against an active control condition in older adult migrants, which few studies have addressed. Trial registration ClinicalTrials.gov NCT05615337 (date of registration: 27 September 2022; date of record verification: 14 November 2022).

Sleep disturbances are common in depression, but their neurobiological correlates are poorly understood. Recent evidence suggests links between insula dysfunction and sleep dysregulation. This study aimed to explore the association of sleep quality and structural and functional characteristics of the insula in major depressive disorder (MDD). We included 47 patients with MDD and 15 healthy controls (HC) matched for age and sex. Sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI). Patients were classified into two subgroups with poor sleep (PAT-PS, PSQI > 8) and normal sleep (PAT-NS, PSQI ≤ 8), respectively. MRI-scans were acquired using structural and functional resting-state sequences. We analysed cortical thickness of bilateral insulae and connectivity strength of the insula to the whole brain using intrinsic connectivity. Group differences were assessed with a mixed-model MANCOVA controlling for age and sex. Patients had higher PSQI-scores than HC. PAT-PS (n = 21) and PAT-NS (n = 26) did not differ regarding age, sex and depression severity. Insular cortical thickness was reduced in PAT-PS compared to both HC and PAT-NS. Additionally, PAT-PS had lower insular intrinsic connectivity than HC. In contrast, there were no significant group differences in insular intrinsic connectivity between PAT-NS and HC. Across all subjects, PSQI-total was negatively associated with insular cortical thickness and insular intrinsic connectivity. Insular intrinsic connectivity within patients was negatively associated with depression severity. PSQI-total and depression severity did not correlate significantly. In conclusion, our results demonstrate that sleep disturbances in MDD patients are associated with structural and functional impairments of the insula.

BackgroundHead and neck squamous cell carcinomas (HNSCC) are highly heterogeneous tumors. In the harsh tumor microenvironment (TME), metabolic reprogramming and mitochondrial dysfunction may lead to immunosuppressive phenotypes. Aerobic glycolysis is needed for the activation of cytotoxic T-cells and the absence of glucose may hamper the full effector functions of cytotoxic T-cells. To test the effect of mitochondrial dysfunction on cytotoxic T cell function, slice cultures (SC) of HNSCC cancer were cultivated under different metabolic conditions.MethodsTumor samples from 21 patients with HNSCC were collected, from which, SC were established and cultivated under six different conditions. These conditions included high glucose, T cell stimulation, and temporarily induced mitochondrial dysfunction (MitoDys) using FCCP and oligomycin A with or without additional T cell stimulation, high glucose and finally, a control medium. Over three days of cultivation, sequential T cell stimulation and MitoDys treatments were performed. Supernatant was collected, and SC were fixed and embedded. Granzyme B was measured in the supernatant and in the SC via immunohistochemistry (IHC). Staining of PD1, CD8/Ki67, and cleaved­caspase­3 (CC3) were performed in SC.ResultsHematoxylin eosin stains showed that overall SC quality remained stable over 3 days of cultivation. T cell stimulation, both alone and combined with MitoDys, led to significantly increased granzyme levels in SC and in supernatant. Apoptosis following T cell stimulation was observed in tumor and stroma. Mitochondrial dysfunction alone increased apoptosis in tumor cell aggregates. High glucose concentration alone had no impact on T cell activity and apoptosis. Apoptosis rates were significantly lower under conditions with high glucose and MitoDys (p=0.03).ConclusionStimulation of tumor-infiltrating lymphocytes in SC was feasible, which led to increased apoptosis in tumor cells. Induced mitochondrial dysfunction did not play a significant role in the activation and function of TILs in SC of HNSCC. Moreover, high glucose concentration did not promote cytotoxic T cell activity in HNSCC SC.