Granzyme B-activated IL18 potentiates αß and γδ CAR T cell immunotherapy in a tumor-dependent manner.

Interleukin (IL)18 is a potent pro-inflammatory cytokine that is activated upon caspase 1 cleavage of the latent precursor, pro-IL18. Therapeutic T cell armoring with IL18 promotes autocrine stimulation and positive modulation of the tumor microenvironment (TME). However, existing strategies are imperfect since they involve constitutive/poorly regulated activity or fail to modify the TME. Here, we have substituted the caspase 1 cleavage site within pro-IL18 with that preferred by granzyme B, yielding GzB-IL18. We demonstrate that GzB-IL18 is constitutively released but remains functionally latent unless chimeric antigen receptor (CAR) T cells are activated, owing to concomitant granzyme B release. Armoring with GzB-IL18 enhances cytolytic activity, proliferation, interferon (IFN)-γ release, and anti-tumor efficacy by a similar magnitude to constitutively active IL18. We also demonstrate that GzB-IL18 provides a highly effective armoring strategy for γδ CAR T cells, leading to enhanced metabolic fitness and significant potentiation of therapeutic activity. Finally, we show that constitutively active IL18 can unmask CAR T cell-mediated cytokine release syndrome in immunocompetent mice. By contrast, GzB-IL18 promotes anti-tumor activity and myeloid cell re-programming without inducing such toxicity. Using this stringent system, we have tightly coupled the biological activity of IL18 to the activation state of the host CAR T cell, favoring safer clinical implementation of this technology.

Whisker kinematics in the cerebellum.

The whisker system is widely used as a model system for understanding sensorimotor integration. Purkinje cells in the crus regions of the cerebellum have been reported to linearly encode whisker midpoint, but it is unknown whether the paramedian and simplex lobules as well as their target neurons in the cerebellar nuclei also encode whisker kinematics and if so which ones. Elucidating how these kinematics are represented throughout the cerebellar hemisphere is essential for understanding how the cerebellum coordinates multiple sensorimotor modalities. Exploring the cerebellar hemisphere of mice using optogenetic stimulation, we found that whisker movements can be elicited by stimulation of Purkinje cells in not only crus1 and crus2, but also in the paramedian lobule and lobule simplex; activation of cells in the medial paramedian lobule had on average the shortest latency, whereas that of cells in lobule simplex elicited similar kinematics as those in crus1 and crus2. During spontaneous whisking behaviour, simple spike activity correlated in general better with velocity than position of the whiskers, but it varied between protraction and retraction as well as per lobule. The cerebellar nuclei neurons targeted by the Purkinje cells showed similar activity patterns characterized by a wide variety of kinematic signals, yet with a dominance for velocity. Taken together, our data indicate that whisker movements are much more prominently and diversely represented in the cerebellar cortex and nuclei than assumed, highlighting the rich repertoire of cerebellar control in the kinematics of movements that can be engaged during coordination. KEY POINTS: Excitation of Purkinje cells throughout the cerebellar hemispheres induces whisker movement, with the shortest latency and longest duration within the paramedian lobe. Purkinje cells have differential encoding for the fast and slow components of whisking. Purkinje cells encode not only the position but also the velocity of whiskers. Purkinje cells with high sensitivity for whisker velocity are preferentially located in the medial part of lobule simplex, crus1 and lateral paramedian. In the downstream cerebellar nuclei, neurons with high sensitivity for whisker velocity are located at the intersection between the medial and interposed nucleus.

Multi-omics gut microbiome signatures in obese women: role of diet and uncontrolled eating behavior.

BACKGROUND: Obesity and related co-morbidities represent a major health challenge nowadays, with a rapidly increasing incidence worldwide. The gut microbiome has recently emerged as a key modifier of human health that can affect the development and progression of obesity, largely due to its involvement in the regulation of food intake and metabolism. However, there are still few studies that have in-depth explored the functionality of the human gut microbiome in obesity and even fewer that have examined its relationship to eating behaviors. METHODS: In an attempt to advance our knowledge of the gut-microbiome-brain axis in the obese phenotype, we thoroughly characterized the gut microbiome signatures of obesity in a well-phenotyped Italian female cohort from the NeuroFAST and MyNewGut EU FP7 projects. Fecal samples were collected from 63 overweight/obese and 37 normal-weight women and analyzed via a multi-omics approach combining 16S rRNA amplicon sequencing, metagenomics, metatranscriptomics, and lipidomics. Associations with anthropometric, clinical, biochemical, and nutritional data were then sought, with particular attention to cognitive and behavioral domains of eating. RESULTS: We identified four compositional clusters of the gut microbiome in our cohort that, although not distinctly associated with weight status, correlated differently with eating habits and behaviors. These clusters also differed in functional features, i.e., transcriptional activity and fecal metabolites. In particular, obese women with uncontrolled eating behavior were mostly characterized by low-diversity microbial steady states, with few and poorly interconnected species (e.g., Ruminococcus torques and Bifidobacterium spp.), which exhibited low transcriptional activity, especially of genes involved in secondary bile acid biosynthesis and neuroendocrine signaling (i.e., production of neurotransmitters, indoles and ligands for cannabinoid receptors). Consistently, high amounts of primary bile acids as well as sterols were found in their feces. CONCLUSIONS: By finding peculiar gut microbiome profiles associated with eating patterns, we laid the foundation for elucidating gut-brain axis communication in the obese phenotype. Subject to confirmation of the hypotheses herein generated, our work could help guide the design of microbiome-based precision interventions, aimed at rewiring microbial networks to support a healthy diet-microbiome-gut-brain axis, thus counteracting obesity and related complications.

Perampanel and childhood absence epilepsy: A real life experience.

Objectives: The aim of our study was to evaluate the effectiveness and tolerability of perampanel (PER) as first add-on and as second line monotherapy in subjects with childhood absence epilepsy. Methods: Our sample consisted of 20 patients with childhood absence epilepsy, aged between 8 and 10, already in therapy with a first antiseizure medication with incomplete seizure control. PER was added as first add-on in a dose ranging from 3 to 8 mg/die with 1- 2 mg/week increments. The patients that were seizure-free were shifted to a PER monotherapy. All patients underwent a standardized neuropsychological evaluation in order to assess non-verbal intelligence and executive functions before adding PER and after 6 months of drug therapy. All parents completed two questionnaires, in order to assess the emotional-behavioral problems and parental stress. Results: 15/20 patients responded to add-on PER and were seizure-free, in 3/20 patients we observed a reduction of seizure frequency <50%, and in the 2 remaining patients the add-on therapy with PER did not lead to a reduction in seizures frequency from baseline. The patients who were seizure-free were switched to PER monotherapy. 9/15 patients remained seizure-free in monotherapy with PER. In the first month of therapy with PER 2/20 patients (10%) reported mild, transient side effects of irritability, headache and dizziness, which did not lead to discontinuation of therapy. Adjunctive treatment with PER did not negatively affect non-verbal intelligence, executive functions, emotional/behavioral symptoms of children and parental stress levels. Significance: Our clinical experience in real life showed that PER appears to be effective in the control of absence seizures in childhood absence epilepsy, with a favorable tolerability profile. PER would seem effective on absence seizures even in monotherapy. Further studies with larger samples, longer follow-up and controlled vs. placebo (or other first choice antiseizure medications) are needed to confirm our data.

Migraine and epilepsy: Social cognition skills in pediatric population.

INTRODUCTION: The goal of the present study was to comparatively analyze Social Cognition skills in a pediatric population diagnosed with Migraine or Epilepsy, compared to Typically Developing children (TD). The secondary aim was to relate Social Cognition skills with other migraine- or epilepsy-related variables and with executive and cognitive functions. MATERIALS AND METHODS: In our cross-sectional observational study 119 children and adolescents (aged 6-16) with Migraine or Focal Epilepsy and 61 TD peers were recruited. Both the clinical groups and TD peers performed a neuropsychological evaluation through standardized test to assess Theory of Mind (TM), Emotion Recognition through facial expression (ER), executive function and non-verbal cognitive abilities. RESULTS: Children and adolescents with Migraine or Focal Epilepsy showed comparable scores between each other, however their scores were significantly lower than their TD peers, in both ER and TM. Social Cognition skills were significantly related to executive functions. CONCLUSION: Our study suggests that some chronic neurological conditions in childhood, such as Migraine and Epilepsy, may be associated with difficulties in Social Cognition skills, and that these difficulties may be related to a deficit in executive functions. The relationship between these two higher cognitive abilities should be further explored in future studies. Our results also suggest the importance of monitoring cognitive abilities in pediatric patients with Migraine or Epilepsy, in order to detect early impairment and ensure the necessary support.

Olivocerebellar control of movement symmetry.

Coordination of bilateral movements is essential for a large variety of animal behaviors. The olivocerebellar system is critical for the control of movement, but its role in bilateral coordination has yet to be elucidated. Here, we examined whether Purkinje cells encode and influence synchronicity of left-right whisker movements. We found that complex spike activity is correlated with a prominent left-right symmetry of spontaneous whisker movements within parts, but not all, of Crus1 and Crus2. Optogenetic stimulation of climbing fibers in the areas with high and low correlations resulted in symmetric and asymmetric whisker movements, respectively. Moreover, when simple spike frequency prior to the complex spike was higher, the complex spike-related symmetric whisker protractions were larger. This finding alludes to a role for rebound activity in the cerebellar nuclei, which indeed turned out to be enhanced during symmetric protractions. Tracer injections suggest that regions associated with symmetric whisker movements are anatomically connected to the contralateral cerebellar hemisphere. Together, these data point toward the existence of modules on both sides of the cerebellar cortex that can differentially promote or reduce the symmetry of left and right movements in a context-dependent fashion.

Prospects for Development of Induced Pluripotent Stem Cell-Derived CAR-Targeted Immunotherapies.

Technologies required to generate induced pluripotent stem cells (iPSC) were first described 15 years ago, providing a strong impetus to the field of regenerative medicine. In parallel, immunotherapy has finally emerged as a clinically meaningful modality of cancer therapy. In particular, impressive efficacy has been achieved in patients with selected haematological malignancies using ex vivo expanded autologous T cells engineered to express chimeric antigen receptors (CARs). While solid tumours account for over 90% of human cancer, they currently are largely refractory to this therapeutic approach. Nonetheless, given the considerable innovation taking place worldwide in the CAR field, it is likely that effective solutions for common solid tumours will emerge in the near future. Such a development will create significant new challenges in the scalable delivery of these complex, costly and individualised therapies. CAR-engineered immune cell products that originate from iPSCs offer the potential to generate unlimited numbers of homogeneous, standardised cell products in which multiple defined gene modification events have been introduced to ensure safety, potency and reproducibility. Here, we review some of the emerging strategies in use to engineer CAR-expressing iPSC-derived drug products.

Functional Convergence of Autonomic and Sensorimotor Processing in the Lateral Cerebellum.

The cerebellum is involved in the control of voluntary and autonomic rhythmic behaviors, yet it is unclear to what extent it coordinates these in concert. We studied Purkinje cell activity during unperturbed and perturbed respiration in lobules simplex, crus 1, and crus 2. During unperturbed (eupneic) respiration, complex spike and simple spike activity encode the phase of ongoing sensorimotor processing. In contrast, when the respiratory cycle is perturbed by whisker stimulation, mice concomitantly protract their whiskers and advance their inspiration in a phase-dependent manner, preceded by increased simple spike activity. This phase advancement of respiration in response to whisker stimulation can be mimicked by optogenetic stimulation of Purkinje cells and prevented by cell-specific genetic modification of their AMPA receptors, hampering increased simple spike firing. Thus, the impact of Purkinje cell activity on respiratory control is context and phase dependent, highlighting a coordinating role for the cerebellar hemispheres in aligning autonomic and sensorimotor behaviors.

Social cognition and executive functions in children and adolescents with focal epilepsy.

OBJECTIVES: Deficits in facial emotion recognition and Theory of Mind are frequent in patients with epilepsy. Although this evidence, studies on pediatric age are few and the relation between these abilities and other cognitive domain remains to be better elucidated. The purpose of our study is to evaluate facial emotion recognition and Theory of Mind in children and adolescents with focal epilepsy, and correlate them with intelligence and executive functions. MATERIALS AND METHODS: Our work is a cross-sectional observational study. Sixty-two children and adolescents aged between 7-16 years diagnosed by focal epilepsy and 32 sex/age-matched controls were recruited. All participants were administered a standardized battery tests to assess social cognition (NEPSY-II), executive functions (EpiTrack Junior) and cognitive non-verbal level (Raven Progressive Matrices). RESULTS: Emotion recognition mean score was significantly lower in the epilepsy group than in the controls to Student's t-test (p<0.05). Epilepsy group showed an impairment in happiness, sadness, anger and fear recognition, compared to controls (p<0.05). Theory of Mind mean score was also significantly lower in epilepsy group than controls (p<0.05). Deficits in emotion recognition seemed to be related to low age at onset of epilepsy, long duration of disease, low executive functions and low non-verbal intelligence. Deficits in Theory of Mind seemed to be related to a high seizure frequency. CONCLUSIONS: Our results suggest that children and adolescents with focal epilepsy had deficit in facial emotion recognition and Theory of Mind, compared to their peer. Both these difficulties seem to be related to some features of epilepsy itself. Our results also suggest that deficits in facial emotion recognition are potentially related to difficulties in executive functions and non-verbal intelligence. More studies are needed to confirm these hypotheses.

Perampanel tolerability in children and adolescents with focal epilepsy: Effects on behavior and executive functions.

OBJECTIVES: Perampanel (PER) is a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist recently approved for focal and generalized epilepsies as an add-on therapy. It is well tolerated and effective as treatment of various pediatric epilepsy syndromes; PER does not seem to negatively affect the cognitive profile of children and adolescents, but its influence on executive functions is still to be assessed. METHODS: Our sample included 37 children aged 12-18 years, with focal pharmacoresistant epilepsy already in therapy with 2 or 3 antiepileptic drug (AED); PER was added with 1 mg/week increments up to a dose of 2-4 mg/day. Changes in executive functions were assessed by the EpiTrack Junior test. Emotional and behavioral aspects were evaluated through the interview for parents Child Behavior Checklist (CBCL). Both tests were performed before taking PER and after 6 and 12 months of treatment. RESULTS: After 12 months of PER in 22/30 patients, global score of the EpiTrack Junior test remained almost unchanged; in 7/30 patients, this score improved. The CBCL did not show significant changes in emotional or behavioral problems. CONCLUSIONS: Adjunctive treatment with PER did not negatively affect executive functions that could also be improved. No emotional/behavioral negative effects have been reported, and this suggests a good tolerability in the middle/long term.

Effects on executive functions of antiepileptic monotherapy in pediatric age.

OBJECTIVES: Cognitive abilities and executive functions in children and adolescents are important indicators of quality of life as well as academic and social achievements. Cognitive and executive functioning are often impaired in patients with epilepsy and can be exacerbated by seizures and antiseizure drugs. The aim of our observational retrospective study was to assess executive functioning in patients with pediatric epilepsy, currently taking a single antiseizure medication. MATERIALS AND METHODS: Records of 172 children and adolescents aged between 6 and 18 years (mean age = 12 ±â€¯3.4 years) with newly diagnosed epilepsy who had not yet commenced an antiepileptic treatment were included in the study. Longitudinal changes in executive functioning were assessed using the EpiTrack Junior test at baseline, before the introduction of antiepileptic monotherapy, and at 3-month, 6-month, and 9-month follow-up visits. All patients commenced a single antiepileptic treatment (levetiracetam n = 54; valproic acid n = 52; ethosuximide n = 20; oxcarbazepine n = 22; carbamazepine n = 24). Age, sex, seizure types, and seizure baseline frequency were also recorded. RESULTS: Relative to baseline, Epitrack Junior mean scores deteriorated at the 9-month follow-up visit for patients taking valproic acid, ethosuximide, and carbamazepine, but this was only statistically significant for patients taking carbamazepine. In contrast, mean scores improved for subjects taking levetiracetam and oxcarbazepine at the 9-month follow-up visit relative to baseline, but this was only statistically significant for patients taking levetiracetam. CONCLUSIONS: Levetiracetam was the only antiseizure medication that led to slight improvements in executive functioning; whereas carbamazepine led to deteriorations in cognitive functioning. Further research using double-blinded, placebo-controlled trials are needed to confirm these results.

Psychogenic nonepileptic seizures in pediatric population: A review.

INTRODUCTION: Psychogenic nonepileptic seizures (PNES) are observable abrupt paroxysmal changes in behavior or consciousness that resemble epileptic seizures, but without concurrent electroencephalographic abnormalities. METHODS: In this manuscript, we reviewed literature concerning pediatric PNES and focused on those articles published in the last 10 years, in order to try to understand what the state of the art is at the moment, particularly as regards relationship and differential diagnosis with epilepsy. RESULTS: Psychogenic nonepileptic seizures have been extensively described in literature mainly in adults and less frequently in children. Despite the potential negative impact of a misdiagnosis (unnecessary investigations and antiepileptic drugs, structured pathological behavioral patterns), in literature there is little information regarding the real prevalence, clinical features, treatment, and outcome of PNES in children and adolescents. CONCLUSION: Psychogenic nonepileptic seizures are common but frequently missed entity in pediatric population. Diagnosis could be difficult, especially in those children who have both epileptic and nonepileptic seizures; video EEG and home video can help clinicians in diagnosis. More studies are needed to better classify PNES in children and facilitate diagnosis and treatment.

Cognitive Profile, Emotional-Behavioral Features, and Parental Stress in Boys With 47,XYY Syndrome.

OBJECTIVE: To describe (a) the observed cognitive, emotional, and behavioral phenotype in a cohort of male children with 47,XYY syndrome and (b) stress levels in their parents. METHODS: We conducted a cross-sectional observational study of 11 boys diagnosed with 47,XYY syndrome and compared them with 11 age-matched boys with normal karyotype (46,XY). The participants performed standardized assessments of cognitive function, emotional state, and behavioral features; the parents completed a questionnaire evaluating parental stress. All data were analyzed using parametric and nonparametric statistical methods. RESULTS: All of the boys exhibited a normal cognitive profile. However, emotional-behavioral profiling revealed that internalizing and externalizing problems were more prevalent in the 47,XYY group. In addition, the stress levels of the parents of the 47,XYY group were reportedly higher than those of the parents of the 46,XY group. We also found that the time of the diagnosis had an effect on the mothers' stress levels; that is, postnatal fetal 47,XYY diagnosis was associated with higher maternal stress, whereas prenatal fetal 47,XYY diagnosis was not. CONCLUSIONS: Generally, 47,XYY syndrome is associated with certain cognitive, emotional, and behavioral features. High stress levels have been reported by the mothers of 47,XYY boys who had been diagnosed postnatally because of unexpected developmental delay and/or learning difficulties. The present study highlights the need to better define the neuropsychiatric phenotype of 47,XYY children; namely, the effect of the chromosomal abnormality on their cognitive function and emotional-behavioral (internalizing and externalizing) features. This study could improve prenatal counseling and pediatric surveillance.

Cognitive profile in BECTS treated with levetiracetam: A 2-year follow-up.

INTRODUCTION: Benign epilepsy with centrotemporal spikes (BECTS) is a common epileptic syndrome in childhood, characterized by brief and infrequent partial motor seizures, with or without generalization and mostly recurring during sleep. Because of its favorable efficacy, tolerability, and safety profile, levetiracetam (LEV) monotherapy is often administered in these patients. Long-term effects of LEV therapy and its influence on cognitive functions remain controversial. PURPOSE: This evaluated the changes in the cognitive profile of children with BECTS treated with LEV monotherapy for 2 years, compared with a control group of children with specific learning disabilities. METHOD: Our patient cohort included 20 children aged 8-14 years diagnosed as having BECTS and administered LEV monotherapy and 10 age/sex-matched controls with specific learning disabilities. All participants underwent a standardized test for assessing cognitive profile (Wechsler Intelligence Scale for Children - Fourth Edition [WISC-IV]) before drug therapy and after 2 years of treatment. Average LEV blood level and electroencephalographic (EEG) recordings were periodically monitored. Several factors such as age, sex, response to therapy, and EEG pattern changes were considered. Statistical analysis was performed using Student's t-test for paired and independent samples. p < 0.05 was considered statistically significant. RESULTS: Children administered LEV for 24 months showed a mild but statistically significant improvement in overall cognitive abilities. Verbal skills, visual-perceptual reasoning, working memory, and processing speed showed slight but significant improvement. In the control group, cognitive profile remained substantially unchanged at 2-year follow-up. CONCLUSIONS: Not only do our data suggest a nonworsening of the cognitive profile in BECTS with LEV but, on the contrary, cognitive scores also improved over time, unlike the control group.

Parental stress in pediatric epilepsy after therapy withdrawal.

OBJECTIVE: The objective of the study was to explore stress levels in the parents of children with idiopathic epilepsy at different time points of the disease, specifically, at the time of diagnosis, during follow-up, and 1 and 2 years after discontinuation of antiepileptic drugs. METHODS: Our study included 50 patients between 5 and 14 years of age, who were diagnosed with childhood absence epilepsy or idiopathic focal epilepsy with Rolandic paroxysms. Parents of the participants independently completed the Parenting Stress Index-Short Form at the time of initial diagnosis, and when the children started antiepileptic drugs (Time 0), and at 1 year (Time 1) and 2 years (Time 2) after discontinuation of therapy. RESULTS: At Time 0, parental stress levels were increased, both in mothers and fathers, with average scores in the "clinical range" of the parental distress (PD), dysfunctional parent-child interaction (P-CDI), and total stress (TS) scales. At Time 1, the scores on these scales remained high. At Time 2, a mild reduction in the stress scores was observed in both parents, despite values remaining in the "clinical range" for all the scales. CONCLUSIONS: Results suggested that parents of children with epilepsy were not reassured about the child's condition, even after clinical improvement. Parental stress levels remained higher than expected, even 2 years after the discontinuation of therapy and freedom from seizures. This was probably due to concerns with the reappearance of new seizures or a more severe type of epilepsy with the discontinuation of drug(s), and feelings of inadequacy with their parental role(s).

Epilepsy and genetic in Rett syndrome: A review.

INTRODUCTION: Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder that primarily affects girls, with an incidence of 1:10,000-20,000. The diagnosis is based on clinical features: an initial period of apparently normal development (ages 6-12 months) followed by a rapid decline with regression of acquired motor skills, loss of spoken language and purposeful hand use, onset of hand stereotypes, abnormal gait, and growth failure. The course of the disease, in its classical form, is characterized by four stages. Three different atypical variants of the disease have been defined. Epilepsy has been reported in 60%-80% of patients with RTT; it differs among the various phenotypes and genotypes and its severity is an important contributor to the clinical severity of the disease. METHODS: In this manuscript we reviewed literature on RTT, focusing on the different genetic entities, the correlation genotype-phenotype, and the peculiar epileptic phenotype associated to each of them. RESULTS: Mutations in MECP2 gene, located on Xq28, account for 95% of typical RTT cases and 73.2% of atypical RTT. CDKL5 and FOXG1 are other genes identified as causative genes in atypical forms of RTT. In the last few years, a lot of new genes have been identified as causative genes for RTT phenotype. CONCLUSIONS: Recognizing clinical and EEG patterns in different RTT variants may be useful in diagnosis and management of these patients.

Parental stress in a sample of children with epilepsy.

OBJECTIVE: To assess maternal and paternal stress in two groups of children with different types of epilepsy, at the time of diagnosis and after one year of follow-up. METHODS: We investigated parental stress in a sample of 85 children aged between 2 and 14 years, divided into two groups based on the diagnosis: Group 1 (50 patients) with childhood absence epilepsy or idiopathic focal epilepsy with rolandic discharges and Group 2 (35 patients) with different forms of drug-resistant epilepsy. Parents independently completed the Parental Stress Index-Short Form at Time 0, when they received the diagnosis and patients started therapy, and at Time 1, after 1 year of follow-up. RESULTS: We found high levels of stress in both mothers and fathers at Time 0, without statistically significant differences between the two groups. At Time 1, stress values were unchanged in Group 1 mothers; conversely, the levels of stress in Group 1 fathers reduced, with average values that all fell within the "normal range." In Group 2, stress levels were reduced both in mothers and in fathers at Time 1, compared to Time 0, but equally fell into the "pathological range," for both parents. CONCLUSION: In our study, the diagnosis of the epilepsy itself tended to increase parental stress, apparently regardless of the severity of the epilepsy; even after a period of follow-up, when the epilepsy was better controlled, overall parental stress remained high. It might have been related to feelings of parental inadequacy or concerns about issues such as safety or the outcome for the child.

Food addiction distinguishes an overweight phenotype that can be reversed by low calorie diet.

Similarities in neural activation patterns in obese and substance-dependent subjects led to the food addiction concept, but studies exploiting this issue for obesity stratification are missing. We assessed brain activation in response to food cues using 18 F-2-fluoro-2-deoxy-glucose-PET in 36 overweight women, stratified by low or high food addiction groups according to the Yale Food Addiction Scale (YFAS). Assessments were repeated after a 3-month diet. We found greater activation in thalamus, hypothalamus, midbrain, putamen, and occipital cortex (reward), but not in prefrontal and orbitofrontal cortices (control/reward receipt) in the high-YFAS versus low-YFAS group. In high-YFAS subjects, orbitofrontal responsiveness was inversely related to YFAS severity and hunger rating, and positive associations were observed between regional brain activation and lipid intake. A 3-month diet abolished group differences in brain activation. Our data suggest that food addiction distinguishes an overweight phenotype that can be reversed by diet, opening to personalized strategies in obesity treatment.