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- Mapping functional traces of opioid memories in the rat brainPublication . Gomes-Ribeiro, Joana; Summavielle, Teresa; Martins, João; Sereno, José; Coelho, Joana E.; Deslauriers-Gauthier, Samuel; Remondes, Miguel; Castelo-Branco, Miguel; Lopes, Luísa V.; Summavielle, TeresaAddiction to psychoactive substances is a maladaptive learned behaviour. Contexts surrounding drug use integrate this aberrant mnemonic process and hold strong relapse-triggering ability. Here, we asked where context and salience might be concurrently represented in the brain during retrieval of drug–context paired associations. For this, we developed a morphine-conditioned place preference protocol that allows contextual stimuli presentation inside a magnetic resonance imaging scanner and investigated differences in activity and connectivity at context recall. We found context-specific responses to stimulus onset in multiple brain regions, namely, limbic, sensory and striatal. Differences in functional interconnectivity were found among amygdala, lateral habenula, and lateral septum. We also investigated alterations to resting-state functional connectivity and found increased centrality of the lateral septum in a proposed limbic network, as well as increased functional connectivity of the lateral habenula and hippocampal ‘cornu ammonis’ 1 region, after a protocol of associative drug–context. Finally, we found that pre- conditioned place preference resting-state connectivity of the lateral habenula and amygdala was predictive of inter-individual conditioned place preference score differences. Overall, our findings show that drug and saline-paired contexts establish distinct memory traces in overlapping functional brain microcircuits and that intrinsic connectivity of the habenula, septum, and amygdala likely underlies the individual maladaptive contextual learning to opioid exposure. We have identified functional maps of acquisition and retrieval of drug-related memory that may support the relapse- triggering ability of opioid-associated sensory and contextual cues. These findings may clarify the inter-individual sensitivity and vulnerability seen in addiction to opioids found in humans.
- Intersectin1/cdc42 signaling regulates methamphetamine-induced neuronal remodeling in the hippocampusPublication . Terceiro, Ana Filipa; Lobo, Andrea; Socodato, Renato; Canedo, Teresa; Silva, Ana Isabel; Cavadas, Bruno; Carvalhais, Lia G.; Aroso, Miguel; Morello, Gabriela M.; Aguiar, Paulo; Magalhães, Ana; Carvalho, Ana Luísa; Relvas, João B.; Fonseca, Rosalina; Summavielle, Teresa; Summavielle, TeresaThe development and maintenance of drug addiction triggered by psychoactive substances, such as methamphetamine (Meth), is strongly influenced by synaptic and morphological adaptations in the brain. The hippocampus has a key role in the formation of maladaptive drug-context associations and relapse. However, the mechanisms regulating this complex process are not completely understood. Recent studies highlight that the actin cytoskeleton and its regulatory proteins play a fundamental role in morphological and behavioral plasticity associated with drug use. Here, we show that a binge pattern of Meth administration is sufficient to increase hippocampal neurite outgrowth and dendritic spine density leading to augmented basal synaptic transmission and impaired long-term potentiation (LTP) response. To study the molecular pathways affected by Meth, we used embryonic primary neuron cultures from the hippocampus and performed RNA Sequencing from isolated soma or neurites compartments, FRET microscopy, biochemical analyses, and morphometric measurements of dendrites to demonstrate that intersectin (Itsn)1/cdc42 signaling is an important mediator of Meth-induced morphological adaptations, specifically in the synaptic compartment. Furthermore, AAV-mediated depletion of neuronal cdc42 in the hippocampus prevented Meth-induced changes in cytoarchitecture and their consequent impact on neuronal functionality. Our results highlight relevant compartment-associated changes in the activity of Itsn1/cdc42 pathway that critically regulate Meth-induced neuronal remodeling and plasticity.
- Meningeal γδ T cells facilitate bacterial entry into the brain in neonatal meningitis and trigger long-term behavioural sequelaePublication . Lorga, Inês; Soares, Joana; Bravo, Joana; Mesquita, Pedro; Ribeiro, Nuno; Rodrigues, João; Hassan, Ahmed; Mesquita, Morgana; Cavadas, Bruno; Georgiev, Hristo; Magalhães, Ana; Summavielle, Teresa; Vilanova, Manuel; Ribot, Julie C.; Andrade, Elva Bonifácio; Bonifácio Andrade, Elva; Summavielle, TeresaNeonatal bacterial meningitis is a life-threatening condition and a leading cause of neurodevelopmental impairment among survivors. Despite its prevalence, the role of meningeal immunity on disease pathology during early life remains largely unexplored. Using a clinically relevant mouse model of neonatal group B streptococcal meningitis and single-cell RNA sequencing, we observed that IL-17A (IL-17)-producing γδ T cells (γδ17 T cells) accumulate in the meninges during the acute phase of infection and persist throughout the lifespan. Importantly, mice deficient in γδ T cells or in IL-17 show a significantly lower bacterial colonisation in the brain parenchyma, and IL-17 neutralisation in the cerebrospinal fluid leads to a similar phenotype. Reduced blood-brain barrier permeability in the absence of γδ T cells results in decreased bacterial invasion and diminished microglia activation. Wild-type but not γδ T cell-deficient mice surviving infection exhibit increased hyperactivity and open space anxiety during early adulthood, a behavioural profile that may reflect attention deficit and hyperactivity (ADHD)-like tendencies. Altogether, these findings establish a pathogenic role for meningeal γδ17 T cells in early life, uncovering a key mechanism that drives long-term sequelae in GBS neonatal meningitis.
- Consensus on covert awareness: a Delphi studyPublication . Schnakers, Caroline; Overbeek, Berno; Fullmer, Niko; Teixeira, Liliana; Zandalasini, Matteo; Yatsko, Kseniia; Morrissey, Ann-Marie; Zasler, Nathan; Estraneo, AnnaIdentifying wilful brain activity in patients with disorders of consciousness is critical, as some patients fail to exhibit behavioural signs of consciousness at the bedside but respond to active tasks via neuroimaging or electrophysiological measures. Standardized terminology for this subgroup is absent while it is essential for advancing research and clinical care. The objective of this study was to determine the level of consensus among a large group of international experts on terminology and definitions for this clinical entity, as described by terms such as covert awareness, cognitive motor dissociation, functional locked-in syndrome, and non-behavioural minimally conscious state. A Delphi study was conducted using REDCap to evaluate expert agreement on terminology and definitions. The study was conducted among international experts, primarily from Europe/UK, the USA and other regions. Ninety-six experts participated. Among these, 75 (78%) completed both rounds. Participants were predominantly clinical scientists (71%) working in rehabilitation settings (63%). A Delphi method was followed. Consensus on terminology and related definitions was defined as a median score of 5, an interquartile range ≤1 and ≥75% agreement (scores of 4 or 5). Within two rounds, consensus was achieved for over two- thirds of the statements. The term ‘Covert Awareness’ and its associated definition were identified as the preferred terminology by an international expert panel. We recommend the use of ‘Covert Awareness’ since our large group of international experts consistently agreed on such preferred term for this subgroup of patients with disorders of consciousness. This consensus (>75% agreement) establishes a foundation both for future research and clinical standardization. The findings have implications for improving diagnostic accuracy and advancing understanding of covert awareness, although further study is needed to refine and apply the agreed-upon definition in clinical practice.
- Optimizing neurobehavioral assessment for patients with disorders of consciousness: Proposal of a comprehensive pre-assessment checklist for cliniciansPublication . Keech, Kristen; Schnakers, Caroline; Murtaugh, Brooke; O’Brien, Katherine; Slomine, Beth; Briand, Marie-Michèle; Formisano, Rita; Thibaut, Aurore; Estraneo, Anna; Noé, Enrique; Gosseries, Olivia; Teixeira, Liliana da Conceição; da Conceição Teixeira, LilianaClinicians are challenged by the ambiguity and uncertainty in assessing level of consciousness in individuals with disorder of consciousness (DoC). There are numerous challenges to valid and reliable neurobehavioral assessment and classification of DoC due to multiple environmental and patient-related biases including behavioral fluctuation and confounding or co-occurring medical conditions. Addressing these biases could impact accuracy of assessment and is an important aspect of the DoC assessment process. A pre-assessment checklist was developed by a group of interdisciplinary DoC clinical experts and researchers based on the existing literature, current validated tools, and expert opinions. Once finalized, the checklist was electronically distributed to clinicians with a range of experience in neurobehavioral assessment with DoC. Respondents were asked to use the checklist prior to completing a neurobehavioral assessment. A survey was also provided to respondents to obtain feedback regarding checklist feasibility and utility in optimizing the behavioral assessments. Thirty-three clinicians completed the survey after using the checklist. Over half of the respondents were a combination of physicians, neuropsychologists, and physical therapists. All respondents served the adult DoC population and 42% percent had over ten years of clinical experience. Eighty percent reported they found the format of the checklist useful and easy to use. All respondents reported the checklist was relevant to preparing for behavioral assessment in the DoC population. Eighty-four percent reported they would recommend the use of the tool to other clinicians. The use of a pre-assessment checklist was found to be feasible and efficacious in increasing interdisciplinary clinician’s ability to optimize the patient and environment in preparation for neurobehavioral assessment. Initial results of clinicians’ perception of the utility of a pre-assessment checklist were positive. However, further validation of the tool is needed with larger sample sizes to improve representation of clinical use across disciplines and care settings.
- A systematic review of chest-worn sensors in cardiac assessment: technologies, advantages, and limitationsPublication . Machado, Ana; Ferreira, Filipa; Ferreira, Simão; Almeida-Antunes, Natália; Carvalho, Paulo; Melo, Pedro; Rocha, Nuno; Rodrigues, Matilde A.; Rodrigues, Matilde; Martins de Almeida Melo, Pedro MiguelThis study reviews the scientific use of chest-strap wearables, analyzing their advantages and limitations, following PRISMA guidelines. Eligible studies assessed chest-strap devices in adults and reported physiological outcomes such as heart rate, heart rate variability, R–R intervals, or electrocardiographic waveform morphology. Studies involving implanted devices, wrist-worn wearables, or lacking validation against reference standards were excluded. Searches were conducted in PubMed, Scopus, Web of Science, and ScienceDirect for studies published in the last 10 years. The quality of the studies was assessed using the Mixed Methods Appraisal Tool, and results were synthesized narratively. Thirty-two studies were included. The most frequently evaluated devices were the Polar H10 and Zephyr BioHarness 3.0, which showed strong correlations with electrocardiography at rest and during light-to-moderate activity. Reported limitations included motion artefacts, poor strap placement, sweating, and degradation of the skin–electrode interface. None of the devices had CE or FDA approval for clinical use, and most studies were conducted in controlled settings, limiting generalizability. Ergonomic concerns such as discomfort during prolonged wear and restricted mobility were also noted. Overall, chest-strap sensors showed good validity and were widely used in validation studies. However, technical refinements and large-scale field trials are needed for broader clinical and occupational application. This review is registered in PROSPERO and is part of the SIREN project.
- Can lycopene be considered an effective protection against cardiovascular disease?Publication . Rodrigues, João Costa; Pinho, O.; Monteiro, Pedro Ribeiro Rocha; Costa-Rodrigues, Joao; Monteiro, PedroLycopene is a bioactive component mainly found in tomato. It is characterized by a high antioxidant potential, the highest among carotenoids. Mainly due to this property, lycopene has been suggested to display many beneficial effects, including its potential cardioprotective role. Despite some contradictory observations, which appear to be mainly caused by discrepancies in the different experimental protocols applied in the different studies, growing evidence points to clear benefits of lycopene in the maintenance of cardiovascular function and health. The knowledge about lycopene’s preventive effects in atherosclerosis, and other cardiovascular diseases, must be translated into changes in food patterns, aiming to increase the consumption of tomato, tomato-containing products, or other foods with high lycopene content, which can have an important impact on cardiovascular disease, particularly in countries where this represents a major public health concern.
- Assessing carbohydrate counting accuracy: Current limitations and future directionsPublication . Amorim, Débora; Miranda, Francisco; Santos, Andreia; Graça, Luís; Rodrigues, João; Rocha, Mara; Pereira, Maria Aurora; Sousa, Clementina; Felgueiras, Paula; Abreu, Carlos; Costa-Rodrigues, JoaoDiabetes mellitus is a prevalent chronic autoimmune disease with a high impact on global health, affecting millions of adults and resulting in significant morbidity and mortality. Achieving optimal blood glucose levels is crucial for diabetes management to prevent acute and long-term complications. Carbohydrate counting (CC) is widely used by patients with type 1 diabetes to adjust prandial insulin bolus doses based on estimated carbohydrate content, contributing to better glycemic control and improved quality of life. However, accurately estimating the carbohydrate content of meals remains challenging for patients, leading to errors in bolus insulin dosing. This review explores the current limitations and challenges in CC accuracy and emphasizes the importance of personalized educational programs to enhance patients’ abilities in carbohydrate estimation. Existing tools for assessing patient learning outcomes in CC are discussed, highlighting the need for individualized approaches tailored to each patient’s needs. A comprehensive review of the relevant literature was conducted to identify educational programs and assessment tools dedicated to training diabetes patients on carbohydrate counting. The research aims to provide insights into the benefits and limitations of existing tools and identifies future research directions to advance personalized CC training approaches. By adopting a personalized approach to CC education and assessment, healthcare professionals can empower patients to achieve better glycemic control and improve diabetes management. Moreover, this review identifies potential avenues for future research, paving the way for advancements in personalized CC training and assessment approaches and further enhancing diabetes management strategies.
- Total sacrectomy rehabilitation: Implementation of the international classification of functioning, disability, and health model – A case reportPublication . Lopes, Alfredo A.; Mesquita, Inês; Torres, Rui; Torres, Rui; Lopes, Alfredo; Mesquita, InêsThis study aims to outline an evaluative diagnostic process and intervention for a patient who underwent total sacrectomy based on the International Classification of Functioning, Disability, and Health (ICF) model. A 70-year-old male with a history of an aggressive sacral chordoma experiencing intense pain, constipation, and polyuria without the sensation of bladder filling, underwent a total sacrectomy. Two evaluations at two-time points were conducted 12 weeks apart. The patient then underwent an individualized rehabilitation program tailored to address impairments, activity limitations, and participation restrictions. The care plan was adjusted based on the patient’s health status and relevant personal and environmental factors. The Barthel Scale scores improved from 60 to 80. Motor scores on the American Spinal Injury Association scale increased from 62 to 66, while sensory scores for light touch improved from 86 to 96. However, pain scores remained stable at 86. Functional reach tests showed notable enhancements, with anterior reach increasing from 16.4 cm to 23.7 cm and lateral reach from 9.6 cm to 15.2 cm. The patient also showed progress in mobility, increasing the number of steps taken from 0 to 10. This case report highlights the positive therapeutic outcomes achieved, illustrating improvements in functional activities and patient independence, thereby underscoring the effectiveness of the ICF model in managing patients undergoing total sacrectomy.
- The cardiometabolic impact of rebaudioside a exposure during the reproductive stagePublication . Bracchi, Isabella; Morais, Juliana; Coelho, João Almeida; Ferreira, Ana Filipa; Alves, Inês; Mendes, Cláudia; Correia, Beatriz; Gonçalves, Alexandre; Guimarães, João Tiago; Falcão-Pires, Inês; Keating, Elisa; Negrão, RitaSince foods rich in refined sugars promote obesity, the use of non-caloric sweeteners has gained popularity, and their consumption by pregnant women has increased. Stevia (a non-caloric sweetener) consumption was considered safe for humans by the European Food Safety Authority in a dose of up to 4 mg/kg body weight/day. However, the World Health Organization recommended in 2023 the restraint of these sweeteners at any life stage, highlighting the need for research on pregnant women and early stages of development. So, we aimed to study the effects of chronic consumption of the main sweetener compound of stevia (Rebaudioside A) during the reproductive stage. Female rats were treated with Rebaudioside A (4 mg steviol equivalents/kg body weight/day) in the drinking water from 4 weeks before mating until weaning. Food and water consumption, blood glucose and lipids, as well as heart structure, function and mitochondrial function, were assessed. Rebaudioside A decreased heart size, cardiomyocyte area and fibrosis without repercussions on cardiac or mitochondrial function. Both fasting blood glucose and cholesterol decreased. This work suggests that stevia consumption at this dose may be safe for females during the reproductive stage. However, more studies are mandatory to explore the effects of stevia consumption on offspring’s health.