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This functional magnetic resonance imaging (fMRI) study examined resting-state (RS) connectivity in adolescent and adult patients with anorexia nervosa (AN) using symptom provocation paradigms. Differential food reward mechanisms were investigated through separate assessments of responses to food images and low-caloric/high-caloric food consumption. Thirteen young (≤ 21 years) and seventeen adult (> 21 years) patients with AN and age-matched controls underwent two stimulus-driven fMRI sessions involving RS scans before and after the presentation of food-related stimuli and food consumption. Graph theory and machine learning were used for analyzing the fMRI and clinical data. Healthy controls (HCs) showed widespread developmental changes, while young participants with AN exhibited cerebellum differences for high-calorie food. Young individuals with AN displayed increased connectivity during the consumption of potato chips compared to zucchini, with no differences in adults with AN. Multiparametric machine learning accurately distinguished young individuals with AN from healthy controls based on RS connectivity following food visual stimulation ("anticipatory") and consumption ("consummatory"). This study highlights the differential food reward mechanisms and minimal developmental changes in RS connectivity from youth to adulthood in individuals with AN compared to healthy controls. Young individuals with AN demonstrated heightened reactivity to high-caloric foods, while adults showed decreased responsiveness, potentially due to desensitization. These findings shed light on aberrant eating behaviors in individuals with AN and contribute to our understanding of the chronicity of the disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Mendez-Torrijos, Selvakumar, Kreitz, Roesch, Dörfler, Paslakis, Krehbiel, Steins-Löber, Kratz, Horndasch and Hess.)

Background: The preplanned interim analysis of the COMMANDS trial showed greater efficacy of luspatercept than epoetin alfa for treating anaemia in erythropoiesis-stimulating agent (ESA)-naive patients with transfusion-dependent, lower-risk myelodysplastic syndromes. In this Article, we report the results of the primary analysis of the trial., Methods: COMMANDS is a phase 3, open-label, randomised, controlled trial conducted at 142 sites in 26 countries. Eligible patients were those aged 18 years or older, with myelodysplastic syndromes of very low risk, low risk, or intermediate risk (as defined by the Revised International Prognostic Scoring System), who were ESA-naive and transfusion dependent, and had a serum erythropoietin concentration of less than 500 U/L. Patients were stratified by baseline red blood cell transfusion burden, serum erythropoietin concentration, and ring sideroblast status, and randomly allocated (1:1) to receive luspatercept (1·0-1·75 mg/kg body weight, subcutaneously, once every 3 weeks) or epoetin alfa (450-1050 IU/kg body weight, subcutaneously, once a week; maximum total dose 80 000 IU) for at least 24 weeks. The primary endpoint was red blood cell transfusion independence lasting at least 12 weeks with a concurrent mean haemoglobin increase of at least 1·5 g/dL (weeks 1-24), evaluated in the intention-to-treat population. The safety population included all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov (NCT03682536; active, not recruiting)., Findings: Between Jan 2, 2019, and Sept 29, 2022, 363 patients were screened and randomly allocated: 182 (50%) to luspatercept and 181 (50%) to epoetin alfa. Median age was 74 years (IQR 69-80), 162 (45%) patients were female, and 201 (55%) were male. 289 (80%) were White, 44 (12%) were Asian, and two (1%) were Black or African American. 23 (6%) were Hispanic or Latino and 311 (86%) were not Hispanic or Latino. Median follow-up for the primary endpoint was 17·2 months (10·4-27·7) for the luspatercept group and 16·9 months (10·1-26·6) for the epoetin alfa group. A significantly greater proportion of patients in the luspatercept group reached the primary endpoint (110 [60%] vs 63 [35%]; common risk difference on response rate 25·4% [95% CI 15·8-35·0]; p<0·0001). Median follow-up for safety analyses was 21·4 months (IQR 14·2-32·4) for the luspatercept group and 20·3 months (12·7-30·9) for the epoetin alfa group. Common grade 3-4 treatment-emergent adverse events occurring among luspatercept recipients (n=182) were hypertension (19 [10%] patients), anaemia (18 [10%]), pneumonia (ten [5%]), syncope (ten [5%]), neutropenia (nine [5%]), thrombocytopenia (eight [4%]), dyspnoea (eight [4%]), and myelodysplastic syndromes (six [3%]); and among epoetin alfa recipients (n=179) were anaemia (14 [8%]), pneumonia (14 [8%]), neutropenia (11 [6%]), myelodysplastic syndromes (ten [6%]), hypertension (eight [4%]), iron overload (seven [4%]), and COVID-19 pneumonia (six [3%]). The most common serious treatment-emergent adverse events in both groups were pneumonia (nine [5%] luspatercept recipients and 13 [7%] epoetin alfa recipients) and COVID-19 (eight [4%] luspatercept recipients and ten [6%] epoetin alfa recipients). One death (due to acute myeloid leukaemia) considered to be luspatercept-related was reported at the interim analysis., Interpretation: Luspatercept represents a new standard of care for ESA-naive patients with transfusion-dependent, lower-risk myelodysplastic syndromes. Significantly more patients had red blood cell transfusion independence and haematological improvement with luspatercept than with epoetin alfa, with benefits observed across patient subgroups., Funding: Celgene and Acceleron Pharma., Competing Interests: Declaration of interests Editorial and medical writing support were funded by Bristol Myers Squibb. MGDP reports receiving honoraria from and advisory or data safety monitoring board fees from Bristol Myers Squibb. GG-M reports receiving consulting fees from Bristol Myers Squibb; research support from AbbVie, Astex, Bristol Myers Squibb, Chordia, Curis, Genentech, Novartis, Rigel Pharmaceuticals, and Zentalis; and honoraria from Astex and Curis. VS reports receiving honoraria from AbbVie, Bristol Myers Squibb, and Novartis; travel support from AbbVie and Jazz Pharmaceuticals; and advisory or data safety monitoring board fees from AbbVie, Bristol Myers Squibb, CTI BioPharma, Curis, Geron, Gilead, Keros, Menarini, Novartis, Servier, and Syros. AMZ reports receiving grant support from AbbVie, Amgen, Astex, Bristol Myers Squibb, Celgene, Geron, Kura, Novartis, Otsuka, Shattuck Labs, and Syros; and consulting fees and honoraria from AbbVie, Agios, Akeso Pharma, ALX Oncology, Amgen, Astellas Pharma, BeiGene, BioCryst, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Chiesi, Daiichi Sankyo, Epizyme, Faron, Genentech, Geron, Gilead, Glycomimetics, Hikma, Janssen, Karyopharma, Keros, Kura, Kyowa Kirin, Lava Therapeutics, Medus, Notable, Novartis, Orum, Otsuka, Pfizer, Regeneron, Rigel Pharmaceuticals, Schrodinger, Servier, Sumitomo Pharma, Syndax, Syros, Taiho, Takeda, Treadwell, Vincerx, and Zentalis. RSK reports receiving grant support from Bristol Myers Squibb; consulting fees from Geron, Janssen, and Sumitomo Pharma; speakers bureau fees from AbbVie, Jazz Pharmaceuticals, Pharma Essentia, Rigel Pharmaceuticals, Servio, and Sobi; and advisory or data safety monitoring board fees from AbbVie, Bristol Myers Squibb, DSI, Jazz Pharmaceuticals, Pharma Essentia, Rigel Pharmaceuticals, Servio, Sobi, and Sumitomo Pharma. JS reports receiving grant support from Amgen Australia, Astex Pharmaceuticals, and Bristol Myers Squibb; consulting fees paid to himself from Astellas Pharma, Mundipharma, Novartis, Otsuka, and Pfizer; speakers bureau fees paid to himself and his institution from Mundipharma and Novartis; support for meeting attendance from AstraZeneca (no payment to healthcare provider); being a named investigator on patent PCT/AU2021/050562 assigned to his institution; trial steering committee fees paid to his institution from Bristol Myers Squibb; and serving an unpaid appointment on the Australasia Leukaemia and Lymphoma Group Scientific Advisory Committee. DV reports receiving consulting fees from Amgen, Astellas Pharma, Bristol Myers Squibb, Jazz Pharmaceuticals, Kite Pharma, Merck Sharp & Dohme, Novartis, Sanofi, and Sobi; honoraria from Agios, Amgen, Astellas Pharma, Bristol Myers Squibb, Gebro, Grifols, Janssen, Jazz Pharmaceuticals, Kite Pharma, Merck Sharp & Dohme, Novartis, Pfizer, Sanofi, and Sobi; travel support from Bristol Myers Squibb, Jazz Pharmaceuticals, Novartis, Sanofi, and Sobi; and advisory or data safety monitoring board fees from Amgen, Bristol Myers Squibb, Grifols, Jazz Pharmaceuticals, Novartis, Servier, and Sobi. AJ reports receiving support for study materials from Bristol Myers Squibb; consulting fees from Bristol Myers Squibb; honoraria from AbbVie, Bristol Myers Squibb, and Novartis; travel support from AbbVie and Novartis; advisory or data safety monitoring board fees from AbbVie, Bristol Myers Squibb, GSK, and Novartis; and a leadership or fiduciary role as the head of the Czech MDS Group. JL, RP, SK, KLK, TP, and YL are employed by and own stock in Bristol Myers Squibb. JZ is employed by Bristol Myers Squibb. VP is employed by and owns stock in Bristol Myers Squibb and owns stock in Merck. SR is employed by, owns stock in, and has received travel support from Bristol Myers Squibb and owns stock in Celgene. AD reports receiving honoraria from Bristol Myers Squibb; travel support from Johnson & Johnson; and advisory or data safety monitoring board fees from Swixx BioPharma. TC reports receiving consulting fees from AbbVie, Agios, BluePrint, Bristol Myers Squibb/Celgene, Jazz Pharmaceuticals, Novartis, and Servier; honoraria from Astellas, Bristol Myers Squibb/Celgene, Incyte, Jazz Pharmaceuticals, Novartis, Servier, and Takeda; travel support from AbbVie, Bristol Myers Squibb/Celgene, Gilead, Novartis, Pfizer, and Servier; and advisory or data safety monitoring board fees from Astellas, Bristol Myers Squibb/Celgene, Incyte, Jazz Pharmaceuticals, Novartis, Servier, and Takeda. PF reports receiving grant support from AbbVie, Agios, Bristol Myers Squibb, and Novartis; and honoraria from AbbVie, Agios, Bristol Myers Squibb, and Novartis. UP reports receiving grant support paid to GWT-TUD, from Amgen and Janssen; grant support, paid to University of Leipzig, from Bristol Myers Squibb, Merck, and Novartis; consulting fees from AbbVie, Bristol Myers Squibb, Curis, Geron, Janssen, and Novartis; honoraria from Bristol Myers Squibb and Novartis; and fees for serving on a steering committee and travel support from Bristol Myers Squibb. All other authors declare no competing interests., (2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Alcohol consumption is a widespread phenomenon throughout the world. However, how recreational alcohol use evolves into alcohol use disorder (AUD) remains poorly understood. The Smpd3 gene and its coded protein neutral sphingomyelinase (NSM) are associated with alcohol consumption in humans and alcohol-related behaviors in mice, suggesting a potential role in this transition. Using multiparametric magnetic resonance imaging, we characterized the role of NSM in acute and chronic effects of alcohol on brain anatomy and function in female mice. Chronic voluntary alcohol consumption (16 vol% for at least 6 days) affected brain anatomy in WT mice, reducing regional structure volume predominantly in cortical regions. Attenuated NSM activity prevented these anatomical changes. Functional MRI linked these anatomical adaptations to functional changes: Chronic alcohol consumption in mice significantly modulated resting state functional connectivity (RS FC) in response to an acute ethanol challenge (i.p. bolus of 2 g kg -1 ) in heterozygous NSM knockout (Fro), but not in WT mice. Acute ethanol administration in alcohol-naïve WT mice significantly decreased RS FC in cortical and brainstem regions, a key finding that was amplified in Fro mice. Regarding direct pharmacological effects, acute ethanol administration increased the regional cerebral blood volume (rCBV) in many brain areas. Here, chronic alcohol consumption otherwise attenuated the acute rCBV response in WT mice but enhanced it in Fro mice. Altogether, these findings suggest a differential role for NSM in acute and chronic functional brain responses to alcohol. Therefore, targeting NSM may be useful in the prevention or treatment of AUD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Functional magnetic resonance imaging (fMRI) visualizes brain structures at increasingly higher resolution and better signal-to-noise ratio (SNR) as field strength increases. Yet, mapping the blood oxygen level dependent (BOLD) response to distinct neuronal processes continues to be challenging. Here, we investigated the characteristics of 7 T-fMRI compared to 3 T-fMRI in the human brain beyond the effect of increased SNR and verified the benefits of 7 T-fMRI in the detection of tiny, highly specific modulations of functional connectivity in the resting state following a motor task., Methods: 18 healthy volunteers underwent two resting state and a stimulus driven measurement using a finger tapping motor task at 3 and 7 T, respectively. The SNR for each field strength was adjusted by targeted voxel size variation to minimize the effect of SNR on the field strength specific outcome. Spatial and temporal characteristics of resting state ICA, network graphs, and motor task related activated areas were compared. Finally, a graph theoretical approach was used to detect resting state modulation subsequent to a simple motor task., Results: Spatial extensions of resting state ICA and motor task related activated areas were consistent between field strengths, but temporal characteristics varied, indicating that 7 T achieved a higher functional specificity of the BOLD response than 3 T-fMRI. Following the motor task, only 7 T-fMRI enabled the detection of highly specific connectivity modulations representing an "offline replay" of previous motor activation. Modulated connections of the motor cortex were directly linked to brain regions associated with memory consolidation., Conclusion: These findings reveal how memory processing is initiated even after simple motor tasks, and that it begins earlier than previously shown. Thus, the superior capability of 7 T-fMRI to detect subtle functional dynamics promises to improve diagnostics and therapeutic assessment of neurological diseases., Competing Interests: SK and AH are CEOs of BioCom GbR, a company that sells MagnAn analysis software. They did not get any financial benefit from providing the software for the study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kreitz, Mennecke, Konerth, Rösch, Nagel, Laun, Uder, Dörfler and Hess.)

Background: Erythropoiesis-stimulating agents (ESAs) are the standard-of-care treatment for anaemia in most patients with lower-risk myelodysplastic syndromes but responses are limited and transient. Luspatercept promotes late-stage erythroid maturation and has shown durable clinical efficacy in patients with lower-risk myelodysplastic syndromes. In this study, we report the results of a prespecified interim analysis of luspatercept versus epoetin alfa for the treatment of anaemia due to lower-risk myelodysplastic syndromes in the phase 3 COMMANDS trial., Methods: The phase 3, open-label, randomised controlled COMMANDS trial is being conducted at 142 sites in 26 countries. Eligible patients were aged 18 years or older, had a diagnosis of myelodysplastic syndromes of very low risk, low risk, or intermediate risk (per the Revised International Prognostic Scoring System), were ESA-naive, and required red blood cell transfusions (2-6 packed red blood cell units per 8 weeks for ≥8 weeks immediately before randomisation). Integrated response technology was used to randomly assign patients (1:1, block size 4) to luspatercept or epoetin alfa, stratified by baseline red blood cell transfusion burden (<4 units per 8 weeks vs ≥4 units per 8 weeks), endogenous serum erythropoietin concentration (≤200 U/L vs >200 to <500 U/L), and ring sideroblast status (positive vs negative). Luspatercept was administered subcutaneously once every 3 weeks starting at 1·0 mg/kg body weight with possible titration up to 1·75 mg/kg. Epoetin alfa was administered subcutaneously once a week starting at 450 IU/kg body weight with possible titration up to 1050 IU/kg (maximum permitted total dose of 80 000 IU). The primary endpoint was red blood cell transfusion independence for at least 12 weeks with a concurrent mean haemoglobin increase of at least 1·5 g/dL (weeks 1-24), assessed in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. The COMMANDS trial was registered with ClinicalTrials.gov, NCT03682536 (active, not recruiting)., Findings: Between Jan 2, 2019 and Aug 31, 2022, 356 patients were randomly assigned to receive luspatercept (178 patients) or epoetin alfa (178 patients), comprising 198 (56%) men and 158 (44%) women (median age 74 years [IQR 69-80]). The interim efficacy analysis was done for 301 patients (147 in the luspatercept group and 154 in the epoetin alfa group) who completed 24 weeks of treatment or discontinued earlier. 86 (59%) of 147 patients in the luspatercept group and 48 (31%) of 154 patients in the epoetin alfa group reached the primary endpoint (common risk difference on response rate 26·6; 95% CI 15·8-37·4; p<0·0001). Median treatment exposure was longer for patients receiving luspatercept (42 weeks [IQR 20-73]) versus epoetin alfa (27 weeks [19-55]). The most frequently reported grade 3 or 4 treatment-emergent adverse events with luspatercept (≥3% patients) were hypertension, anaemia, dyspnoea, neutropenia, thrombocytopenia, pneumonia, COVID-19, myelodysplastic syndromes, and syncope; and with epoetin alfa were anaemia, pneumonia, neutropenia, hypertension, iron overload, COVID-19 pneumonia, and myelodysplastic syndromes. The most common suspected treatment-related adverse events in the luspatercept group (≥3% patients, with the most common event occurring in 5% patients) were fatigue, asthenia, nausea, dyspnoea, hypertension, and headache; and none (≥3% patients) in the epoetin alfa group. One death after diagnosis of acute myeloid leukaemia was considered to be related to luspatercept treatment (44 days on treatment)., Interpretation: In this interim analysis, luspatercept improved the rate at which red blood cell transfusion independence and increased haemoglobin were achieved compared with epoetin alfa in ESA-naive patients with lower-risk myelodysplastic syndromes. Long-term follow-up and additional data will be needed to confirm these results and further refine findings in other subgroups of patients with lower-risk myelodysplastic syndromes, including non-mutated SF3B1 or ring sideroblast-negative subgroups., Funding: Celgene and Acceleron Pharma., Competing Interests: Declaration of interests UP reports receiving grant support, paid to GWT-TUD, from Amgen; lecture fees and grant support, paid to the University of Leipzig, from Amgen; fees for serving on a steering committee, consulting fees, and travel support from Bristol Myers Squibb; grant support, paid to GWT-TUD, from Janssen Biotech; grant support, paid to University Dresden, from Merck and Novartis; lecture and consulting fees from Novartis; and consulting fees from AbbVie, Curis, and Geron. UP is also a member of the Medical and Scientific Advisory Board of the MDS Foundation. VS reports receiving research funding, paid to University of Florence, from Bristol Myers Squibb; honoraria from Bristol Myers Squibb; honoraria and travel support from Janssen; advisory board fees from AbbVie, Bristol Myers Squibb, CTI BioPharma, Geron, Gilead, Novartis, Otsuka, Servier, and Syros; and serving as the President of the Scientific Committee of the Italian Foundation of Myelodysplastic Syndromes. AMZ reports receiving grant support from AbbVie, ADC Therapeutics, Amgen, Aprea, Astex, AstraZeneca, Boehringer-Ingelheim, Cardiff Oncology, Bristol Myers Squibb, Incyte, Medimmune, Novartis, Otsuka, Pfizer, Takeda, and Trovagene; consulting fees from AbbVie, Acceleron, Agios, Amgen, Aprea, Astellas Pharma, BeyondSpring, Bristol Myers Squibb, Boehringer-Ingelheim, Cardiff Oncology, Cardinal Health, Daiichi Sankyo, Epizyme, Geron, Gilead, Incyte, Ionis, Janssen, Jazz Pharmaceuticals, Kura, Novartis, Otsuka, Pfizer, Seattle Genetics, Syndax, Taiho, Takeda, Trovagene, and Tyme; travel support from Cardiff Oncology, Novartis, and Pfizer; and serving on clinical trial committees of AbbVie, Bristol Myers Squibb, Geron, Gilead, Kura, and Novartis. RSK reports receiving grant support from Bristol Myers Squibb; speaker bureau fees from AbbVie, CTI BioPharma, Jazz Pharmaceuticals, Pharma Essentia, and Servio; and advisory board fees from AbbVie, Bristol Myers Squibb, CTI BioPharma, Geron, Jazz Pharmaceuticals, Novartis, Taiho, and Rigel Pharmaceuticals. JS reports receiving trial-related costs, paid to Monash Health, from Bristol Myers Squibb; grant support, paid to Monash University, from Amgen Australia, Astex Pharmaceuticals, and Bristol Myers Squibb; consultancy fees from Astellas Pharma, Bristol Myers Squibb, Mundipharma, Novartis, Otsuka, and Pfizer; speaker bureau fees from Mundipharma; holding patents WO2017/059319 A2 and WO2011/160170 A1, assigned to Peter MacCallum Cancer Centre, and WO2021/243421 A1, assigned to Monash University; and serving as a Deputy Chair of the Australasia Leukaemia and Lymphoma Group, Scientific Advisory Committee. DV reports receiving consulting fees from Amgen, Astellas Pharma, Bristol Myers Squibb, Jazz Pharmaceuticals, Kite Pharma, Merck Sharp & Dohme, Novartis, Sanofi, and Sobi; honoraria from Amgen, Astellas Pharma, Bristol Myers Squibb, Gebro, Grifols, Janssen, Jazz Pharmaceuticals, Kite Pharma, Merck Sharp & Dohme, Novartis, Pfizer, Sanofi, and Sobi; travel support from Amgen, Bristol Myers Squibb, and Jazz Pharmaceuticals; and advisory or data safety monitoring board fees from Novartis. AJ reports receiving consulting fees from AbbVie and Bristol Myers Squibb; honoraria from AbbVie, Bristol Myers Squibb, and Novartis; travel support from AbbVie; advisory or data safety monitoring board fees from AbbVie and Bristol Myers Squibb; and a leadership or fiduciary role in the Czech MDS Group. IST reports receiving consulting and speaker bureau fees from Pfizer. JL reports being employed by and owning stock in Bristol Myers Squibb. JZ reports being employed by and owning stock in Bristol Myers Squibb. ACG reports being employed by and owning stock in Bristol Myers Squibb. SK reports being employed by and owning stock in Bristol Myers Squibb. VP reports being employed by Bristol Myers Squibb and owning stock in Merck. KLK reports being employed by and owning stock in Bristol Myers Squibb and owning stock in Pfizer. SR reports being employed by, owning stock in, and receiving travel support from Bristol Myers Squibb. JKS reports being employed by and owning stock in Bristol Myers Squibb. SH reports being employed by Bristol Myers Squibb. SV reports being employed by and owning stock in Bristol Myers Squibb. TP reports being employed by and owning stock in Bristol Myers Squibb. TC reports receiving consulting fees from AbbVie, Celgene, Jazz Pharmaceuticals, Novartis, and Servier; honoraria from Celgene, Novartis, Servier, Syros, and Takeda; travel support from AbbVie, Celgene, Novartis, and Pfizer; and advisory or data safety monitoring board fees from Novartis. PF reports receiving honoraria from Bristol Myers Squibb and the Groupe Francophone des Myélodysplasies and serving as the chairman of the Groupe Francophone des Myélodysplasies. GG-M reports receiving grant support from Celgene. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

While it is well established that the isoform 2 of the hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN2) plays an important role in the development and maintenance of pain, the role of the closely related HCN4 isoform in the processing of nociceptive signals is not known. HCN4 channels are highly expressed in the thalamus, a region important for stimulus transmission and information processing. We used a brain-specific HCN4-knockout mouse line (HCN4-KO) to explore the role of HCN4 channels in acute nociceptive processing using several behavioral tests as well as a multimodal magnetic resonance imaging (MRI) approach. Functional MRI (fMRI) brain responses were measured during acute peripheral thermal stimulation complemented by resting state (RS) before and after stimulation. The data were analyzed by conventional and graph-theoretical approaches. Finally, high-resolution anatomical brain data were acquired. HCN4-KO animals showed a central thermal, but not a mechanical hypersensitivity in behavioral experiments. The open field analysis showed no significant differences in motor readouts between HCN4-KO and controls but uncovered increased anxiety in the HCN4-KO mice. Thermal stimulus-driven fMRI (s-fMRI) data revealed increased response volumes and response amplitudes for HCN4-KO, most pronounced at lower stimulation temperatures in the subcortical input, the amygdala as well as in limbic/hippocampal regions, and in the cerebellum. These findings could be cross-validated by graph-theoretical analyses. Assessment of short-term RS before and after thermal stimulation revealed that stimulation-related modulations of the functional connectivity only occurred in control animals. This was consistent with the finding that the hippocampus was found to be smaller in HCN4-KO. In summary, the deletion of HCN4 channels impacts on processing of acute nociception, which is remarkably manifested as a thermal hypersensitive phenotype. This was mediated by the key regions hypothalamus, somatosensory cortex, cerebellum and the amygdala. As consequence, HCN4-KO mice were more anxious, and their brain-wide RS functional connectivity could not be modulated by thermal nociceptive stimulation., Competing Interests: The author AH declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer EB declared a past co-authorship with the authors AH and IW to the handling editor., (Copyright © 2023 Häfele, Kreitz, Ludwig, Hess and Wank.)

Alcohol use, abuse, and addiction, and resulting health hazards are highly sex-dependent with unknown mechanisms. Previously, strong links between the SMPD3 gene and its coded protein neutral sphingomyelinase 2 (NSM) and alcohol abuse, emotional behavior, and bone defects were discovered and multiple mechanisms were identified for females. Here we report strong sex-dimorphisms for central, but not for peripheral mechanisms of NSM action in mouse models. Reduced NSM activity resulted in enhanced alcohol consumption in males, but delayed conditioned rewarding effects. It enhanced the acute dopamine response to alcohol, but decreased monoaminergic systems adaptations to chronic alcohol. Reduced NSM activity increased depression- and anxiety-like behavior, but was not involved in alcohol use for the self-management of the emotional state. Constitutively reduced NSM activity impaired structural development in the brain and enhanced lipidomic sensitivity to chronic alcohol. While the central effects were mostly opposite to NSM function in females, similar roles in bone-mediated osteocalcin release and its effects on alcohol drinking and emotional behavior were observed. These findings support the view that the NSM and multiple downstream mechanism may be a source of the sex-differences in alcohol use and emotional behavior., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Resiniferatoxin (RTX), an extract from the spurge plant Euphorbia resinifera, is a potent agonist of the transient receptor potential cation channel subfamily V member 1 (TRPV1), mainly expressed on peripheral nociceptors-a prerequisite for nociceptive heat perception. Systemic overdosing of RTX can be used to desensitize specifically TRPV1-expressing neurons, and was therefore utilized here to selectively characterize the influence of TRPV1-signaling on central nervous system (CNS) temperature processing. Resting state and CNS temperature processing of male rats were assessed via functional magnetic resonance imaging before and after RTX injection. General linear model-based and graph-theoretical network analyses disentangled the underlying distinct CNS circuitries. At baseline, rats displayed an increase of nociception-related response amplitude and activated brain volume that correlated highly with increasing stimulation temperatures. In contrast, RTX-treated rats showed a clear disruption of thermal nociception, reflected in a missing increase of CNS responses to temperatures above 48°C. Graph-theoretical analyses revealed two distinct brain subnetworks affected by RTX: one subcortical (brainstem, lateral and medial thalamus, hippocampus, basal ganglia and amygdala), and one cortical (primary sensory, motor and association cortices). Resting state analysis revealed first, that peripheral desensitization of TRPV1-expressing neurons did not disrupt the basic resting-state-network of the brain. Second, only at baseline, but not after RTX, noxious stimulation modulated the RS-network in regions associated with memory formation (e.g. hippocampus). Altogether, the combination of whole-brain functional magnetic resonance imaging and RTX-mediated desensitization of TRPV1-signaling provided further detailed insight into cerebral processing of noxious temperatures., Competing Interests: AH reports grants from BMBF (NeuroImpa 01EC1403C and NeuroRad 02NUK034D) during the conduct of the study. Other than that, the authors have no financial conflict of interest to declare. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

For fMRI in animal models, the combination of low-dose anesthetic, isoflurane (ISO), and the sedative medetomidine (MED) has recently become an advocated regimen to achieve stable neuronal states and brain networks in rats that are required for reliable task-induced BOLD fMRI. However, in mice the temporal stability of neuronal states and networks in resting-state (rs)-fMRI experiments during the combined ISO/MED regimen has not been systematically investigated. Using a multimodal approach with optical calcium (Ca 2+ ) recordings and rs-fMRI, we investigated cortical neuronal/astrocytic Ca 2+ activity states and brain networks at multiple time points while switching from anesthesia with 1% ISO to a combined ISO/MED regimen. We found that cortical activity states reached a steady-state 45 min following start of MED infusion as indicated by stable Ca 2+ transients. Similarly, rs-networks were not statistically different between anesthesia with ISO and the combined ISO/MED regimen 45 and 100 min after start of MED. Importantly, during the transition time we identified changed rs-network signatures that likely reflect the different mode of action of the respective anesthetic; these included a dose-dependent increase in cortico-cortical functional connectivity (FC) presumably caused by reduction of ISO concentration and decreased FC in subcortical arousal nuclei due to MED infusion. Furthermore, we report detection of visual stimulation-induced BOLD fMRI during the stable ISO/MED neuronal state 45 min after induction. Based on our findings, we recommend a 45-minute waiting period after switching from ISO anesthesia to the combined ISO/MED regimen before performing rs- or task-induced fMRI experiments., (Copyright © 2021. Published by Elsevier Inc.)

Mental disorders are highly comorbid and occur together with physical diseases, which are often considered to arise from separate pathogenic pathways. We observed in alcohol-dependent patients increased serum activity of neutral sphingomyelinase. A genetic association analysis in 456,693 volunteers found associations of haplotypes of SMPD3 coding for NSM-2 (NSM) with alcohol consumption, but also with affective state, and bone mineralisation. Functional analysis in mice showed that NSM controls alcohol consumption, affective behaviour, and their interaction by regulating hippocampal volume, cortical connectivity, and monoaminergic responses. Furthermore, NSM controlled bone-brain communication by enhancing osteocalcin signalling, which can independently supress alcohol consumption and reduce depressive behaviour. Altogether, we identified a single gene source for multiple pathways originating in the brain and bone, which interlink disorders of a mental-physical co-morbidity trias of alcohol abuse-depression/anxiety-bone disorder. Targeting NSM and osteocalcin signalling may, thus, provide a new systems approach in the treatment of a mental-physical co-morbidity trias., (© 2021. The Author(s).)