Abstract Background Cognitive dysfunction is a prevalent and debilitating symptom of post-COVID-19 condition with limited evidence-based interventions. Here, we assessed the efficacy of cognitive training (CT) alone and combined with transcranial direct current stimulation (tDCS) for cognitive enhancement in post-COVID-19 patients. Methods Neuromod-COV was a phase IIb, prospective, randomized, open-label, blinded-endpoint trial conducted at University Medicine Greifswald, Germany. The tDCS intervention was evaluated through a double-blind, sham-controlled design. Adults aged 18-60 with confirmed SARS-CoV-2 infection ≥ 6 weeks prior and post-infection cognitive complaints were eligible. Participants were randomly assigned (1:1:1) to CT with active tDCS (CT+AtDCS), CT with sham tDCS (CT+StDCS), or progressive muscle relaxation (PMR, non-cognitive control intervention) with sham tDCS. Intervention consisted of nine 20-minute sessions over three weeks of CT (letter updating task) or PMR with 2 mA tDCS (active/sham) applied over the left dorsolateral prefrontal cortex. The primary outcome was untrained working memory (WM; measured by N-back task accuracy) comparing CT with PMR at post-intervention. Secondary outcomes included trained and untrained WM, visuospatial memory, and self-report measures at post-intervention and 1-month follow-up comparing CT vs. PMR and CT+AtDCS vs. CT+StDCS. The trial was registered at ClinicalTrials.gov ( NCT04944147 ). Results Between October 1, 2021, and August 7, 2024, 60 participants were randomized (76.7% female) to CT+AtDCS ( n = 20), CT+StDCS ( n = 20), or PMR ( n = 20). CT did not improve untrained WM at post-intervention compared with PMR (primary outcome: β = 1.59, 95% CI - 1.30 to 4.48, p = 0.278; 1-back: β = 2.52, 95% CI -1.27 to 6.31, p = 0.191; 2-back: β = 0.66, 95% CI -3.12 to 4.44, p = 0.732). However, CT+AtDCS enhanced untrained WM at post-intervention and follow-up, and visuospatial memory at post-intervention compared with CT+StDCS (secondary outcomes). No intervention improved self-report outcomes. No serious adverse events occurred and incidence rate ratios were similar between groups. Conclusion CT alone did not improve untrained WM performance. However, CT with tDCS enhanced untrained WM and visuospatial memory, suggesting potential benefits of combined neuromodulation approaches for cognitive enhancement in post-COVID-19 patients.

Understanding and modulating memory functions in older adults continues to be a fundamental challenge for neuroscientific research. Given age-associated declines in long-range connectivity, network approaches targeting these connections are of particular interest. We investigated whether dual-site transcranial alternating current stimulation can modulate episodic (sequential) memory in cognitively healthy older adults (N = 44, aged 60-80 years). In a sham-controlled crossover design, participants received in-phase (0°) and anti-phase (180°) transcranial alternating current stimulation during a temporal order memory task, with a counterbalanced order of conditions. We computed source analysis-based weighted phase lag indices and corrected amplitude envelope correlation between left hemispheric fronto-parietal stimulation targets from resting-state electroencephalography to quantify modulation of functional connectivity, and conducted analyses of phase angles between these targets. No overall memory effects were observed in either active stimulation conditions, compared with sham. However, the results showed an interaction between memory modulation and age, indicating that the older the participants the higher the memory improvement in the anti-phase condition. Functional coupling increase was observed in both anti- and in-phase conditions as an elevated weighted phase lag indices theta change, compared with sham. No differences were observed for weighted phase lag indices in other frequency bands (alpha, beta) or for the corrected amplitude envelope correlation (theta, alpha, beta). Theta phase angle shifts were increased in the anti-phase compared with the sham condition. Further, in the anti-phase condition, the increase in theta connectivity was linked to age and memory improvement, indicating a potential mechanistic link between neurophysiological and cognitive outcomes. In sum, our findings suggest that dual-site anti-phase stimulation may increase functional connectivity in older adults with large interindividual variability in memory effects, warranting further investigation to optimize stimulation strategies.

Abstract Primary headache disorders, particularly migraine, rank among the leading causes of disability worldwide and impose substantial social and economic burden. Multimodal headache treatment (MMHT) combines pharmacologic, physiotherapeutic and cognitive-behavioural interventions and has shown benefit in high-burden patients, yet the psychological factors associated with sustained improvement remain unclear. Self-efficacy (SE) supports active coping, whereas the chance-related multidimensional health locus of control (CMHLC-C) reflects belief in uncontrollable outcomes. We hypothesised that these control beliefs are modifiable through intervention and that their baseline levels are associated with subsequent improvement in headache burden. Adults with primary headache disorders were enrolled in a prospective observational study and participated in a one-week MMHT at a tertiary neurological day clinic. Headache impact (HIT-6; primary endpoint), monthly headache days (MHD), and highest headache pain severity (HHPS) were measured three months before treatment (waiting-list baseline), at the start and end of MMHT, and at 3-, 6-, and 9-month follow-up. The waiting-list period served as a within-person pre-treatment comparator for spontaneous change. Baseline headache-management SE and MHLC-C subscales were tested as predictors of longitudinal HIT-6 trajectories using a generalized linear mixed model with visit as a repeated factor. Sixty-five patients were included in the analytic cohort (84.6% female; mean age 40.6 ± 13.3 years; 89.8% migraine). HIT-6 decreased from 63.2 at the waiting-list baseline to 59.0 at nine months (p<.001). MHD was reduced from 17.9 ± 8.0 to 12.2 ± 7.5 days, and 44% experienced a ≥ 30% reduction. HHPS also decreased throughout follow-up. Mean SE increased significantly during MMHT and early follow-up, whereas CMHLC-C showed only small changes over time. The mixed model was significant (F(2,165) = 7.25, p<.001). Higher baseline SE predicted larger reductions in HIT-6 (β=−0.55, t(165) = − 2.62, p=.010), whereas greater belief in chance predicted smaller reductions (β = 0.85, t(165) = 2.80, p=.006). In this prospective observational study with a waiting-list comparator, MMHT was associated with sustained reductions in headache impact, headache frequency, and pain severity. Baseline self-efficacy and chance-related control beliefs independently predicted treatment response and may represent clinically relevant stratification targets in personalised headache care.

Importance Postoperative delirium (POD) occurs as a significant complication after elective surgery. Objective To investigate the modulation of delirium incidence by transcranial electric stimulation (tES). Design, Setting, and Participants A double-blind, sham-controlled randomized clinical trial (Modulating Delirium Through Stimulation [MODEST]) was conducted at University Medicine Greifswald, Germany, from February 8, 2024, to January 15, 2025. Patients were aged 65 years or older who were scheduled to undergo elective surgery. Exclusion criteria were any history of neurological or psychiatric disease, or intake of central nervous system–active medication. Data were analyzed from June 10, 2025, to June 5, 2026. Intervention α-Transcranial alternating current stimulation (tACS) of the salience network, transcranial direct current stimulation (tDCS) of the frontoparietal network (dosing: 20 minutes, 2 mA), or sham, in the postanesthesia care unit (PACU) after major elective surgery. Main Outcomes and Measures The primary outcome was POD incidence in the ward during 1 of up to 5 postoperative days for the comparison of tACS vs the sham group. The secondary outcomes included POD in the ward for the comparison of tDCS vs sham group, POD in PACU, POD severity and motor type, and postoperative pain. Prespecified subgroup analyses opted to test the dependence of POD incidence on age, sex, duration, and type of surgery, baseline cognitive function, and preoperative pain levels. Results A total of 225 patients (mean [SD] age, 73.0 [6.0] years; 59.6% [134] male) were randomly assigned to tACS (n = 68), tDCS (n = 83), or sham stimulation (n = 74). No substantial between group differences were observed for POD incidence in ward (tACS, 11.5% [6 of 52]; tDCS, 14.3% [9 of 63]; sham, 9.2% [6 of 65]; tACS vs sham: odds ratio [OR], 1.60 [95% CI, 0.47-5.46]; P = .45; tDCS vs sham: OR, 1.51 [95% CI, 0.49-4.68]; P = .47) or in PACU (tACS, 14.6% [7 of 48]; tDCS, 21.4% [12 of 56]; sham, 21.7% [13 of 60]; tACS vs sham: OR, 0.95 [95% CI, 0.38-2.36]; P = .91; tDCS vs sham: OR, 0.91 [95% CI, 0.36-2.30]; P = .83). Further secondary analyses of POD severity and motor type, and modulation of pain levels, did not show any substantial difference between stimulation groups. Prespecified subgroup analyses revealed different modulation of POD incidence in PACU depending on duration of surgery (OR, 0.15 [95% CI, 0.02-0.97]; P = .046), indicating that tACS may reduce POD incidence for patients with longer surgery (absolute risk difference for POD in the tACS compared with the sham group, for a surgical duration of 3 to 5 hours of −26.6% to −46.5%). Ratings of adverse events did not differ between groups (incidence rate ratio, 2.3 [95% CI, 0.8-6.5]), and no serious adverse events were reported. Conclusions and Relevance In this randomized clinical trial of tES for POD, there was no evidence for a uniform effect of postoperative tES on the incidence of POD, but it suggested a benefit of parietal α oscillatory enhancement for patients with longer surgery. Future research has to test the specific effect on vulnerable groups, examine the optimal timing for tES application to modulate POD, and investigate the value of personalizing tES parameters. Trial Registration German Clinical Trials Register: DRKS00033703

Background/Objectives: Monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway are effective drugs for migraine prevention. The worsening of symptoms after treatment discontinuation has raised the question of whether these agents are associated with sustained central neurophysiological adaptation. This study investigated treatment-associated changes in sensory processing and cortical network efficiency during preventive treatment with CGRP monoclonal antibodies (mAbs). Methods: Twenty-two patients with episodic migraine (21 female, 46.2 ± 13.8 years) and 22 age- and sex-matched healthy controls underwent visual and somatosensory evoked-potential (VEP, SSEP) assessments and quantitative electroencephalography (qEEG). Patients were investigated before treatment initiation (V0) and after 3 months of CGRP mAb treatment (V3). Healthy controls were assessed once. Results: The lack of habituation of VEPs at V0 shifted toward habituation at V3 following treatment with CGRP mAbs (Δslope: -0.37 ± 0.83, p = 0.03). VEP habituation at V3 no longer differed significantly from controls. SSEP amplitudes remained stable and did not differ significantly between groups across the study interval. Exploratory qEEG parameters indicated a less efficient cortical network organization at V0 that was no longer significantly different from controls at V3. Conclusions: Three months of CGRP mAb treatment was associated with a partial normalization of selected neurophysiological parameters, particularly VEP habituation and exploratory qEEG network measures. Given the study design and small sample size, these findings indicate adaptive changes in multi-domain processing, yet these should not be overinterpreted as proof of disease modification.

OBJECTIVE:To evaluate the effects of a short, structured multimodal day-clinic program on health-related quality of life and disability in patients with primary headache disorders. BACKGROUND:Although monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway have substantially advanced migraine prophylaxis, a large proportion of patients remain insufficiently controlled. Residual disability, comorbidities, and contraindications highlight the need for complementary nonpharmacological approaches. Multimodal programs combining medical, psychological, and behavioral strategies have proven effective in chronic pain but remain insufficiently studied in primary headache populations, particularly in the context of modern pharmacological options. METHODS:In this quasi-experimental pre-post study at the neurological day clinic of University of Greifswald, we investigated a 5-day multimodal treatment program delivered by an interdisciplinary team. Patients were recruited between January and July 2021. The intervention comprised medical consultations, psychological therapy, physiotherapy, occupational therapy, structured education, and relaxation training. Patient-reported outcomes were assessed with the Veterans RAND 12-Item Health Survey (VR-12; primary end points: mental component summary [MCS] and physical component summary [PCS]), the Depression Anxiety Stress Scales (DASS-21), the Headache Impact Test (HIT-6), and headache diaries. Assessments were performed during the pre-admission waiting period (V0), at admission (V1), and at 3, 6, and 9 months after treatment (V2-V4). Primary analyses focused on changes from baseline to 3 months, with exploratory analyses for extended follow-up. RESULTS:A total of 92 patients were included, most with migraine (83%). The VR-12 MCS improved significantly over time (F[2,162] = 3.23, p = 0.042; nominal), increasing from an estimated marginal mean of 36.9 (95% CI, 33.35-40.45) at baseline (V0) to 38.3 (95% CI, 35.54-41.06) at V1, and 41.5 (95% CI, 37.55-45.45) at 3 months (V2). Focusing on the pre-specified baseline-to-3-month contrast, MCS improved from V0 to V2 (mean difference, 4.63; 95% CI, 1.02-8.24; p = 0.012; Holm-Bonferroni padj = 0.024). PCS showed no significant changes (F[2,162] = 0.95, p = 0.387), with estimated marginal means of 38.3 (95% CI, 36.13-40.47) at V0, 37.7 (95% CI, 35.73-39.67) at V1, and 39.0 (95% CI, 36.24-41.76) at V2. Headache frequency did not change significantly across V0-V2 (F[2,148] = 0.49, p = 0.616). HIT-6 scores decreased significantly (64.7 ± 3.6 at V0, 64.8 ± 5.0 at V1, and 60.8 ± 5.4 at V2; F[2,148] = 5.63, p = 0.004). DASS-21 subscales showed nonsignificant reductions at 3 months, with exploratory analyses indicating gradual improvements at 6 and 9 months. CONCLUSION:A short, structured multimodal program in a day-clinic setting significantly improved the mental component of health-related quality of life and reduced headache-related disability in patients with primary headache disorders. Although physical functioning and headache frequency did not change significantly at 3 months, the program provided clinically relevant benefits in coping and mental health. These findings highlight multimodal day-clinic treatment as a valuable component of comprehensive headache care, even in the era of CGRP-targeted treatment options.

Background: Delirium affects 10–30% of acute stroke patients, is associated with poor outcomes and places a substantial burden on healthcare staff. Evidence-based prevention and treatment strategies are limited, resulting in heterogeneous and poorly standardised delirium management in acute stroke care. Objectives: We aimed to describe real-world delirium management in German and Austrian stroke units (SUs) and to delineate the extent of practice variation in prevention and treatment. Design: We conducted a cross-sectional, web-based survey of stroke neurologists working at SUs in Austria and Germany. Methods: The 30-item questionnaire assessed professional background, delirium prevention and pharmacological treatment approaches. Descriptive statistics and exploratory subgroup analyses were performed. Results: Seventy responses from 63 SUs were analysed (median physician SU experience, 14.5 years). Delirium was estimated to affect 20% of patients and was perceived as highly burdensome for both physicians and nurses (median score, 9/10 each). Delirium prevention measures were established in 42 (67%) SUs but routinely applied to all patients in only 12 (19%), mainly due to staffing shortages (nurses, 48%; physicians, 25%). Pharmacological delirium treatment was reported by all respondents. Benzodiazepines were preferred for alcohol withdrawal delirium (60%) and antipsychotics for hyperactive or mixed delirium (59%). α2-Agonists were the most common escalation therapy across these subtypes (46%–67%). Conclusion: Delirium management in German and Austrian SUs is highly heterogeneous, limited by staffing constraints and strongly relies on non-evidence-based pharmacological strategies. These findings highlight critical gaps in care and call for enhanced staffing and stroke-specific trials to inform evidence-based delirium management.

Importance:Postoperative delirium (POD) occurs as a significant complication after elective surgery. Objective:To investigate the modulation of delirium incidence by transcranial electric stimulation (tES). Design, Setting, and Participants:A double-blind, sham-controlled randomized clinical trial (Modulating Delirium Through Stimulation [MODEST]) was conducted at University Medicine Greifswald, Germany, from February 8, 2024, to January 15, 2025. Patients were aged 65 years or older who were scheduled to undergo elective surgery. Exclusion criteria were any history of neurological or psychiatric disease, or intake of central nervous system-active medication. Data were analyzed from June 10, 2025, to June 5, 2026. Intervention:α-Transcranial alternating current stimulation (tACS) of the salience network, transcranial direct current stimulation (tDCS) of the frontoparietal network (dosing: 20 minutes, 2 mA), or sham, in the postanesthesia care unit (PACU) after major elective surgery. Main Outcomes and Measures:The primary outcome was POD incidence in the ward during 1 of up to 5 postoperative days for the comparison of tACS vs the sham group. The secondary outcomes included POD in the ward for the comparison of tDCS vs sham group, POD in PACU, POD severity and motor type, and postoperative pain. Prespecified subgroup analyses opted to test the dependence of POD incidence on age, sex, duration, and type of surgery, baseline cognitive function, and preoperative pain levels. Results:A total of 225 patients (mean [SD] age, 73.0 [6.0] years; 59.6% [134] male) were randomly assigned to tACS (n = 68), tDCS (n = 83), or sham stimulation (n = 74). No substantial between group differences were observed for POD incidence in ward (tACS, 11.5% [6 of 52]; tDCS, 14.3% [9 of 63]; sham, 9.2% [6 of 65]; tACS vs sham: odds ratio [OR], 1.60 [95% CI, 0.47-5.46]; P = .45; tDCS vs sham: OR, 1.51 [95% CI, 0.49-4.68]; P = .47) or in PACU (tACS, 14.6% [7 of 48]; tDCS, 21.4% [12 of 56]; sham, 21.7% [13 of 60]; tACS vs sham: OR, 0.95 [95% CI, 0.38-2.36]; P = .91; tDCS vs sham: OR, 0.91 [95% CI, 0.36-2.30]; P = .83). Further secondary analyses of POD severity and motor type, and modulation of pain levels, did not show any substantial difference between stimulation groups. Prespecified subgroup analyses revealed different modulation of POD incidence in PACU depending on duration of surgery (OR, 0.15 [95% CI, 0.02-0.97]; P = .046), indicating that tACS may reduce POD incidence for patients with longer surgery (absolute risk difference for POD in the tACS compared with the sham group, for a surgical duration of 3 to 5 hours of -26.6% to -46.5%). Ratings of adverse events did not differ between groups (incidence rate ratio, 2.3 [95% CI, 0.8-6.5]), and no serious adverse events were reported. Conclusions and Relevance:In this randomized clinical trial of tES for POD, there was no evidence for a uniform effect of postoperative tES on the incidence of POD, but it suggested a benefit of parietal α oscillatory enhancement for patients with longer surgery. Future research has to test the specific effect on vulnerable groups, examine the optimal timing for tES application to modulate POD, and investigate the value of personalizing tES parameters. Trial Registration:German Clinical Trials Register: DRKS00033703.

BACKGROUND:Antipsychotic-induced weight gain (AIWG) is a major clinical concern, affecting approximately 30% of patients. Clinical predictors explain only part of AIWG risk. Genetic and molecular variations are hypothesized to contribute to susceptibility. The purpose of this review is to summarize recent results to identify replicated and novel findings. STUDY DESIGN:Applying PRISMA guidelines, we searched MEDLINE, Embase, and PsycINFO (May 2018-May 2026) for studies on genetic and molecular associations with AIWG, extending our prior review. Reviews, editorials, and conference abstracts were excluded. We extracted study characteristics (design, diagnosis, antipsychotic exposure, sample size, ancestry, genetic variants, and AIWG outcomes) (e.g., ≥7% weight gain, BMI change). RESULTS:Fifty-three studies met inclusion criteria. In candidate gene studies, the most consistently replicated genes associated with AIWG were observed for DRD2, HTR2C, and MC4R. Multiple novel associations were identified by genome-wide association studies (GWAS) (e.g., MAP2K1, ZDBF2, PEPD), polygenic risk scores (PRS) (e.g., body mass index PRS), gene expression (e.g., CYP3A4, EP300), and epigenetic analyses (e.g., cg12034943 at CRTC1). CONCLUSIONS:Polymorphisms in candidate genes related to neurotransmission and appetite regulation continue to be investigated for associations with AIWG, while novel findings have emerged from GWAS, gene expression, and epigenetic studies. Evidence remains inconsistent due to limited replication, methodological variability, sparse ancestry data, and geographical underrepresentation. No single genetic variant is ready for clinical use, and multi-omic and multi-ancestry models are needed to improve prediction and clinical utility.

ABSTRACT Background and Purpose Poststroke delirium (PSD) is common and prognostically relevant, yet under‐detected. Mechanistic and biomarker research is constrained by reliance on an intermittently observed binary phenotype, while delirium reflects one severity level on a continuum of delirium‐related encephalopathy. Quantitative EEG (qEEG) may capture encephalopathy endotypes more directly and enable severity‐spectrum characterization. Methods In this prospective, single‐center, observational cohort study, 87 consecutive patients with acute ischemic stroke or transient ischemic attack were assessed within 48 h using the Confusion Assessment Method (CAM). A 64‐channel EEG was recorded at enrollment; spectral power (delta/theta/alpha/beta) and functional connectivity metrics (phase lag index; amplitude envelope correlation corrected [AECc]) were computed. Neuroinflammatory and systemic biomarkers were quantified from routine serum sampling in an exploratory, add‐on subcohort (n = 31). Results PSD occurred in 28 of 87 (32%). PSD was characterized by spectral slowing and altered AECc. A multivariable qEEG model discriminated PSD with AUC = 0.892 (p < 0.001) and overall accuracy of 81.4% (non‐delirium 89.8%, delirium 63.0%). In the paired EEG plus serum subset, nominal exploratory correlations between qEEG metrics and selected biomarkers suggested links between network dysfunction and inflammatory signaling, including inverse correlations of theta‐band AECc with VILIP‐1 (r = −0.454, p = 0.045) and CX3CL1 (r = −0.604, p = 0.005), whereas biomarker–phenotype associations were less consistent. Conclusions qEEG connectivity provides an encephalopathy‐proximal readout that can detect PSD and may characterize delirium‐related endotypes beyond the intermittently observed clinical phenotype. Findings require validation in larger, multicenter cohorts.

Postoperative delirium (POD) is a frequent and serious complication among elderly surgical patients. Despite its clinical relevance, reliable biomarkers for early identification and pathophysiological insight remain limited. Recent evidence implicates systemic immune activation and complements dysregulation as contributors to cognitive decline after surgery. This study investigated the association between perioperative levels of selected complement pathway proteins and both the incidence and severity of POD. Methods: We performed a secondary analysis of 22 patients aged ≥ 60 years from the prospective CONFESS cohort undergoing elective spine surgery. Complement proteins (C1q, C2, C4), mannose-binding lectin (MBL), Factor D [FD], Factor B [FB], Factor I [FI] were quantified from blood samples collected at baseline, preoperatively, and on postoperative days 1 and 2. POD was assessed using the Nursing Delirium Screening Scale (Nu-DESC) and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria. Delirium severity was rated with the Confusion Assessment Method-Severity (CAM-S) scale. Associations were tested using univariate and multivariate regression analyses. Preoperative levels of FD and C2 were significantly elevated in patients who developed POD (FD: p = 0.023; C2: p = 0.044), while C4 levels trended lower. FD remained an independent predictor of POD in multivariate regression (p = 0.049), although cognitive performance was the only significant predictor when adjusted for surgery duration. Delirium severity was associated with perioperative reductions in C1q, FI, and FB and with increased MBL levels, explaining up to 43% of CAM-S score variance. These findings highlight the role of complement activation-particularly FD, C2, MBL-in the development and clinical expression of POD. Complement profiling may offer a novel approach for risk stratification and therapeutic targeting in perioperative neurocognitive disorders.

Background/Objectives: Medication-overuse headache (MOH) is a disabling condition affecting patients with chronic migraine resulting from excessive use of acute headache medication. It is characterized by both pain modulation and addiction-like mechanisms involving the brainstem raphe, a region critical to serotonergic signaling. This study investigates whether alterations in the brainstem raphe, assessed via transcranial sonography (TCS), are associated with MOH and independent of depressive symptoms, aiming to explore their utility as a biomarker. Methods: This prospective case-control study included 60 migraine patients (15 with MOH) and 7 healthy controls. Comprehensive clinical and psychometric assessments were performed to evaluate headache burden, medication use, and depressive symptoms. TCS was used to assess brainstem raphe echogenicity, with findings analyzed using generalized linear models adjusted for depression. Results: Non-visibility of the brainstem raphe was significantly associated with MOH, with an unadjusted odds ratio (OR) of 6.88 (95% CI: 1.32-36.01, p = 0.02). After adjusting for depressive symptoms, this association remained significant, with an adjusted OR of 1.85 (95% CI: 1.02-3.34, p = 0.041). TCS demonstrated good intraclass correlation, highlighting its reproducibility and ability to detect changes relevant to MOH pathophysiology. Conclusions: Brainstem raphe alterations are associated with MOH and may serve as a potential biomarker for its diagnosis and management. TCS offers a non-invasive, cost-effective tool for identifying MOH-specific mechanisms, which could improve clinical decision-making and support personalized care in chronic headache disorders. Further studies are needed to validate these findings and refine the clinical applications of brainstem-focused diagnostics.

Calcitonin gene-related peptide (CGRP) is involved in the pathophysiology of cluster headache (CH). Prophylactic pharmacologic treatment options for chronic CH (CCH) are limited. The potential effects of erenumab, a CGRP receptor antagonist monoclonal antibody, in treating CCH have not been assessed. To evaluate the superiority of erenumab compared with placebo in the prophylaxis of CCH. A 12-week, double-blind, placebo-controlled randomized clinical trial (CHERUB01) was conducted at 11 sites in Germany from December 2, 2021, to September 27, 2023. Participants (aged 18-65 years) had a diagnosis of CCH, had no previous sufficient response to standard CCH prophylactic medications approved in Germany, and had experienced at least 9 attacks during screening. Loading dose of erenumab (280 mg subcutaneously) or matching placebo in a 1:1 randomization, followed by another dose of erenumab (140 mg subcutaneously) or placebo 4 weeks later. The primary end point was the reduction of mean weekly CH attacks from baseline over weeks 5 and 6. Key secondary end points were 50% responder rates and changes in Patient Global Impression of Improvement (PGI-I) scores. Safety and tolerability were also assessed. A bayesian analysis scheme was used for statistical analysis. This study randomized 81 participants (mean [SD] age, 48.9 [10.4] years; 60 men [74.1%]) with CCH (mean [SD], 21.5 [9.7] attacks per week) to erenumab (n = 41) or placebo (n = 40). Recruitment was stopped prematurely due to insufficient patient numbers meeting the inclusion criteria within the planned recruitment period. The primary end point was not met over weeks 5 and 6 of the double-blind phase because the mean (SD) reduction of weekly CH attacks was −7.3 (8.6) per week for erenumab and −5.9 (10.5) per week for placebo (group difference, −1.5 [95% credible interval [CrI], −5.7 to 2.8]). At weeks 5 and 6, the percentage of participants with a 50% or greater reduction in CH attacks was not significantly different between the erenumab (13 [31.7%]) and placebo (18 [45.0%]) groups (odds ratio, 0.5 [95% CrI, 0.2-1.5]). PGI-I scores were also not different between groups. More participants reported adverse events with erenumab than placebo (27 [65.9%] vs 17 [42.5%]), which were mostly of mild or moderate intensity. In this clinical trial of patients with CCH, blockade of the CGRP receptor with erenumab was not successful in the prophylaxis of attacks. Future studies should revisit the role of CGRP in CCH. ClinicalTrials.gov Identifier: NCT04970355; EudraCT Number: 2020-004399-16

IntroductionThe relevance of electroencephalographic (EEG) biomarkers is increasing, as advancements in spectral analysis enable computational decomposition of complex neural signals into quantitative EEG (qEEG) parameters. Especially the differentiation of periodic and aperiodic components can reveal insights into neural function, disease biomarkers, and therapeutic efficacy. The aim of these analyses from real-world clinical routine EEG recordings was to provide normative values of physiological age-related oscillatory (periodic) and non-rhythmic (aperiodic) activity.MethodsWe analyzed 532 physiological EEGs of patients between 8 and 92 years of age. EEG segments were preprocessed, and the power spectrum was computed using a multitaper method. We decomposed the power spectrum into periodic (peak power, frequency, and bandwidth) and aperiodic (intercept and exponent) components. Linear regression models were used to investigate age-related changes in these parameters.ResultsWe observed significant global age-related changes in the periodic alpha (−0.015 Hz/year) and gamma (+0.013 to +0.031 Hz/year) peak frequency as well as in the aperiodic exponent (−0.003 to −0.004 μV2/Hz/year). In the other parameters there were solely regional or no significant age-related changes.ConclusionDecomposing the power spectrum into periodic and aperiodic components allows for the characterization of age-related changes.SignificanceThis study provides the first spectrum-wide normative characterization of age-related changes in periodic and aperiodic activity, relevant for non-invasive brain stimulation with alternating current targeting ongoing oscillatory activity.

OBJECTIVE:Delirium manifests with comparable clinical presentations, regardless of its heterogeneous etiology. This suggests a final common pathway such as decreased electroencephalography (EEG) phase coupling. This study investigates if amplitude coupling, another mode of neural communication, is altered in delirium due to different etiologies. METHODS:We analyzed EEGs of patients from three sites with either postoperative, poststroke or medical delirium and non-delirious control patients. Amplitude envelope correlation corrected for spatial leakage (AECc) was calculated and Mann-Whitney U-tests were used to compare patients with or without delirium. AECc differences among delirium types were compared using Kruskal-Wallis tests. RESULTS:AECc was significantly increased in delirious (n = 173, age 79.2±9.3 years, 46 % female) as compared to non-delirious (n = 204, age 72.9±13.1 years, 45 % female) patients in the delta (median, effect size of difference: 0.16 vs. 0.12, r = 0.28, p < 0.01) and beta band (0.11 vs. 0.09, r = 0.14, p = 0.04). These changes did not differ among delirium types (p > 0.05). CONCLUSIONS:We found modestly higher delta and beta band AECc in delirium compared to non-delirious control patients, regardless of the presumed etiology. SIGNIFICANCE:This study provides evidence for altered amplitude coupling as mode of impaired neuronal communication in delirium, the role of which should be investigated in future studies of neural network pathophysiology.

Abstract Background Postoperative delirium (POD) is the most common neurological adverse event among elderly patients undergoing surgery. POD is associated with an increased risk for postoperative complications, long-term cognitive decline, an increase in morbidity and mortality as well as extended hospital stays. Delirium prevention and treatment options are currently limited. This study will evaluate the effect of transcranial electrical stimulation (tES) on the incidence of POD. Methods We will perform a randomized, double-blind, sham-controlled trial using single-session postoperative application of tES in the recovery room in 225 patients (> 65 years) undergoing elective major surgery. Patients will be randomly allocated (ratio 1:1:1) to one of three study groups: (1) alpha-tACS over posterior parietal cortex [2 mA, 20 min], (2) anodal tDCS over left dorsolateral prefrontal cortex [2 mA, 20 min], (3) sham [2 mA, 30 s]. Delirium will be screened twice daily with the 3-min diagnostic interview Confusion Assessment Method (3D-CAM) in the 5 days following surgery. The primary outcome is the incidence of POD defined as at least one positive screening during the five first postoperative days compared between tACS and sham groups. Secondary outcomes include delirium severity, duration, phenotype, postoperative pain, postoperative nausea and vomiting, electroencephalographic (EEG) markers, and fluid biomarkers. Discussion If effective, tES is a novel, easily applicable, non-invasive method to prevent the occurrence of POD. The comprehensive neurophysiological and biofluid assessments for markers of (neuro-)inflammation and neurodegeneration will shed light on the pathomechanisms behind POD and further elucidate the (after-)effects of tES. The potential implications for the postoperative recovery comprise enhanced patient safety, neurocognitive outcome, perioperative manageability but also reduced healthcare costs. Trial registration German Clinical Trial Registry DRKS00033703. Registered on February 23, 2024.

To assess the incidence and severity of delirium and subsequent neurological impairment in pediatric intensive care unit (PICU) patients with meningoencephalitis (ME) and sepsis. Prospective study enrolling PICU patients with sepsis or meningoencephalitis (ME) and healthy controls. Daily delirium assessment, repeated electroencephalography, blood sampling at days 1, 3, 5 and lumbar puncture, if clinically indicated, for cerebrospinal fluid (CSF) sampling were performed. Biomarkers of inflammation (CRP, PCT, IL-6), endothelial activation (NT-proCNP), neurodegeneration (NSE, tau), neuroaxonal damage (NfL, NfH, UCHL-1) and glial injury (GFAP, S100B) were measured. Neurological status was assessed using the Functional Status Scale (FSS), the pediatric overall performance category (POPC) and the pediatric cerebral performance scale (PCPC) before admission and after three months. Twenty-four PICU patients (ME n = 9, sepsis n = 15) and eleven controls were enrolled. The delirium incidence was not statistically higher in patients with sepsis (60%, n = 9/15) compared to ME (33%, n = 3/9, p = 0.105). Children with delirium (n = 12) had a higher FSS (10.0 [9.8, 12.0] vs. 7.5 [7.0, 9.0], p = 0.009) at day 1 than children without delirium (n = 12), without significant differences in blood and CSF biomarker levels. Patients with ME presented higher levels of blood NfL compared to sepsis patients at day 3 (16.8 [12.9, 77.5] vs. 10.7 [8.6, 12.2] pg/ml, p = 0.011) and day 5 (16.2 [6.8, 170.4] vs. 12.0 [7.9, 14.3] pg/ml, p = 0.005). Routine EEG results did not differ between the groups, but quantitative EEG parameters representing encephalopathy correlated with biomarkers of brain injury. FSS, POPC and PCPC after three months were identical between in all patients. Independent from the origin of inflammatory stimulation by sepsis or ME delirium is associated with transient neurological dysfunction in PICU patients, without neurological impairment after three months, as confirmed by biomarker levels.