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Aileen McGonigal,1–3 Marie Arthuis,3 Jean-Arthur Micoulaud-Franchi,4,5 Fabrice Bartolomei,1–3 Eric Guedj6–8 1Institut de Neurosciences des Systèmes, INSERM UMR 1106, Marseille, France; 2Aix Marseille University, Faculty of Medicine, Marseille, France; 3Clinical Neurophysiology Department, Timone Hospital, Marseille, France; 4Department of Functional Investigation of the Nervous System, Sleep Clinic, Bordeaux University Hospital, Bordeaux, France; 5USR CNRS 3413, University of Bordeaux, France; 6Biophysics and Nuclear Medicine Department, Timone Hospital, Marseille, France; 7Aix-Marseille University, CERIMED, Marseille, France; 8Aix-Marseille University, CNRS, UMR7289, INT, Marseille, FranceWe have read with interest the recent review entitled “Uncovering the etiology of conversion disorder: insights from functional neuroimaging” by Maryam Ejareh dar and Richard AA Kanaan,1 published in Neuropsychiatric Disease and Treatment. Our paper on resting state brain metabolism measured by positron emission tomography (PET) was included and discussed.2 We were most surprised to see that the authors of the review seem to have misunderstood the findings of our study, which concerned patients with psychogenic non-epileptic seizures (PNES). The authors state that the 16 patients included in our study “were later found to have PNES with comorbid epilepsy”. This is incorrect, since our study included only patients with PNES in whom comorbid epilepsy was excluded. This crucial point is indeed detailed in the Methods section of our article and clearly stated in the abstract: “in all patients, the diagnosis was subsequently confirmed to be PNES with no coexisting epilepsy.” It is thus on the basis of incorrect understanding of our results that Drs Ejareh dar and Kanaan discuss the possible significance of hypometabolism in the anterior cingulate region described in our paper, and erroneously suggest that interpretation of PET findings is complicated by coexistent epilepsy, which was not in fact the case.Read the original article.

Background: Anterior capsulotomy is one of the therapeutic options for refractory obsessive-compulsive disorder (OCD). Safety and efficacy of Gamma Knife Capsulotomy (GKC) have been demonstrated in the past., Objective: To characterize changes induced by GKC using a fixel-based analysis (FBA) and possible predictors of efficacy., Methods: Patients with OCD refractory to other therapies underwent bilateral GKC with 120 Gy as a maximum dose on the anterior limb of the internal capsule (ALIC). The clinical outcome was percent reduction in Yale- Brown Obsessive-Compulsive Scale (Y-BOCS). White Matter changes were analyzed using fixel-based analysis (FBA) for fibre density (FD), fibre-bundle cross-section (FC) and the combination of the two (FDC)., Results: Seven patients underwent GKC. Median follow-up was 13 months (range 12-58 months). Mean (±SD) decrease in Y-BOCS score at last follow-up was 61 % ± 35 % with five patients considered as responders. FBA showed a symmetric FD reduction in the ALIC with extension to the anterior fronto-thalamic radiation; a reduction of FC along the superior longitudinal fasciculus (SLF) in both hemispheres with a predominance in the left one. Reductions in FDC were detected predominantly in the right hemisphere, with a similar pattern to FD reductions and associated with a positive correlation (p < 0.05) between Y-BOCS reduction and fibres passing in the ventral part., Conclusions: GKC is safe and efficient in reducing OCD severity in selected patients. Changes induced in white matter by GKC extend over the ALIC. Reduction of fibres passing the ventral part of the right sided ALIC correlates with better results., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Jirsa Viktor reports financial support was provided by 10.13039/100007586Aix-Marseille University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Cigarette smoking is a major preventable cause of morbidity and mortality. While quitting smoking is the best option, switching from cigarettes to non-combustible alternatives (NCAs) such as e-vapor products is a viable harm reduction approach for smokers who would otherwise continue to smoke. A key challenge for the clinical assessment of NCAs is that self-reported product use can be unreliable, compromising the proper evaluation of their risk reduction potential. In this cross-sectional study of 205 healthy volunteers, we combined comprehensive exposure characterization with in-depth multi-omics profiling to compare effects across four study groups: cigarette smokers (CS), e-vapor users (EV), former smokers (FS), and never smokers (NS). Multi-omics analyses included metabolomics, transcriptomics, DNA methylomics, proteomics, and lipidomics. Comparison of the molecular effects between CS and NS recapitulated several previous observations, such as increased inflammatory markers in CS. Generally, FS and EV demonstrated intermediate molecular effects between the NS and CS groups. Stratification of the FS and EV by combustion exposure markers suggested that this position on the spectrum between CS and NS was partially driven by non-compliance/dual use. Overall, this study highlights the importance of in-depth exposure characterization before biological effect characterization for any NCA assessment study., (© 2024. The Author(s).)

Therapeutic approaches to brain tumors remain a challenge, with considerable limitations regarding delivery of drugs. There has been renewed and increasing interest in translating the popular theranostic approach well known from prostate and neuroendocrine cancer to neurooncology. Although far from perfect, some of these approaches show encouraging preliminary results, such as for meningioma and leptomeningeal spread of certain pediatric brain tumors. In brain metastases and gliomas, clinical results have failed to impress. Perspectives on these theranostic approaches regarding meningiomas, brain metastases, gliomas, and common pediatric brain tumors will be discussed. For each tumor entity, the general context, an overview of the literature, and future perspectives will be provided. Ongoing studies will be discussed in the supplemental materials. As most theranostic agents are unlikely to cross the blood-brain barrier, the delivery of these agents will be dependent on the successful development and clinical implementation of techniques enhancing permeability and retention. Moreover, the international community should strive toward sufficiently large and randomized studies to generate high-level evidence on theranostic approaches with radioligand therapies for central nervous system tumors., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Science is beginning to establish the benefits of the use of virtual reality (VR) in health care. This therapeutic approach may be an appropriate complementary treatment for some mental illnesses. It could prevent high levels of morbidity and improve the physical health of patients. For many years, the literature has shown the health benefits of physical exercise. Physical exercise in a VR environment may improve the management of mild to moderate mental health conditions. In this context, we developed a virtual environment combined with an ergocycle (the augmented physical training for isolated and confined environments [APTICE] system)., Objective: This study aims to investigate the impact of physical exercise in a VR environment., Methods: A total of 14 healthy participants (11 men and 3 women; mean age 43.28, SD 10.60 years) undertook 15 minutes of immersive physical exercise using the system. Measures included mindfulness and immersion disposition, subjective perceptions of sensory information, user experience, and VR experience (ie, psychological state, flow, and presence)., Results: First, the APTICE system appears to be a useful tool because the user experience is positive (subscales in the AttrakDiff questionnaire: pragmatic quality=0.99; hedonic quality-stimulation=1.90; hedonic quality-identification=0.67; attractiveness=1.58). Second, the system can induce a positive psychological state (negative emotion, P=.06) and an experience of flow and presence (P values ranging from <.001 to .04). Third, individual immersive and mindful disposition plays a role in the VR experience (P values ranging from <.02 to .04). Finally, our findings suggest that there is a link between the subjective perception of sensory information and the VR experience (P values ranging from <.02 to .04)., Conclusions: These results indicate that the device is well accepted with positive psychological and exteroceptive outcomes. Overall, the APTICE system could be a proof of concept to explore the benefits of virtual physical exercise in clinical medicine., (©Barbara Le Roy, Charles Martin-Krumm, Charlotte Poupon, Raphaëlle Richieri, Eric Malbos, Fanny Barthélémy, Eric Guedj, Marion Trousselard. Originally published in JMIR Formative Research (https://formative.jmir.org), 22.01.2024.)

Background: Brain [ 18 F]FDG PET is used clinically mainly in the presurgical evaluation for epilepsy surgery and in the differential diagnosis of neurodegenerative disorders. While scans are usually interpreted visually on an individual basis, comparison against normative cohorts allows statistical assessment of abnormalities and potentially higher sensitivity for detecting abnormalities. Little work has been done on out-of-sample databases (acquired differently to the patient data). Combination of different databases would potentially allow better power and discrimination. We fully characterised an unpublished healthy control brain [ 18 F]FDG PET database (Marseille, n = 60, ages 21-78 years) and compared it to another publicly available database (MRXFDG, n = 37, ages 23-65 years). We measured and then harmonised spatial resolution and global values. A collection of patient scans (n = 34, 13-48 years) with histologically confirmed focal cortical dysplasias (FCDs) obtained on three generations of scanners was used to estimate abnormality detection rates using standard software (statistical parametric mapping, SPM12)., Results: Regional SUVs showed similar patterns, but global values and resolutions were different as expected. Detection rates for the FCDs were 50% for comparison with the Marseille database and 53% for MRXFDG. Simply combining both databases worsened the detection rate to 41%. After harmonisation of spatial resolution, using a full factorial design matrix to accommodate global differences, and leaving out controls older than 60 years, we achieved detection rates of up to 71% for both databases combined. Detection rates were similar across the three scanner types used for patients, and high for patients whose MRI had been normal (n = 10/11)., Conclusions: As expected, global and regional data characteristics are database specific. However, our work shows the value of increasing database size and suggests ways in which database differences can be overcome. This may inform analysis via traditional statistics or machine learning, and clinical implementation., (© 2023. The Author(s).)

Introduction: Alpha-synuclein (α-Syn) aggregation, transmission, and contribution to neurotoxicity represent central mechanisms underlying Parkinson's disease. The plant alkaloid "nicotine" was reported to attenuate α-Syn aggregation in different models, but its precise mode of action remains unclear., Methods: In this study, we investigated the effect of 2-week chronic nicotine treatment on α-Syn aggregation, neuroinflammation, neurodegeneration, and motor deficits in D-line α-Syn transgenic mice. We also established a novel humanized neuronal model of α-Syn aggregation and toxicity based on treatment of dopaminergic neurons derived from human induced pluripotent stem cells (iPSC) with α-Syn preformed fibrils (PFF) and applied this model to investigate the effects of nicotine and other compounds and their modes of action., Results and Discussion: Overall, our results showed that nicotine attenuated α-Syn-provoked neuropathology in both models. Moreover, when investigating the role of nicotinic acetylcholine receptor (nAChR) signaling in nicotine's neuroprotective effects in iPSC-derived dopaminergic neurons, we observed that while α4-specific antagonists reduced the nicotine-induced calcium response, α4 agonists (e.g., AZD1446 and anatabine) mediated similar neuroprotective responses against α-Syn PFF-provoked neurodegeneration. Our results show that nicotine attenuates α-Syn-provoked neuropathology in vivo and in a humanized neuronal model of synucleinopathy and that activation of α4β2 nicotinic receptors might mediate these neuroprotective effects., Competing Interests: OA, SJ, AK, RD, DP, CN, JB, EG, NS, DM, and CM are employees of Philip Morris International. MP was a PMI employee at the time of the study and is now retired. JH was a PMI employee at the time of the study and is now an employee of Vectura Fertin Pharma. MF was a PMI employee at the time of the study and is now a co-founder and director of R&D at ND Biosciences, a company developing next-generation therapeutics and diagnostics for neurodegenerative diseases. 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 Fares, Alijevic, Johne, Overk, Hashimoto, Kondylis, Adame, Dulize, Peric, Nury, Battey, Guedj, Sierro, Mc Hugh, Rockenstein, Kim, Rissman, Hoeng, Peitsch, Masliah and Mathis.)

68 Ga-DOTATOC PET could be a noninvasive, highly sensitive, and specific technique for the challenging diagnosis of optic nerve sheath meningioma (ONSM). Our objective was to report the use and results of 68 Ga-DOTATOC PET in suspected ONSM. Twelve subjects who underwent 68 Ga-DOTATOC PET for suspected ONSM in our department were retrospectively included. Standardised clinical and radiological data were collected. The PET examination results were classified as positive or negative, and lesion standardised uptake values (SUV max ) were recorded. 68 Ga-DOTATOC PET confirmed positive uptake in six cases (SUV max > 5), leading to ONSM diagnoses followed by radiation therapy in patients with vision loss. Six 68 Ga-DOTATOC PET scans were considered negative (SUV max < 5); these comprised one case of neurosarcoidosis, one cavernous malformation, and four uncertain diagnoses, leading to further investigation. 68 Ga-DOTATOC PET was helpful in tumour volume delineation before radiation therapy, leading to a decrease in dose exposure. Noninvasive 68 Ga-DOTATOC PET should be performed before treating nonhistologically proven meningiomas with radiotherapy or stereotactic radiosurgery, particularly in cases of uncertain diagnosis with MRI, which characterises most ONSM cases. PET SUV max thresholds to distinguish meningioma from nonspecific uptake in other lesions need to be adapted to ONSM. 68 Ga-DOTATOC PET improves the intraorbital lesion diagnostic approach and therefore impacts therapeutic management.

There is a lack of imaging markers revealing the functional characteristics of different brain regions in paediatric dystonia. In this observational study, we assessed the utility of [18F]2-fluoro-2-deoxy-D-glucose (FDG)-PET in understanding dystonia pathophysiology by revealing specific resting awake brain glucose metabolism patterns in different childhood dystonia subgroups. PET scans from 267 children with dystonia being evaluated for possible deep brain stimulation surgery between September 2007 and February 2018 at Evelina London Children's Hospital (ELCH), UK, were examined. Scans without gross anatomical abnormality (e.g. large cysts, significant ventriculomegaly; n = 240) were analysed with Statistical Parametric Mapping (SPM12). Glucose metabolism patterns were examined in the 144/240 (60%) cases with the 10 commonest childhood-onset dystonias, focusing on nine anatomical regions. A group of 39 adult controls was used for comparisons. The genetic dystonias were associated with the following genes: TOR1A, THAP1, SGCE, KMT2B, HPRT1 (Lesch Nyhan disease), PANK2 and GCDH (Glutaric Aciduria type 1). The acquired cerebral palsy (CP) cases were divided into those related to prematurity (CP-Preterm), neonatal jaundice/kernicterus (CP-Kernicterus) and hypoxic-ischaemic encephalopathy (CP-Term). Each dystonia subgroup had distinct patterns of altered FDG-PET uptake. Focal glucose hypometabolism of the pallidi, putamina or both, was the commonest finding, except in PANK2, where basal ganglia metabolism appeared normal. HPRT1 uniquely showed glucose hypometabolism across all nine cerebral regions. Temporal lobe glucose hypometabolism was found in KMT2B, HPRT1 and CP-Kernicterus. Frontal lobe hypometabolism was found in SGCE, HPRT1 and PANK2. Thalamic and brainstem hypometabolism were seen only in HPRT1, CP-Preterm and CP-term dystonia cases. The combination of frontal and parietal lobe hypermetabolism was uniquely found in CP-term cases. PANK2 cases showed a distinct combination of parietal hypermetabolism with cerebellar hypometabolism but intact putaminal-pallidal glucose metabolism. HPRT1, PANK2, CP-kernicterus and CP-preterm cases had cerebellar and insula glucose hypometabolism as well as parietal glucose hypermetabolism. The study findings offer insights into the pathophysiology of dystonia and support the network theory for dystonia pathogenesis. 'Signature' patterns for each dystonia subgroup could be a useful biomarker to guide differential diagnosis and inform personalized management strategies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Inflammatory bowel disease (IBD) refers to chronic intestinal immune-mediated diseases including two main disease manifestations: ulcerative colitis (UC) and Crohn's disease (CD). Epidemiological, clinical, and preclinical evidence has highlighted the potential anti-inflammatory properties of naturally occurring alkaloids. In the present study, we investigated the potential anti-inflammatory activities of the tobacco alkaloids nicotine and anatabine in a dextran sulfate sodium (DSS)-induced UC mouse model with a fully humanized immune system. Our results show that nicotine significantly reduced all acute colitis symptoms and improved colitis-specific endpoints, including histopathologically assessed colon inflammation, tissue damage, and mononuclear cell infiltration. The tobacco alkaloid anatabine showed similar effectiveness trends, although they were generally weaker or not significant. Gene expression analysis in the context of biological network models of IBD further pinpointed a possible mechanism by which nicotine attenuated DSS-induced colitis in humanized mice. The current study enables further investigation of possible molecular mechanisms by which tobacco alkaloids attenuate UC symptoms.

Anatabine, an alkaloid present in plants of the So lanaceae family (including tobacco and eggplant), has been shown to ameliorate chronic inflammatory conditions in mouse models, such as Alzheimer's disease, Hashimoto's thyroiditis, multiple sclerosis, and intestinal inflammation. However, the mechanisms of action of anatabine remain unclear. To understand the impact of anatabine on cellular systems and identify the molecular pathways that are perturbed, we designed a study to examine the concentration-dependent effects of anatabine on various cell types by using a systems pharmacology approach. The resulting dataset, consisting of measurements of various omics data types at different time points, was analyzed by using multiple computational techniques. To identify concentration-dependent activated pathways, we performed linear modeling followed by gene set enrichment. To predict the functional partners of anatabine and the involved pathways, we harnessed the LINCS L1000 dataset's wealth of information and implemented integer linear programming on directed graphs, respectively. Finally, we experimentally verified our key computational predictions. Using an appropriate luciferase reporter cell system, we were able to demonstrate that anatabine treatment results in NRF2 (nuclear factor-erythroid factor 2-related factor 2) translocation, and our systematic phosphoproteomic assays showed that anatabine treatment results in activation of MAPK signaling. While there are certain areas to be explored in deciphering the exact anti-inflammatory mechanisms of action of anatabine and other NRF2 activators, we believe that anatabine constitutes an interesting molecule for its therapeutic potential in NRF2-related diseases., Competing Interests: All authors are employees of Philip Morris International., (Copyright © 2022 Messinis, Poussin, Latino, Eb-Levadoux, Dulize, Peric, Guedj, Titz, Ivanov, Peitsch and Hoeng.)

Background: SARS-CoV-2 infection can impair diaphragm function at the acute phase but the frequency of diaphragm dysfunction after recovery from COVID-19 remains unknown., Materials and Methods: This study was carried out on patients reporting persistent respiratory symptoms 3-4 months after severe COVID-19 pneumonia. The included patients were selected from a medical consultation designed to screen for recovery after acute infection. Respiratory function was assessed by a pulmonary function test, and diaphragm function was studied by ultrasonography., Results: In total, 132 patients (85M, 47W) were recruited from the medical consultation. During the acute phase of the infection, the severity of the clinical status led to ICU admission for 58 patients (44%). Diaphragm dysfunction (DD) was detected by ultrasonography in 13 patients, two of whom suffered from hemidiaphragm paralysis. Patients with DD had more frequently muscle pain complaints and had a higher frequency of prior cardiothoracic or upper abdominal surgery than patients with normal diaphragm function. Pulmonary function testing revealed a significant decrease in lung volumes and DLCO and the dyspnea scores (mMRC and Borg10 scores) were significantly increased in patients with DD. Improvement in respiratory function was recorded in seven out of nine patients assessed 6 months after the first ultrasound examination., Conclusion: Assessment of diaphragm function by ultrasonography after severe COVID-19 pneumonia revealed signs of dysfunction in 10% of our population. In some cases, ultrasound examination probably discovered an un-recognized pre-existing DD. COVID-19 nonetheless contributed to impairment of diaphragm function. Prolonged respiratory physiotherapy led to improvement in respiratory function in most patients., Clinical Trial Registration: [www.cnil.fr], identifier [#PADS20-207]., Competing Interests: GC was employed by ALTRA BIO. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest., (Copyright © 2022 Boussuges, Habert, Chaumet, Rouibah, Delorme, Menard, Million, Bartoli, Guedj, Gouitaa, Zieleskiewicz, Finance, Coiffard, Delliaux and Brégeon.)

Somatostatin receptor (SSTR)-targeted peptide receptor radionuclide therapy (PRRT) represents a promising approach for treatment-refractory meningiomas progressing after surgery and radiotherapy. The aim of this study was to provide outcomes of patients harboring refractory meningiomas treated by 177Lu-DOTATATE and an overall analysis of progression-free survival at 6 months (PFS-6) of the same relevant studies in the literature. Eight patients with recurrent and progressive WHO grade II meningiomas were treated after multimodal pretreatment with 177Lu-DOTATATE between 2019 and 2022. Primary and secondarily endpoints were progression-free survival at 6-months (PFS-6) and toxicity, respectively. PFS-6 analysis of our case series was compared with other similar relevant studies that included 86 patients treated with either 177Lu-DOTATATE or 90Y-DOTATOC. Our retrospective study showed a PFS-6 of 85.7% for WHO grade II progressive refractory meningiomas. Treatment was clinically and biologically well tolerated. The overall analysis of the previous relevant studies showed a PFS-6 of 89.7% for WHO grade I meningiomas ( n = 29); 57.1% for WHO grade II ( n = 21); and 0 % for WHO grade III ( n = 12). For all grades ( n = 86), including unknown grades, PFS-6 was 58.1%. SSTR-targeted PRRT allowed us to achieve prolonged PFS-6 in patients with WHO grade I and II progressive refractory meningiomas, except the most aggressive WHO grade II tumors. Large scale randomized trials are warranted for the better integration of PRRT in the treatment of refractory meningioma into clinical practice guidelines.

The relationship between posttraumatic stress disorder (PTSD) and focal epilepsy is poorly understood. It has been hypothesized that there is a complex and reciprocal potential reinforcement of the symptoms of each condition. In this study, we investigated whether there are PTSD-specific brain changes in temporal lobe epilepsy (TLE). Brain fluorodeoxyglucose positron emission tomography (PET) metabolism was compared between controls and two groups of TLE patients: one group of 15 patients fulfilling the criteria for a potential diagnosis of PTSD (TLE-PTSD+), another group of 24 patients without a diagnosis of PTSD (TLE-PTSD-), and a group of 30 healthy control participants. We compared the differences in brain PET metabolism among these three groups, and we studied their correlations with interictal and peri-ictal scales of PTSD symptoms. TLE-PTSD+ patients showed more significant hypometabolism involving right temporal and right orbitofrontal cortex in comparison to TLE-PTSD- patients and healthy subjects. Moreover, degree of reduced metabolism in these brain areas correlated with interictal and peri-ictal PTSD questionnaire scores. PTSD in temporal epilepsy is associated with specific changes in neural networks, affecting limbic and paralimbic structures. This illustrates the close intertwining of epileptogenic and psychogenic processes in these patients., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: With the strengths of deep learning, computer-aided diagnosis (CAD) is a hot topic for researchers in medical image analysis. One of the main requirements for training a deep learning model is providing enough data for the network. However, in medical images, due to the difficulties of data collection and data privacy, finding an appropriate dataset (balanced, enough samples, etc.) is quite a challenge. Although image synthesis could be beneficial to overcome this issue, synthesizing 3D images is a hard task. The main objective of this paper is to generate 3D T1 weighted MRI corresponding to FDG-PET. In this study, we propose a separable convolution-based Elicit generative adversarial network (E-GAN). The proposed architecture can reconstruct 3D T1 weighted MRI from 2D high-level features and geometrical information retrieved from a Sobel filter. Experimental results on the ADNI datasets for healthy subjects show that the proposed model improves the quality of images compared with the state of the art. In addition, the evaluation of E-GAN and the state of art methods gives a better result on the structural information (13.73% improvement for PSNR and 22.95% for SSIM compared to Pix2Pix GAN) and textural information (6.9% improvements for homogeneity error in Haralick features compared to Pix2Pix GAN).

PET plays an increasingly important role in the management of brain tumors. This review outlines currently available PET radiotracers and their respective indications. It specifically focuses on 18 F-FDG, amino acid and somatostatin receptor radiotracers, for imaging gliomas, meningiomas, primary central nervous system lymphomas as well as brain metastases. Recent advances in radiopharmaceuticals, image analyses and translational applications to therapy are also discussed. The objective of this review is to provide a comprehensive overview of PET imaging's potential in neuro-oncology as an adjunct to brain MRI for all medical professionals implicated in brain tumor diagnosis and care.

This study aims to evaluate the impact of French national lockdown of 55 days on brain metabolism of patients with neurological disorders. Whole-brain voxel-based PET analysis was used to correlate 18 F-FDG metabolism to the number of days after March 17, 2020 (in 95 patients; mean age: 54.3 years ± 15.7; 59 men), in comparison to the same period in 2019 before the SARS-CoV-2 outbreak (in 212 patients; mean age: 59.5 years ± 15.8; 114 men), and to the first 55 days of deconfinement (in 188 patients; mean age: 57.5 years ± 16.5; 93 men). Lockdown duration was negatively correlated to the metabolism of the sensory-motor cortex with a prevailing effect on the left dominant pyramidal tract and on younger patients, also including the left amygdala, with only partial reversibility after 55 days of deconfinement. Weak overlap was found with the reported pattern of hypometabolism in long COVID (<9%). Restriction of physical activities, and possible related deconditioning, and social isolation may lead to functional disturbances of sensorimotor and emotional brain networks. Of note, this metabolic pattern seems distinct to those reported in long COVID. Further longitudinal studies with longer follow-up are needed to evaluate clinical consequences and relationships on cognitive and mental health against functional deactivation hypothesis, and to extend these findings to healthy subjects in the context of lockdown., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

18 F-FDG PET provides high sensitivity for the pre-surgical assessment of drug-resistant temporal lobe epilepsy (TLE). However, little is known about the metabolic connectivity of epileptogenic networks involved. This study therefore aimed to evaluate the association between metabolic connectivity and seizure outcome in surgically treated TLE., Methods: The study included 107 right-handed patients that had undergone a presurgical interictal 18 F-FDG PET assessment followed by an anterior temporal lobectomy and were classified according to seizure outcome 2 years after surgery. Metabolic connectivity was evaluated by seed correlation analysis in left and right epilepsy patients with a Class Engel IA or > IA outcome and compared to age-, sex- and handedness-matched healthy controls., Results: Increased metabolic connectivity was observed in the >IA compared to the IA group within the operated temporal lobe (respective clusters of 7.5 vs 3.3 cm 3 and 2.6 cm 3 vs 2.2 cm 3 in left and right TLE), and to a lower extent with the contralateral temporal lobe (1.2 vs 0.7 cm 3 and 1.7 cm 3 vs 0.7 cm 3 in left and right TLE). Seed correlations provided added value for the estimated individual performance of seizure outcome over the group comparisons in left TLE (AUC of 0.74 vs 0.67)., Conclusion: Metabolic connectivity is associated with outcome in surgically treated TLE with a strengthened epileptogenic connectome in patients with non-free-seizure outcomes. The added value of seed correlation analysis in left TLE underlines the importance of evaluating metabolic connectivity in network related diseases., 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 © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Trehalose is added in drug formulations to act as fillers or improve aerosolization performance. Its characteristics as a carrier molecule have been explored; however, the fate of trehalose in human airway tissues has not been thoroughly investigated. Here, we investigated the fate of nebulized trehalose using in vitro human air-liquid bronchial epithelial cultures. First, a tracing experiment was conducted using 13 C 12 -trehalose; we measured trehalose distribution in different culture compartments (apical surface liquid, epithelial culture, and basal side medium) at various time points following acute exposure to 13 C 12 -labeled trehalose. We found that 13 C 12 -trehalose was metabolized into 13 C 6 -glucose. The data was then used to model the kinetics of trehalose disappearance from the apical surface of bronchial cultures. Secondly, we evaluated the potential adverse effects of nebulized trehalose on the bronchial cultures after they were acutely exposed to nebulized trehalose up to a level just below its solubility limit (50 g/100 g water). We assessed the ciliary beating frequency and histological characteristics. We found that nebulized trehalose did not lead to marked alteration in ciliary beating frequency and morphology of the epithelial cultures. The in vitro testing approach used here may enable the early selection of excipients for future development of inhalation products., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We aimed to explore brain area(s) involved in the generation of ictal asystole (IA) by analyzing the interictal positron emission tomography (PET) metabolism of patients with IA recorded by video-electroencephalography or video-stereo-electroencephalography. We identified in our cohort of focal epilepsy patients who had undergone presurgical evaluation those who had a recorded period of IA of more than 3 s. We investigated the anatomometabolic changes (interictal 18 F-fluorodeoxyglucose PET) of these patients in comparison with (1) healthy subjects with similar age and sex distribution (n = 19) using whole-brain voxel-based analysis (p-voxel < .001, p-cluster < .05, uncorrected) and (2) patients without IA with similar age and seizure onset zone (n = 55). We found 12 patients with IA. Epilepsy was mainly temporal (four right temporal mesial, four bitemporal, two left temporal lateral, one right temporal lateral, and one right temporal "plus"). Seven patients had negative magnetic resonance imaging. Whole-brain statistical analysis of PET imaging was performed at the voxel level, showing that in comparison to healthy subjects and to epileptic patients without IA, a hypometabolism in the right posterior insula characterized epileptic patients with IA. Our study suggests involvement of the right posterior insula-a part of the central autonomic network-in the pathophysiological mechanism of IA., (© 2021 International League Against Epilepsy.)

We retrospectively examined the relationship between blood biomarkers, in particular the historical mean phenylalanine to tyrosine (Phe:Tyr) ratio, and cerebral glucose metabolism. We hypothesized that the historical mean Phe:Tyr ratio would be more predictive of cerebral glucose metabolism than the phenylalanine (Phe) level alone. We performed a retrospective case series analysis involving 11 adult classical phenylketonuria/hyperphenylalaninemia patients under the care of an Inherited Metabolic & Neuropsychiatry Clinic who had complained of memory problems, collating casenote data from blood biochemistry, and clinical [ 18 F]fluorodeoxyglucose positron emission tomography ([ 18 F]FDG PET). The Phe:Tyr ratio was calculated for individual blood samples and summarized as historical mean Phe:Tyr ratio (Phe:Tyr) and historical standard deviation in Phe:Tyr ratio (SD-Phe:Tyr), for each patient. Visual analyses of [ 18 F]FDG PET revealed heterogeneous patterns of glucose hypometabolism for eight patients. [ 18 F]FDG PET standardized uptake was negatively correlated with Phe in a large cluster with peak localized to right superior parietal gyrus. Even larger clusters of negative correlation that encompassed most of the brain, with frontal peaks, were observed with Phe:Tyr, and SD-Phe:Tyr. Our case series analysis provides further evidence for the association between blood biomarkers, and cerebral glucose hypometabolism. Mean historical blood Phe:Tyr ratio, and its standard deviation over time, appear to be more indicative of global cerebral glucose metabolism in patients with memory problems than Phe., 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 © 2021 McGinnity, Riaño Barros, Guedj, Girard, Symeon, Walker, Barrington, Summers, Pitkanen and Rahman.)

Background: The objective of the study is to define the most appropriate region for intensity normalization in brain 18 FDG PET semi-quantitative analysis. The best option could be based on previous absolute quantification studies, which showed that the metabolic changes related to ageing affect the quasi-totality of brain regions in healthy subjects. Consequently, brain metabolic changes related to ageing were evaluated in two populations of healthy controls who underwent conventional (n = 56) or digital (n = 78) 18 FDG PET/CT. The median correlation coefficients between age and the metabolism of each 120 atlas brain region were reported for 120 distinct intensity normalizations (according to the 120 regions). SPM linear regression analyses with age were performed on most significant normalizations (FWE, p < 0.05)., Results: The cerebellum and pons were the two sole regions showing median coefficients of correlation with age less than - 0.5. With SPM, the intensity normalization by the pons provided at least 1.7- and 2.5-fold more significant cluster volumes than other normalizations for conventional and digital PET, respectively., Conclusions: The pons is the most appropriate area for brain 18 FDG PET intensity normalization for examining the metabolic changes through ageing.

Mice, especially A/J mice, have been widely employed to elucidate the underlying mechanisms of lung tumor formation and progression and to derive human-relevant modes of action. Cigarette smoke (CS) exposure induces tumors in the lungs; but, non-exposed A/J mice will also develop lung tumors spontaneously with age, which raises the question of discriminating CS-related lung tumors from spontaneous ones. However, the challenge is that spontaneous tumors are histologically indistinguishable from the tumors occurring in CS-exposed mice. We conducted an 18-month inhalation study in A/J mice to assess the impact of lifetime exposure to Tobacco Heating System (THS) 2.2 aerosol relative to exposure to 3R4F cigarette smoke (CS) on toxicity and carcinogenicity endpoints. To tackle the above challenge, a 13-gene gene signature was developed based on an independent A/J mouse CS exposure study, following by a one-class classifier development based on the current study. Identifying gene signature in one data set and building classifier in another data set addresses the feature/gene selection bias which is a well-known problem in literature. Applied to data from this study, this gene signature classifier distinguished tumors in CS-exposed animals from spontaneous tumors. Lung tumors from THS 2.2 aerosol-exposed mice were significantly different from those of CS-exposed mice but not from spontaneous tumors. The signature was also applied to human lung adenocarcinoma gene expression data (from The Cancer Genome Atlas) and discriminated cancers in never-smokers from those in ever-smokers, suggesting translatability of our signature genes from mice to humans. A possible application of this gene signature is to discriminate lung cancer patients who may benefit from specific treatments (i.e., EGFR tyrosine kinase inhibitors). Mutational spectra from a subset of samples were also utilized for tumor classification, yielding similar results. "Landscaping" the molecular features of A/J mouse lung tumors highlighted, for the first time, a number of events that are also known to play a role in human lung tumorigenesis, such as Lrp1b mutation and Ros1 overexpression. This study shows that omics and computational tools provide useful means of tumor classification where histopathological evaluation alone may be unsatisfactory to distinguish between age- and exposure-related lung tumors., Competing Interests: YX, KL, FM, JB, KT, LN, EW, EG, RD, DP, DB, SO, NS, NI, PV, JH, and MP are employed by Philip Morris International (PMI). AB is an employee of Histovia GmbH, who was contracted and paid by Philip Morris International (PMI)., (Copyright © 2021 Xiang, Luettich, Martin, Battey, Trivedi, Neau, Wong, Guedj, Dulize, Peric, Bornand, Ouadi, Sierro, Büttner, Ivanov, Vanscheeuwijck, Hoeng and Peitsch.)

Alzheimer's Disease (AD), one of the main causes of death in elderly people, is characterized by Mild Cognitive Impairment (MCI) at prodromal stage. Nevertheless, only part of MCI subjects could progress to AD. The main objective of this paper is thus to identify those who will develop a dementia of AD type among MCI patients. 18 F-FluoroDeoxyGlucose Positron Emission Tomography ( 18 F-FDG PET) serves as a neuroimaging modality for early diagnosis as it can reflect neural activity via measuring glucose uptake at resting-state. In this paper, we design a deep network on 18 F-FDG PET modality to address the problem of AD identification at early MCI stage. To this end, a Multi-view Separable Pyramid Network (MiSePyNet) is proposed, in which representations are learned from axial, coronal and sagittal views of PET scans so as to offer complementary information and then combined to make a decision jointly. Different from the widely and naturally used 3D convolution operations for 3D images, the proposed architecture is deployed with separable convolution from slice-wise to spatial-wise successively, which can retain the spatial information and reduce training parameters compared to 2D and 3D networks, respectively. Experiments on ADNI dataset show that the proposed method can yield better performance than both traditional and deep learning-based algorithms for predicting the progression of Mild Cognitive Impairment, with a classification accuracy of 83.05%.

We report the case of a 72-y-old man with concomitant autoimmune encephalitis and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The patient presented with subacute cerebellar syndrome and myoclonus several days after general infectious symptoms began. Methods: Clinical examination, CT, PET, MRI, and autoantibody testing were performed. Results: The oropharyngeal swab test was positive for SARS-CoV-2. The brain MRI results were normal. Cerebrospinal fluid testing showed normal cell counts, a negative result on reverse-transcription polymerase chain reaction testing, and no oligoclonal banding. Brain 18 F-FDG PET showed diffuse cortical hypometabolism associated with putaminal and cerebellum hypermetabolism, compatible with encephalitis and especially cerebellitis. The immunologic study revealed high titers of IgG autoantibodies in serum and cerebrospinal fluid directed against the nuclei of Purkinje cells, striatal neurons, and hippocampal neurons. Whole-body 18 F-FDG PET and CT scans did not show neoplasia. Treatment with steroids allowed a rapid improvement in symptoms. Conclusion: This clinical case argues for a possible relationship between SARS-CoV-2 infection and autoimmune encephalitis and for the use of 18 F-FDG PET in such a context., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: Digital PET cameras markedly improve sensitivity and spatial resolution of brain 18 F-FDG PET images compared to conventional cameras. Our study aimed to assess whether specific control databases are required to improve the diagnostic performance of these recent advances., Methods: We retrospectively selected two groups of subjects, twenty-seven Alzheimer's Disease (AD) patients and twenty-two healthy control (HC) subjects. All subjects underwent a brain 18 F-FDG PET on a digital camera (Vereos, Philips®). These two group (AD and HC) are compared, using a Semi-Quantitative Analysis (SQA), to two age and sex matched controls acquired with a digital PET/CT (Vereos, Philips®) or a conventional PET/CT (Biograph 6, Siemens®) camera, at group and individual levels. Moreover, individual visual interpretation of SPM T-maps was provided for the positive diagnosis of AD by 3 experienced raters., Results: At group level, SQA using digital controls detected more marked hypometabolic areas in AD (+ 116 cm 3 at p < 0.001 uncorrected for the voxel, corrected for the cluster) than SQA using conventional controls. At the individual level, the accuracy of SQA for discriminating AD using digital controls was higher than SQA using conventional controls (86% vs. 80%, p < 0.01, at p < 0.005 uncorrected for the voxel, corrected for the cluster), with higher sensitivity (89% vs. 78%) and similar specificity (82% vs. 82%). These results were confirmed by visual analysis (accuracies of 84% and 82% for digital and conventional controls respectively, p = 0.01)., Conclusion: There is an urgent need to establish specific digital PET control databases for SQA of brain 18 F-FDG PET images as such databases improve the accuracy of AD diagnosis.

Background: Brain SPECT perfusion and PET metabolism have been, most often interchangeably, proposed to study the underlying pathological process in major depressive disorder (MDD). The objective of this study was to specify similarities and inconsistencies between these two biomarkers according to global characteristics of the disease. We conducted a retrospective study in 16 patients suffering from treatment-resistant MDD who underwent, during the same current episode, a cerebral perfusion SPECT with 99m Tc-HMPAO and a metabolic PET with 18 F-FDG. Whole-brain voxel-based SPM(T) maps were generated in correlation with the number of depressive episodes and in correlation with the depression duration, separately for the two exams (p-voxel < 0.001 uncorrected, k > 20)., Results: No significant correlations were found between brain metabolism and either the number of depressive episodes or the duration of the disease, even at an uncorrected p-voxel < 0.005. On the other hand, the increased number of depressive episodes was correlated with decreased perfusion of the right middle frontal cortex, the right anterior cingulum cortex, the right insula, the right medial temporal cortex and the left precuneus. The increased depression duration was correlated with decreased perfusion of the right anterior cingulum cortex., Conclusions: This preliminary study demonstrates more significant results with brain perfusion compared with glucose metabolism in treatment-resistant MDD, highlighting the value of brain SPECT despite less favourable instrumentation detection compared to PET.

Background: Inflammatory bowel disease (IBD) is the collective term for chronic immune-mediated diseases of unknown, multifactorial etiology, arising from the interplay between genetic and environmental factors and including two main disease manifestations: ulcerative colitis (UC) and Crohn's disease. In the last few decades, naturally occurring alkaloids have gained interest because of their substantial anti-inflammatory effects in several animal models of disease. Studies on mouse models of IBD have demonstrated the anti-inflammatory action of the main tobacco alkaloid, nicotine. In addition, anatabine, a minor tobacco alkaloid also present in peppers, tomato, and eggplant presents anti-inflammatory properties in vivo and in vitro. In this study, we aimed to evaluate the anti-inflammatory properties of nicotine and anatabine in a dextran sulfate sodium (DSS) mouse model of UC., Results: Oral administration of anatabine, but not nicotine, reduced the clinical symptoms of DSS-induced colitis. The result of gene expression analysis suggested that anatabine had a restorative effect on global DSS-induced gene expression profiles, while nicotine only had limited effects. Accordingly, MAP findings revealed that anatabine reduced the colonic abundance of DSS-associated cytokines and increased IL-10 abundance., Conclusions: Our results support the amelioration of inflammatory effects by anatabine in the DSS mouse model of UC, and suggest that anatabine constitutes a promising therapeutic agent for IBD treatment., Competing Interests: Competing interestsAll authors are employees of Philip Morris International., (© The Author(s) 2020.)

Cigarette smoke (CS) causes adverse health effects and, for smoker who do not quit, modified risk tobacco products (MRTPs) can be an alternative to reduce the risk of developing smoking-related diseases. Standard toxicological endpoints can lack sensitivity, with systems toxicology approaches yielding broader insights into toxicological mechanisms. In a 6-month systems toxicology study on ApoE -/- mice, we conducted an integrative multi-omics analysis to assess the effects of aerosols from the Carbon Heated Tobacco Product (CHTP) 1.2 and Tobacco Heating System (THS) 2.2-a potential and a candidate MRTP based on the heat-not-burn (HnB) principle-compared with CS at matched nicotine concentrations. Molecular exposure effects in the lungs were measured by mRNA/microRNA transcriptomics, proteomics, metabolomics, and lipidomics. Integrative data analysis included Multi-Omics Factor Analysis and multi-modality functional network interpretation. Across all five data modalities, CS exposure was associated with an increased inflammatory and oxidative stress response, and lipid/surfactant alterations. Upon HnB aerosol exposure these effects were much more limited or absent, with reversal of CS-induced effects upon cessation and switching to CHTP 1.2. Functional network analysis revealed CS-induced complex immunoregulatory interactions across the investigated molecular layers (e.g., itaconate, quinolinate, and miR-146) and highlighted the engagement of the heme-Hmox-bilirubin oxidative stress axis by CS. This work exemplifies how multi-omics approaches can be leveraged within systems toxicology studies and the generated multi-omics data set can facilitate the development of analysis methods and can yield further insights into the effects of toxicological exposures on the lung of mice., (© 2020 The Authors.)

Background and Significance: There is a need to develop new hypothesis-driven treatment for both both major depression (MD) and schizophrenia in which the risk of depression is 5 times higher than the general population. Major depression has been also associated with poor illness outcomes including pain, metabolic disturbances, and less adherence. Conventional antidepressants are partly effective, and 44% of the subjects remain unremitted under treatment. Improving MD treatment efficacy is thus needed to improve the SZ prognosis. Microbiota-orientated treatments are currently one of the most promising tracks., Method: This work is a systematic review synthetizing data of arguments to develop microbiota-orientated treatments (including fecal microbiota transplantation (FMT)) in major depression and schizophrenia., Results: The effectiveness of probiotic administration in MD constitutes a strong evidence for developing microbiota-orientated treatments. Probiotics have yielded medium-to-large significant effects on depressive symptoms, but it is still unclear if the effect is maintained following probiotic discontinuation. Several factors may limit MD improvement when using probiotics, including the small number of bacterial strains administered in probiotic complementary agents, as well as the presence of a disturbed gut microbiota that probably limits the probiotics' impact. FMT is a safe technique enabling to improve microbiota in several gut disorders. The benefit/risk ratio of FMT has been discussed and has been recently improved by capsule administration., Conclusion: Cleaning up the gut microbiota by transplanting a totally new human gut microbiota in one shot, which is referred to as FMT, is likely to strongly improve the efficacy of microbiota-orientated treatments in MD and schizophrenia and maintain the effect over time. This hypothesis should be tested in future clinical trials., Competing Interests: The authors declare no conflict of interest.

Exposure to cigarette smoke (CS) causes detrimental health effects, increasing the risk of cardiovascular, pulmonary diseases and carcinogenesis in exposed individuals. The impact of CS on Inflammatory Bowel Disease (IBD) has been established by a number of epidemiological and clinical studies. In fact, CS is associated with a higher risk of developing Crohn's disease (CD) while inversely correlates with the development, disease risks, and relapse rate of ulcerative colitis (UC). To investigate the effect of CS exposure on experimental colitis, we performed a comprehensive and integrated comparative analysis of colon transcriptome and microbiome in mice exposed to dextran sodium sulfate (DSS) and CS. Colon transcriptome analysis revealed that CS downregulated specific pathways in a concentration-dependent manner, affecting both the inflammatory state and composition of the gut microbiome. Metagenomics analysis demonstrated that CS can modulate DSS-induced dysbiosis of specific bacterial genera, contributing to resolve the inflammation or accelerate recovery. The risks of smoking far outweigh any possible benefit, thus smoking cessation must always be encouraged because of its significant health benefits. However, the inverse association between active smoking and the development of UC cannot be ignored and the present study lays the foundation for investigating potential molecular mechanisms responsible for the attenuation of colitis by certain compounds of tobacco when decoupled from combustion.