Ethical framework for FACILITATE: a foundation for the return of clinical trial data to participants.

This paper discusses the importance of return of clinical trial data to patients in the context of the FACILITATE project that aims to develop a participant-centric approach for the systematic return of individual clinical trial data. It reflects on the need for an ethical framework to support the return of clinical trial data. The discussion revolves around the developing FACILITATE ethical framework, specifically focusing on the ethical principles that form the foundation of the framework and guidance on how to implement those principles into practice.

Time- and Region-specific Effect of Vortioxetine on Central LPS-induced Transcriptional Regulation of NLRP3 Inflammasome.

BACKGROUND: Inflammasome overactivation, multiprotein complexes that trigger inflammatory responses, plays a critical role in Major Depressive Disorder (MDD) pathogenesis and treatment responses. Indeed, different antidepressants alleviate depression-related behaviours by specifically counteracting the NLRP3 inflammasome signalling pathway. The immunomodulatory effects of vortioxetine (VTX), a multimodal antidepressant with cognitive benefits, were recently revealed to counter memory impairment induced by a peripheral lipopolysaccharide (LPS) injection 24 hours (h) postchallenge. METHODS: The potential link between VTX and NLRP3, along with other inflammasomes, remains unexplored. Hence, adult C57BL/6J male mice (n = 73) were fed with a standard or VTX-enriched diet (600 mg/kg of food, 28 days), injected with LPS (830 µg/kg) or saline, and sacrificed 6/24 h post-LPS. At these time-points, transcriptional effects of LPS and VTX's on NLRP3, NLRP1, NLRC4, AIM2 (inflammasomes), ASC and CASP1 (related subunits) and NEK7 mediator (NLRP3 regulator) were assessed in dorsal and ventral hippocampal subregions, frontal-prefrontal cortex and hypothalamus, brain regions serving behavioural-cognitive functions impaired in MDD. RESULTS: Varied expression patterns of inflammasomes were revealed, with long-term NLRP3 and ASC transcriptional changes observed in response to LPS. It was discovered that VTX counteracted the LPS-mediated NLRP3 and ASC upregulation in memory-related brain areas like the dorsal hippocampus at 24 h time-point, potentially via regulating NEK7 expression. No VTX-mediated transcriptional effects were observed on other inflammasomes, reinforcing a potentially specific modulation on the NLRP3 inflammasome signalling pathway. CONCLUSION: Thus, a novel VTX's molecular mechanism in modulating the NLRP3 inflammasome in a time- and area-specific manner in the brain was highlighted, with significant clinical implications in treating depression and cognitive impairments.

Behavioral and transcriptional effects of carnosine in the central ring ganglia of the pond snail Lymnaea stagnalis.

Carnosine is a naturally occurring endogenous dipeptide with well-recognized anti-inflammatory, antioxidant, and neuroprotective effects at the central nervous system level. To date, very few studies have been focused on the ability of carnosine to rescue and/or enhance memory. Here, we used a well-known invertebrate model system, the pond snail Lymnaea stagnalis, and a well-studied associative learning procedure, operant conditioning of aerial respiration, to investigate the ability of carnosine to enhance long-term memory (LTM) formation and reverse memory obstruction caused by an immune challenge (i.e., lipopolysaccharide [LPS] injection). Exposing snails to 1 mM carnosine for 1 h before training in addition to enhancing memory formation resulted in a significant upregulation of the expression levels of key neuroplasticity genes (i.e., glutamate ionotropic receptor N-methyl-d-aspartate [NMDA]-type subunit 1-LymGRIN1, and the transcription factor cAMP-response element-binding protein 1-LymCREB1) in snails' central ring ganglia. Moreover, pre-exposure to 1 mM carnosine before an LPS injection reversed the memory deficit brought about by inflammation, by preventing the upregulation of key targets for immune and stress response (i.e., Toll-like receptor 4-LymTLR4, molluscan defense molecule-LymMDM, heat shock protein 70-LymHSP70). Our data are thus consistent with the hypothesis that carnosine can have positive benefits on cognitive ability and be able to reverse memory aversive states induced by neuroinflammation.

Different stressors uniquely affect the expression of endocannabinoid-metabolizing enzymes in the central ring ganglia of Lymnaea stagnalis.

The endocannabinoid system (ECS) plays an important role in neuroprotection, neuroplasticity, energy balance, modulation of stress, and inflammatory responses, acting as a critical link between the brain and the body's peripheral regions, while also offering promising potential for novel therapeutic strategies. Unfortunately, in humans, pharmacological inhibitors of different ECS enzymes have led to mixed results in both preclinical and clinical studies. As the ECS has been highly conserved throughout the eukaryotic lineage, the use of invertebrate model organisms like the pond snail Lymnaea stagnalis may provide a flexible tool to unravel unexplored functions of the ECS at the cellular, synaptic, and behavioral levels. In this study, starting from the available genome and transcriptome of L. stagnalis, we first identified putative transcripts of all ECS enzymes containing an open reading frame. Each predicted protein possessed a high degree of sequence conservation to known orthologues of other invertebrate and vertebrate organisms. Sequences were confirmed by qualitative PCR and sequencing. Then, we investigated the transcriptional effects induced by different stress conditions (i.e., bacterial LPS injection, predator scent, food deprivation, and acute heat shock) on the expression levels of the enzymes of the ECS in Lymnaea's central ring ganglia. Our results suggest that in Lymnaea as in rodents, the ECS is involved in mediating inflammatory and anxiety-like responses, promoting energy balance, and responding to acute stressors. To our knowledge, this study offers the most comprehensive analysis so far of the ECS in an invertebrate model organism.

The Impact of Music Therapy in a Pediatric Oncology Setting: An Italian Observational Network Study.

BACKGROUND: Music Therapy (MT) is a non-pharmacological, art-based intervention that employs music experiences within a therapeutic alliance to attend to clients' physical, emotional, cognitive, and social requirements. This is the first study aiming at investigating the impact of MT on the psychological facets of children suffering from cancer. METHODS: The study, combining the AQR and m-YPAS assessment tools, evaluated behavioral, sound-musical, and interactive parameters in pediatric oncology patients undergoing MT sessions during hospitalization. Fifty patients admitted to the Paediatric Oncology and Haematology Unit at Policlinico S. Orsola Hospital in Bologna, Italy, were enrolled, irrespective of their treatment regimen. Data collection occurred on the first day of the MT session between 3 p.m. and 5 p.m., with observations conducted by independent observers. In addition to traditional statistical analysis, network analysis was used to explore the combined interactions of all parameters, effectively discerning the distinctive roles played by each one during therapy sessions and their influence on all others. RESULTS: Network analysis highlighted distinct patterns of interactions among parameters during the various sessions, emphasizing the role of positive emotions and a calm setting, the child's ability to take the initiative in sessions, their sense of agency, and the parent's role in guiding them. Significant differences were recorded at each time point between all variables considered. CONCLUSIONS: The results of this innovative study may pave the way for future multicenter studies aimed at further exploring the role of MT in children undergoing both curative and palliative treatments for cancer.

Low TGF-ß1 plasma levels are associated with cognitive decline in Down syndrome.

Almost all individuals with Down's syndrome (DS) show the characteristic neuropathological features of Alzheimer's disease (AD) by the age of 40, yet not every individual with DS experiences symptoms of AD later in life. Similar to neurotypical developing subjects, AD in people with DS lasts for a long preclinical phase in which biomarkers follow a predictable order of changes. Hence, a prolonged asymptomatic period precedes the onset of dementia, underscoring the importance of identifying new biomarkers for the early detection and monitoring of cognitive decline in individuals with DS. Blood-based biomarkers may offer an alternative non-invasive strategy for the detection of peripheral biological alterations paralleling nervous system pathology in an early phase of the AD continuum. In the last few years, a strong neurobiological link has been demonstrated between the deficit of transforming growth factor-ß1 (TGF-ß1) levels, an anti-inflammatory cytokine endowed with neuroprotective activity, and early pro-inflammatory processes in the AD brain. In this clinical prospective observational study, we found significant lower plasma TGF-ß1 concentrations at the first neuropsychological evaluation (baseline = T0) both in young adult DS individuals (19-35 years) and older DS subjects without AD (35-60 years) compared to age- and sex-matched healthy controls. Interestingly, we found that the lower TGF-ß1 plasma concentrations at T0 were strongly correlated with the following cognitive decline at 12 months. In addition, in young individuals with DS, we found, for the first time, a negative correlation between low TGF-ß1 concentrations and high TNF-α plasma concentrations, a pro-inflammatory cytokine that is known to be associated with cognitive impairment in DS individuals with AD. Finally, adopting an ex vivo approach, we found that TGF-ß1 concentrations were reduced in parallel both in the plasma and in the peripheral blood mononuclear cells (PBMCs) of DS subjects, and interestingly, therapeutic concentrations of fluoxetine (FLX) applied to cultured PBMCs (1 µM for 24 h) were able to rescue TGF-ß1 concentrations in the culture media from DS PBMCs, suggesting that FLX, a selective serotonin reuptake inhibitor (SSRI) endowed with neuroprotective activity, might rescue TGF-ß1 concentrations in DS subjects at higher risk to develop cognitive decline.

A translational and multidisciplinary approach to studying the Garcia effect, a higher form of learning with deep evolutionary roots.

Animals, including humans, learn and remember to avoid a novel food when its ingestion is followed, hours later, by sickness - a phenomenon initially identified during World War II as a potential means of pest control. In the 1960s, John Garcia (for whom the effect is now named) demonstrated that this form of conditioned taste aversion had broader implications, showing that it is a rapid but long-lasting taste-specific food aversion with a fundamental role in the evolution of behaviour. From the mid-1970s onward, the principles of the Garcia effect were translated to humans, showing its role in different clinical conditions (e.g. side-effects linked to chemotherapy). However, in the last two decades, the number of studies on the Garcia effect has undergone a considerable decline. Since its discovery in rodents, this form of learning was thought to be exclusive to mammals; however, we recently provided the first demonstration that a Garcia effect can be formed in an invertebrate model organism, the pond snail Lymnaea stagnalis. Thus, in this Commentary, after reviewing the experiments that led to the first characterization of the Garcia effect in rodents, we describe the recent evidence for the Garcia effect in L. stagnalis, which may pave the way for future studies in other invertebrates and mammals. This article aims to inspire future translational and ecological studies that characterize the conserved mechanisms underlying this form of learning with deep evolutionary roots, which can be used to address a range of different biological questions.

Snails go on a fast when acetylsalicylic acid comes along with heat stress: A possible effect of HSPs and serotonergic system on the feeding response.

A novel food followed by sickness, causes a taste-specific conditioned aversion, known as the 'Garcia effect'. We recently found that both a heat shock stressor (30 °C for 1 h - HS) and the bacterial lipopolysaccharide (LPS) can be used as 'sickness-inducing' stimuli to induce a Garcia effect in the pond snail Lymnaea stagnalis. Additionally, if snails are exposed to acetylsalicylic acid (ASA) present in aspirin tablets before the LPS injection, the formation of the Garcia effect is prevented. Here, we hypothesized that exposing snails to crushed aspirin before the HS (ASA-HS) would prevent the HS-induced 'sickness state' and - therefore -the Garcia effect. Unexpectantly, the ASA-HS procedure induced a generalized and long-lasting feeding suppression. We thus investigate the molecular effects underlying this phenomenon. While the exposure to the HS alone resulted in a significant upregulation of the mRNA levels of the Heat Shock Protein 70 (HSP 70) in snails' central ring ganglia, the ASA-HS procedure induced an even greater upregulation of HSP70, suggesting that the ASA-HS combination causes a severe stress response that inhibits feeding. Additionally, we found that the ASA-HS procedure induced a significant downregulation of the mRNA levels of genes involved with the serotoninergic system which regulates feeding in snails. Finally, the ASA-HS procedure prevented HS-induced upregulation of the mRNA levels of key neuroplasticity genes. Our study indicates that two sickness-inducing stimuli can have different physiological responses even if behavioral outcomes are similar under some learning contexts.

Investigating the interactions between multiple memory stores in the pond snail Lymnaea stagnalis.

The pond snail Lymnaea stagnalis exhibits various forms of associative learning including (1) operant conditioning of aerial respiration where snails are trained not to open their pneumostome in a hypoxic pond water environment using a weak tactile stimulus to their pneumostome as they attempt to open it; and (2) a 24 h-lasting taste-specific learned avoidance known as the Garcia effect utilizing a lipopolysaccharide (LPS) injection just after snails eat a novel food substance (carrot). Typically, lab-inbred snails require two 0.5 h training sessions to form long-term memory (LTM) for operant conditioning of aerial respiration. However, some stressors (e.g., heat shock or predator scent) act as memory enhancers and thus a single 0.5 h training session is sufficient to enhance LTM formation lasting at least 24 h. Here, we found that snails forming a food-aversion LTM following Garcia-effect training exhibited enhanced LTM following operant condition of aerial respiration if trained in the presence of the food substance (carrot) they became averse to. Control experiments led us to conclude that carrot becomes a 'sickness' risk signal and acts as a stressor, sufficient to enhance LTM formation for another conditioning procedure.

The dynamic interaction between symptoms and pharmacological treatment in patients with major depressive disorder: the role of network intervention analysis.

INTRODUCTION: The Major Depressive Disorder (MDD) is a mental health disorder that affects millions of people worldwide. It is characterized by persistent feelings of sadness, hopelessness, and a loss of interest in activities that were once enjoyable. MDD is a major public health concern and is the leading cause of disability, morbidity, institutionalization, and excess mortality, conferring high suicide risk. Pharmacological treatment with Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin Noradrenaline Reuptake Inhibitors (SNRIs) is often the first choice for their efficacy and tolerability profile. However, a significant percentage of depressive individuals do not achieve remission even after an adequate trial of pharmacotherapy, a condition known as treatment-resistant depression (TRD). METHODS: To better understand the complexity of clinical phenotypes in MDD we propose Network Intervention Analysis (NIA) that can help health psychology in the detection of risky behaviors, in the primary and/or secondary prevention, as well as to monitor the treatment and verify its effectiveness. The paper aims to identify the interaction and changes in network nodes and connections of 14 continuous variables with nodes identified as "Treatment" in a cohort of MDD patients recruited for their recent history of partial response to antidepressant drugs. The study analyzed the network of MDD patients at baseline and after 12 weeks of drug treatment. RESULTS: At baseline, the network showed separate dimensions for cognitive and psychosocial-affective symptoms, with cognitive symptoms strongly affecting psychosocial functioning. The MoCA tool was identified as a potential psychometric tool for evaluating cognitive deficits and monitoring treatment response. After drug treatment, the network showed less interconnection between nodes, indicating greater stability, with antidepressants taking a central role in driving the network. Affective symptoms improved at follow-up, with the highest predictability for HDRS and BDI-II nodes being connected to the Antidepressants node. CONCLUSION: NIA allows us to understand not only what symptoms enhance after pharmacological treatment, but especially the role it plays within the network and with which nodes it has stronger connections.

A network study to differentiate suicide attempt risk profiles in male and female patients with major depressive disorder.

Suicide attempts are a possible consequence of Major Depressive Disorder (MDD), although their prevalence varies across different epidemiological studies. Suicide attempt is a significant predictor of death by suicide, highlighting its importance in understanding and preventing tragic outcomes. Researchers are increasingly recognizing the need to study the differences between males and females, as several distinctions emerge in terms of the characteristics, types and motivations of suicide attempts. These differences emphasize the importance of considering gender-specific factors in the study of suicide attempts and developing tailored prevention strategies. We conducted a network analysis to represent and investigate which among multiple neurocognitive, psychosocial, demographic and affective variables may prove to be a reliable predictor for identifying the 'suicide attempt risk' (SAR) in a sample of 81 adults who met DSM-5 criteria for MDD. Network analysis resulted in differences between males and females regarding the variables that were going to interact and predict the SAR; in particular, for males, there is a stronger link toward psychosocial aspects, while for females, the neurocognitive domain is more relevant in its mnestic subcomponents. Network analysis allowed us to describe otherwise less obvious differences in the risk profiles of males and females that attempted to take their own lives. Different neurocognitive and psychosocial variables and different interactions between them predict the probability of suicide attempt unique to male and female patients.

Public Preferences for Digital Health Data Sharing: Discrete Choice Experiment Study in 12 European Countries.

BACKGROUND: With new technologies, health data can be collected in a variety of different clinical, research, and public health contexts, and then can be used for a range of new purposes. Establishing the public's views about digital health data sharing is essential for policy makers to develop effective harmonization initiatives for digital health data governance at the European level. OBJECTIVE: This study investigated public preferences for digital health data sharing. METHODS: A discrete choice experiment survey was administered to a sample of European residents in 12 European countries (Austria, Denmark, France, Germany, Iceland, Ireland, Italy, the Netherlands, Norway, Spain, Sweden, and the United Kingdom) from August 2020 to August 2021. Respondents answered whether hypothetical situations of data sharing were acceptable for them. Each hypothetical scenario was defined by 5 attributes ("data collector," "data user," "reason for data use," "information on data sharing and consent," and "availability of review process"), which had 3 to 4 attribute levels each. A latent class model was run across the whole data set and separately for different European regions (Northern, Central, and Southern Europe). Attribute relative importance was calculated for each latent class's pooled and regional data sets. RESULTS: A total of 5015 completed surveys were analyzed. In general, the most important attribute for respondents was the availability of information and consent during health data sharing. In the latent class model, 4 classes of preference patterns were identified. While respondents in 2 classes strongly expressed their preferences for data sharing with opposing positions, respondents in the other 2 classes preferred not to share their data, but attribute levels of the situation could have had an impact on their preferences. Respondents generally found the following to be the most acceptable: a national authority or academic research project as the data user; being informed and asked to consent; and a review process for data transfer and use, or transfer only. On the other hand, collection of their data by a technological company and data use for commercial communication were the least acceptable. There was preference heterogeneity across Europe and within European regions. CONCLUSIONS: This study showed the importance of transparency in data use and oversight of health-related data sharing for European respondents. Regional and intraregional preference heterogeneity for "data collector," "data user," "reason," "type of consent," and "review" calls for governance solutions that would grant data subjects the ability to control their digital health data being shared within different contexts. These results suggest that the use of data without consent will demand weighty and exceptional reasons. An interactive and dynamic informed consent model combined with oversight mechanisms may be a solution for policy initiatives aiming to harmonize health data use across Europe.

Emotional, Behavioral, and Physical Health Consequences in Caregivers of Children with Cancer: A Network Analysis Differentiation in Mothers' and Fathers' Reactivity.

BACKGROUND: Pediatric cancer presents mental and physical challenges for patients and their caregivers. However, parental distress has been understudied despite its negative impact on quality of life, disability, and somatic disorders. Parents of oncopediatric patients experience high levels of suffering with their resilience tested throughout their children's illness. Identifying at-risk parents and offering specific treatments is crucial and urgent to prevent or alleviate negative outcomes. METHODS: This study used statistical and network analyses to examine symptom patterns assessed by the Kellner Symptom Questionnaire in 16 fathers and 23 mothers at different time points: diagnosis, treatment, and discharge. RESULTS: The results indicated significantly higher distress levels in parents of oncopediatric children compared to the control reference population. Gender-specific differences in symptom profiles were observed at each time point, and symptoms showed a gradual but non-significant decrease over time. CONCLUSIONS: The network analysis yielded valuable insights that, when applied in clinical practice, can guide the implementation of timely treatments to prevent and manage parental distress, thus addressing long-term, stress-related issues in primary caregivers of children diagnosed and treated for cancer.

Narrative Review of the Complex Interaction between Pain and Trauma in Children: A Focus on Biological Memory, Preclinical Data, and Epigenetic Processes.

The incidence and collective impact of early adverse experiences, trauma, and pain continue to increase. This underscores the urgent need for translational efforts between clinical and preclinical research to better understand the underlying mechanisms and develop effective therapeutic approaches. As our understanding of these issues improves from studies in children and adolescents, we can create more precise preclinical models and ultimately translate our findings back to clinical practice. A multidisciplinary approach is essential for addressing the complex and wide-ranging effects of these experiences on individuals and society. This narrative review aims to (1) define pain and trauma experiences in childhood and adolescents, (2) discuss the relationship between pain and trauma, (3) consider the role of biological memory, (4) decipher the relationship between pain and trauma using preclinical data, and (5) examine the role of the environment by introducing the importance of epigenetic processes. The ultimate scope is to better understand the wide-ranging effects of trauma, abuse, and chronic pain on children and adolescents, how they occur, and how to prevent or mitigate their effects and develop effective treatment strategies that address both the underlying causes and the associated physiological and psychological effects.

Care When It Counts: Establishing Trauma-Sensitive Care as a Preventative Approach for 0-3-Year-Old Children Suffering from Trauma and Chronic Stress.

Adverse childhood experiences are an important societal concern. Children aged 0-3 are particularly vulnerable to unpredictable chronic stress due to the critical period for brain development and attachment. Trauma-sensitive care is a preventative approach to reduce the burden of stressful experiences by committing to positive relationships. Professional caregivers are ideally placed to offer trauma-sensitive care; however, earlier research reveals that the tools they need to consciously apply trauma-sensitive care principles are missing. The current study organized living labs (co-creative research method) to present trauma-sensitive care as a preventative approach aimed at children aged 0-3. Two living labs were organized in Belgium and Hungary, where professional caregivers collaborated to create a protocol that offers guidelines on how to implement trauma-sensitive care. The resulting protocol included a theoretical foundation on trauma as well as a translation of these guidelines into practical recommendations. The protocol was evaluated by incorporating it into a training intervention delivered to 100 professional caregivers from childcare organizations across four European countries. The protocol received positive feedback from participants, with results indicating a self-reported increase in knowledge, attitude and practice of trauma-sensitive care principles. We conclude that this trauma-sensitive care protocol is a promising answer to the needs of professional caregivers working with children aged 0-3.

Neuropsychological Outcomes of Children Treated for Brain Tumors.

Central nervous system (CNS) neoplasms are the most common solid tumors diagnosed in children. CNS tumors represent the leading cause of cancer death and cancer-related morbidity for children less than 20 years of age, although there has been a moderate increase in survival rates over the past several decades. The average survival at 5 years now nearly reaches 75%, and for some, non-malignant histology approximates 97% at 20 years from diagnosis. Neurological, cognitive, and neuropsychological deficits are the most disabling long-term effects of brain tumors in children. Childhood is a time of extreme brain sensitivity and the time of life in which most brain development occurs. Thus, the long-term toxicities that children treated for CNS tumors experience can affect multiple developmental domains and day-to-day functioning, ultimately leading to a poor quality of survival (QoS). We reviewed literature focusing on the risk factors for cognitive and neuropsychological impairment in pediatric patients treated for brain tumors with the aim of better understanding who is at major risk and what the best strategies for monitoring these patients are.

Novel taste, sickness, and memory: Lipopolysaccharide to induce a Garcia-like effect in inbred and wild strains of Lymnaea stagnalis.

Food is not only necessary for our survival but also elicits pleasure. However, when a novel food is followed sometime later by nausea or sickness animals form a long-lasting association to avoid that food. This phenomenon is called the 'Garcia effect'. We hypothesized that lipopolysaccharide (LPS) could be used as the sickness-inducing stimulus to produce a Garcia-like effect in inbred and wild populations of Lymnaea stagnalis. We first demonstrated that the injection of 25 µg (6.25 µg/mL) of Escherichia coli-derived LPS serotype O127:B8 did not by itself alter snails' feeding behavior. Then we showed that the presentation of a novel appetitive stimulus (i.e., carrot slurry) and LPS resulted in a taste-specific and long-lasting feeding suppression (i.e., the Garcia-like effect). We also found strain-specific variations in the duration of the long-term memory (LTM). That is, while the LTM for the Garcia-like effect in W-strain snails persisted for 24h, LTM persisted for 48h in freshly collected Margo snails and their F1 offspring. Finally, we demonstrated that the exposure to a non-steroidal anti-inflammatory drug, aspirin (acetylsalicylic acid) before the LPS injection prevented both the LPS-induced sickness state and the Garcia-like effect from occurring. The results of this study may pave the way for new research that aims at (1) uncovering the conserved molecular mechanisms underlying the Garcia-like effect, (2) understanding how cognitive traits vary within and between species, and (3) creating a holistic picture of the complex dialogue between the immune and central nervous systems.

Predictors of functional outcome in patients with major depression and bipolar disorder: A dynamic network approach to identify distinct patterns of interacting symptoms.

The purpose of this study is to use a dynamic network approach as an innovative way to identify distinct patterns of interacting symptoms in patients with Major Depressive Disorder (MDD) and patients with Bipolar Type I Disorder (BD). More precisely, the hypothesis will be testing that the phenotype of patients is driven by disease specific connectivity and interdependencies among various domains of functioning even in the presence of underlying common mechanisms. In a prospective observational cohort study, hundred-forty-three patients were recruited at the Psychiatric Clinic "Villa dei Gerani" (Catania, Italy), 87 patients with MDD and 56 with BD with a depressive episode. Two nested sub-groups were treated for a twelve-week period, which allowed us to explore differences in the pattern of symptom distribution (central vs. peripheral) and their connectedness (strong vs weak) before (T0) and after (T1) treatment. All patients underwent a complete neuropsychological evaluation at baseline (T0) and at T1. A network structure was computed for MDD and BD patients at T0 and T1 from a covariance matrix of 17 items belonging to three domains-neurocognitive, psychosocial, and mood-related (affective) to identify what symptoms were driving the networks. Clinically relevant differences were observed between MDD and BD, at T0 and after 12 weeks of pharmacological treatment. At time T0, MDD patients displayed an affective domain strongly connected with the nodes of psychosocial functioning, while direct connectivity of the affective domain with the neurocognitive cluster was absent. The network of patients with BD, in contrast, revealed a cluster of highly interconnected psychosocial nodes but was guided by neurocognitive functions. The nodes related to the affective domain in MDD are less connected and placed in the periphery of the networks, whereas in BD they are more connected with psychosocial and neurocognitive nodes. Noteworthy is that, from T0 to T1 the "Betweenness" centrality measure was lower in both disorders which means that fewer "shortest paths" between nodes pass through the affective domain. Moreover, fewer edges were connected directly with the nodes in this domain. In MDD patients, pharmacological treatment primarily affected executive functions which seem to improve with treatment. In contrast, in patients with BD, treatment resulted in improvement of overall connectivity and centrality of the affective domain, which seems then to affect and direct the overall network. Though different network structures were observed for MDD and BD patients, data suggest that treatment should include tailored cognitive therapy, because improvement in this central domain appeared to be fundamental for better outcomes in other domains. In sum, the advantage of network analysis is that it helps to predict the trajectory of future phenotype related disease manifestations. In turn, this allows new insights in how to balance therapeutic interventions, involving different fields of function and combining pharmacological and non-pharmacological treatment modalities.

Behavioral and Transcriptional Effects of Short or Prolonged Fasting on the Memory Performances of Lymnaea stagnalis.

INTRODUCTION: The Garcia effect, a solid learning paradigm, was used to investigate the molecular and behavioral effects induced by different lengths of fasting on the cognitive functions in the pond snail Lymnaea stagnalis, a valid model system. METHODS: Three experimental groups were used: moderately hungry snails, food-deprived for 1 day (D1 snails), severely hungry snails (D5 snails), fasting for 5 days, and satiated snails with ad libitum access to food (AL snails). In the Garcia effect, a single pairing of an appetitive stimulus with a heat stressor results in a learned taste-specific negative hedonic shift. D5 snails were injected with bovine insulin and D1 snails with the insulin receptor antibody (Ab). As a control group, AL snails were injected with saline. Gene expression analyses were performed by real-time PCR in snails' central nervous system (CNS). RESULTS: AL snails are "average learners," D1 snails are the best performers, whereas the D5 ones do not show the Garcia effect. Severely fasting snails injected with insulin 3 h before the training procedure show the Garcia effect, whereas injecting 1-day fasting snails with insulin receptor Ab blocks their ability to express memory. The differences in memory performances are associated with changes in the expression levels of selected targets involved in neuronal plasticity, energy homeostasis, and stress response. DISCUSSION: Our results suggest that short-term fasting creates an optimal internal state in L. stagnalis' CNS, allowing a spike in insulin release and an upregulation of genes involved in neuroplasticity. Long-term fasting, instead, upregulates genes involved in energy homeostasis and animal survival.