Strasbourg Translational Neuroscience and Psychiatry

The diagnosis of amyotrophic lateral sclerosis requires identifying degeneration in both brain and bulbospinal motor neurons. However, detecting cortical dysfunction remains challenging, as peripheral symptoms often overshadow upper motor neuron signs. Although transcranial magnetic stimulation and MRI are valuable tools, transcranial magnetic stimulation is challenged as disease progresses but also at early stage in some patients, and brain MRI shows in most cohorts no significant change at the time of diagnosis. This emphasizes the need for neuromarkers facilitating detection of cortical dysfunction and longitudinal monitoring. EEG offers promising avenues. Accordingly, we recently identified altered theta-gamma phase–amplitude coupling in amyotrophic lateral sclerosis. The present study aimed to further explore phase–amplitude coupling in patients, focusing not only on theta and gamma bands but also on alpha and beta bands, and the link with handedness and brain structure. Resting-state EEG was recorded in 26 patients with amyotrophic lateral sclerosis and 26 age- and sex-matched controls, alongside anatomical and diffusion MRI. PAC was calculated between slow and gamma oscillations at five sensorimotor electrodes bilaterally. Grey and white matter integrity was evaluated through cortical thickness measurements and diffusion metrics along the corticospinal tract. Results revealed significantly decreased theta-gamma PAC in the dominant hemisphere of patients, without changes in band powers or other frequency couplings. MRI confirmed well-known handedness-related brain structural asymmetry in both groups, although it was less pronounced in patients. Specifically, diffusion metrics were altered in the most caudal segment (brainstem level) of the pyramidal tract within the dominant hemisphere in patients. These findings align with lateralized theta-gamma PAC alterations and the greater vulnerability of the dominant hemisphere to amyotrophic lateral sclerosis. No correlation was found between electrophysiological and diffusion metrics, likely because they are related to different mechanisms: PAC alteration being presumably linked to excitation/inhibition imbalance preceding upper motor neuron degeneration. Moreover, theta–gamma PAC was found to be particularly altered in patients with altered cognitive scores, consistent with previous findings in patients with mild cognitive impairment. Lastly, receiver operating characteristic analyses demonstrated that PAC outperformed diffusion MRI in diagnostic accuracy, underscoring its potential as a very sensitive marker of cortical dysfunction in amyotrophic lateral sclerosis. Although these results need validation in a larger cohort at different stages of the disease and across different forms (sporadic and familial), they confirm that PAC can detect cortical dysfunctions in amyotrophic lateral sclerosis.

Introduction: Sleep disorders in the insomnia spectrum, as well as nightmares, are among the most sensitive and persistent symptoms in children with post-traumatic stress disorder (PTSD). There is currently no reference treatment or specific pharmacological treatment recommendation on the management of sleep disturbances in children and adolescents suffering from PTSD, despite the fact that they have a significant effect on daytime functioning and overall mental health of children as well as on family’s health and quality of life. In this respect, paediatric prolonged-release melatonin (PedPRM) has shown significant beneficial effects on insomnia disorders in children with autism spectrum disorders and positive effects on anxiety and depressive symptomatology. Our study will be the first randomized controlled trial to examine the efficacy of PedPRM melatonin on sleep disorders in children and adolescents with PTSD, as well as on PTSD symptoms, associated daytime functioning and overall mental health in these children and their caregivers. Methods/design: The MelatoSOM-Kids-PTSD study (French national hospital-based clinical research programme) will be a multi-centre prospective double-blind placebo-controlled parallel group clinical trial investigating the efficacy of paediatric prolonged-release melatonin to alleviate sleep disturbances in children and adolescents with PTSD (120 participants recruited over a 24-month period). The experimental group will be treated with active prolonged-release melatonin over 13 weeks (PedPRM). The control group will receive a placebo. The primary endpoint will be the difference in sleep diary derived total sleep time after 13 weeks of treatment in the PedPRM group versus placebo group. Secondary endpoints will be the differences in objective sleep quality parameters and daytime functioning before and after treatment, in children with PTSD and their caregivers. Discussion: This paper describes the MelatoSOM-Kids-PTSD protocol, which will evaluate the effectiveness of melatonin, a treatment that has already demonstrated an excellent benefit-risk ratio in the paediatric population over 4 years.

Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly evolving neurodegenerative disease arising from the loss of glutamatergic corticospinal neurons (CSN) and cholinergic motoneurons (MN). Here, we performed comparative cross-species transcriptomics of CSN using published snRNA-seq data from the motor cortex of ALS and control postmortem tissues, and performed longitudinal RNA-seq on CSN purified from male Sod1G86R mice. We report that CSN undergo ER stress and altered mRNA translation, and identify the transcription factor CREB3 and its regulatory network as a resilience marker of ALS, not only amongst vulnerable neuronal populations, but across all neuronal populations as well as other cell types. Using genetic and epidemiologic analyses we further identify the rare variant CREB3R119G (rs11538707) as a positive disease modifier in ALS. Through gain of function, CREB3R119G decreases the risk of developing ALS and the motor progression rate of ALS patients.

Distributed leadership is currently the most studied leadership model in education. This study posits that there is not a single best model or blueprint for distributed leadership, but that schools should foster manifestations of distributed leadership to support professional development and school improvement. The school leader can support distributed leadership. In this study we examined dimensions of distributed leadership when teachers collaborate in two Dutch schools, which were selected after an elaborate selection process—quantitatively through an online survey and a benchmark method and qualitatively through additional focus group interviews. Within these schools, which were considered as critical cases, data were collected through semi‐structured interviews with teachers (14) and school leaders (three), focus groups with teachers and school leaders (three) and observation of teachers collaborating (four). Data were analysed by inductively labelling and thematising relevant fragments. This was checked by a second researcher, ensuring the validity of the findings. Based on our findings we propose four manifestations of distributed leadership in teacher collaboration and discuss the role of the school leader in supporting these manifestations. This role is larger than one might expect. Depending on the situation, school leaders can either formally manage structurally designed manifestations of distributed leadership, which requires transactional leadership, or facilitate relational manifestations of distributed leadership, which requires transformational leadership.

Bipolar disorder (BD) and emotion dysregulation present substantial challenges for individuals and healthcare providers. Although pharmacological treatments remain the primary approach, psychosocial interventions show promise in addressing sub-threshold symptoms and deepening understanding of mood and emotion dysregulation mechanisms. The European Network for Bipolar Emotion Regulation (ENBER) aims to close the gap between research and clinical practice by offering practical insights for clinicians while contributing to scientific discourse on BD and emotion regulation (ER). This perspective paper identifies key questions for the field, suggesting directions for future research and highlighting promising interventions, such as Dialectical Behaviour Therapy (DBT), which have shown potential to reduce emotion dysregulation and improve personal recovery in BD. Future research should explore the flexibility and context-appropriateness of ER strategies, considering how current mood states significantly impact these dynamics. The commentary advocates for personalised treatment approaches that address individual differences in symptoms and ER capabilities, recommending innovative methodologies to better understand and apply ER in BD.Incorporating patient perspectives into research design is also a necessary focus for future research, having the potential to improve recovery and quality of life for individuals with BD.

Presynaptic Hyperexcitability Reversed by Positive Allosteric Modulation of a GABABR Epilepsy Variant Marielle Minere, Martin Mortensen, Valentina Dorovykh, Gary Warnes, Dean Nizetic, Trevor G Smart, Saad B Hannan. Brain. 2024: awae232. doi/10.1093/brain/awae232/7717204 Gamma-aminobutyric acid B receptors (GABABRs) are key membrane proteins that continually adapt the excitability of the nervous system. These G-protein-coupled receptors are activated by the brain's premier inhibitory neurotransmitter GABA. They are obligate heterodimers composed of GABA-binding GABABR1 and G-protein-coupling GABABR2 subunits. Recently, three variants (G693W, S695I, and I705N) have been identified in the gene (GABBR2) encoding for GABABR2. Individuals that harbor any of these variants exhibit severe developmental epileptic encephalopathy and intellectual disability, but the underlying pathogenesis that is triggered in neurons remains unresolved. Using a range of confocal imaging, flow cytometry, structural modeling, biochemistry, live cell Ca2+ imaging of presynaptic terminals, whole-cell electrophysiology of HEK-293T cells and neurons, and 2-electrode voltage clamping of Xenopus oocytes we have probed the biophysical and molecular trafficking and functional profiles of G693W, S695I, and I705N variants.We report that all 3-point mutations impair neuronal cell surface expression of GABABRs, reducing signaling efficacy. However, a negative effect is evident for 1 variant perturbed neurotransmission by elevating presynaptic Ca2+ signaling. This is reversed by enhancing GABABR signaling via positive allosteric modulation.Our results highlight the importance of studying neuronal receptors expressed in nervous system tissue and provide new mechanistic insights into how GABABR variants can initiate neurodevelopmental disease while highlighting the translational suitability and therapeutic potential of allosteric modulation for correcting these deficits.

Background: Opioid Use Disorder (OUD) often provokes dramatic consequences in terms of increased morbi-mortality. Two medications have mainly been worldwide used for OUD (MOUD), buprenorphine and methadone. Recently, however, some reports have highlighted the use of Morphine Sulfate (MS) mainly obtained without a prescription but used as MOUD by opioid users and especially People Who Inject Substances (PWIS). We propose to characterize the prevalence and distribution of MOUD and MS use in PWIS. Methods: This study examines the use of MOUD and MS amongst French PWIS recruited in harm reduction facilities and drug consumption rooms in the context of the COSINUS (Cohort to assess structural and individual factors in drug use) study. Results: MOUD are prescribed, respectively, to one-third and one-fifth of PWIS, whereas a half of them declared MS consumption without prescription. MS users live with higher precariousness and are younger than non-users. MS is associated with salt cocaine and heroin use. It is often consumed with methadone and more rarely with buprenorphine and we hypothesized that this is probably linked to buprenorphine's pharmacological antagonism. Discussion: Our results show the high prevalence of MS consumption and highlight the importance of considering the highly restricted possibility of prescribing MS as MOUD. Its association with methadone raises the question of their synergistic action on craving and mental disorders. The profiles of opioid users who could benefit from MS with or without methadone must be examined to improve their care but with the utmost caution, given the risk of overdose.

Background: The objective of this study (registered under number 2020 006) was to assess the internal consistency of the revised Mental Health Professional Culture Inventory (MHPCI) scale, which comprises 15 items, among mental health service workers in Romania. Methods: To examine the psychometric properties of the MHPCI questionnaire within the Romanian population, we employed two main methods: The partial credit model (PCM) and Exploratory factor analysis (EFA). Results: A total of 94 individuals were interviewed, and among them, 71 provided complete responses to the questionnaire. All 15 items demonstrate a strong fit with the PCM, as indicated by mean-square (MSQ) outfit and MSQ infit values falling within the range of 0.5 to 1.5. But items 3 and 11 exhibit MSQ values greater than 1.5, suggesting that it may be challenging to predict individuals’ responses to these items. The KMO index stands at 0.7, surpassing the recommended threshold of 0.6, signifying an acceptable level of suitability. Nevertheless, only 59.3% of the total variance is accounted for by the first four factors, and these factors do not align with the dimensions identified in the original article. Conclusion: The internal structure of the Romanian version of the MHPCI demonstrates satisfactory psychometric properties. These properties will need to be further validated through additional studies conducted in diverse socio-cultural contexts.

Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. Here we performed genome-wide association studies meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of phenotypic variance. We observed gene expression in specific neural cell types across differentiation time points, including genes involved in intracellular signaling and brain aging-related processes. Polygenic scores for brain volumes showed predictive ability when applied to individuals of diverse ancestries. We observed causal genetic effects of brain volumes with Parkinson’s disease and attention-deficit/hyperactivity disorder. Findings implicate specific gene expression patterns in brain development and genetic variants in comorbid neuropsychiatric disorders, which could point to a brain substrate and region of action for risk genes implicated in brain diseases.

Ataxia with anti-regulator of G-protein signaling 8 autoantibodies (RGS8-Abs) is an autoimmune disease recently described in four patients. The present study aimed to identify other patients with RGS8-Abs, describe their clinical features, including the link between RGS8-related autoimmune cerebellar ataxia (ACA) and cancer. Patients with RGS8-Abs were identified retrospectively in the biological collections of the French Reference Center for Paraneoplastic Neurological Syndrome and the University of California San Francisco Center for Encephalitis and Meningitis. Clinical data were collected, and cerebrospinal fluid, serum, and tumor pathological samples were retrieved to characterize the autoantibodies and the associated malignancies. Only three patients with RGS8-Abs were identified. All of them presented with a pure cerebellar ataxia of mild to severe course, unresponsive to current immunotherapy regimens for ACA. Two patients presented with a Hodgkin lymphoma of the rare specific subtype called nodular lymphocyte-predominant Hodgkin lymphoma, with very mild extension. Autoantibodies detected in all patients enriched the same epitope on the RGS8 protein, which is an intracellular protein physiologically expressed in Purkinje cells but also ectopically expressed specifically in lymphoma cells of patients with RGS8-related ACA. The present results and those of the four cases previously described suggest that RGS8-Abs define a new paraneoplastic neurological syndrome of extreme rarity found mostly in middle-aged males that associates pure cerebellar ataxia and a particular lymphoma specifically expressing the RGS8 antigen. As in other paraneoplastic ACA with intracellular antigen, the disease course is severe, and patients tend to exhibit a poor response to immune therapy.

The etiology of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) is complex and considered multifactorial. The majority of ALS cases are sporadic, but familial cases also exist. Estimates of heritability range from 8% to 61%, indicating that additional factors beyond genetics likely contribute to ALS. Numerous environmental factors are considered, which may add up and synergize throughout an individual’s lifetime building its unique exposome. One level of integration between genetic and environmental factors is epigenetics, which results in alterations in gene expression without modification of the genome sequence. Methylation reactions, targeting DNA or histones, represent a large proportion of epigenetic regulations and strongly depend on the availability of methyl donors provided by the ubiquitous one-carbon (1C) metabolism. Thus, understanding the interplay between exposome, 1C metabolism, and epigenetic modifications will likely contribute to elucidating the mechanisms underlying altered gene expression related to ALS and to developing targeted therapeutic interventions. Here, we review evidence for 1C metabolism alterations and epigenetic methylation dysregulations in ALS, with a focus on the impairments reported in neural tissues, and discuss these environmentally driven mechanisms as the consequences of cumulative exposome or late environmental hits, but also as the possible result of early developmental defects.

Background: Healthcare workers’ mental health has been impacted by the COVID-19 pandemic, emphasizing the need for mental health interventions in this population. Online cognitive behavioral therapy (CBT) is efficient to reduce stress and may reach numerous professionals. We developed “MyHealthToo”, an online CBT program to help reduce stress among healthcare workers during the COVID-19 pandemic. Objective: The aim of our study is to investigate the efficacy of an online CBT program on stress and mental health conditions among healthcare workers during a health crisis. Methods: We performed a multicentric randomized controlled trial among 155 participants allocated either to the experimental or active control group (bibliotherapy). The primary outcome was the decrease of perceived stress scores (PSS-10) post-treatment. Secondary outcomes included depression, insomnia and PTSD symptoms along with self-reported resilience and ruminations. Assessments were scheduled pretreatment, mid-treatment (4 weeks), post-treatment (8 weeks), and at 1-month and 4-months follow-up. Results: For both interventions, mean changes on the PSS-10 were significant post-therapy (W8), as at 1-month (W12) and 4-months (W24) follow-ups. The between-group comparison showed no difference at any time point (ps > 0.88). Work-related ruminations significantly decreased in the experimental group with a significant between-group difference at W8 (Δ = 􀀀 1.83 [􀀀 3.57; 􀀀 0.09], p = 0.04). Posttraumatic stress symptoms significantly decreased in the experimental group with a significant between-group difference at W12 (Δ = 􀀀 1.41 [􀀀 2.68; 􀀀 0.14], p = 0.03). The decrease in work-related ruminations at W8 mediated the decrease in posttraumatic stress symptoms at W12 (p = 0.048).

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by the death of upper (UMN) and lower motor neurons (LMN) in the motor cortex, brainstem, and spinal cord. Despite decades of research, ALS remains incurable, challenging to diagnose, and of extremely rapid progression. A unifying feature of sporadic and familial forms of ALS is cortical hyperexcitability, which precedes symptom onset, negatively correlates with survival, and is sufficient to trigger neurodegeneration in rodents. Using electrocorticography in the Sod1 G86R and Fus Δ NLS/+ ALS mouse models and standard electroencephalography recordings in patients with sporadic ALS, we demonstrate a deficit in theta-gamma phase-amplitude coupling (PAC) in ALS. In mice, PAC deficits started before symptom onset, and in patients, PAC deficits correlated with the rate of disease progression. Using mass spectrometry analyses of CNS neuropeptides, we identified a presymptomatic reduction of noradrenaline (NA) in the motor cortex of ALS mouse models, further validated by in vivo two-photon imaging in behaving SOD1 G93A and Fus Δ NLS/+ mice, that revealed pronounced reduction of locomotion-associated NA release. NA deficits were also detected in postmortem tissues from patients with ALS, along with transcriptomic alterations of noradrenergic signaling pathways. Pharmacological ablation of noradrenergic neurons with DSP-4 reduced theta-gamma PAC in wild-type mice and administration of a synthetic precursor of NA augmented theta-gamma PAC in ALS mice. Our findings suggest theta-gamma PAC as means to assess and monitor cortical dysfunction in ALS and warrant further investigation of the NA system as a potential therapeutic target.

Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

Opioid use disorder (OUD) is characterized by a lack of control in opioid use, resulting in psychological distress and deficits in interpersonal and social functioning. OUD is often associated with psychiatric comorbidities that increase the severity of the disorder. The consequences of OUD are dramatic in terms of increased morbi-mortality. Specific medications and psychotherapies are essential tools not only in the treatment of OUD but also in the prevention of suicide and overdoses. In our review, we assess the different types of psychotherapies (counseling, motivational interviewing, contingency management, cognitive-behavioral therapy, and dialectical-behavior therapy) that are delivered to opioid users, either associated or un-associated with OUD medications and/or medications for psychiatric disabilities. We describe the application of these therapies first to adult opioid users and then to adolescents. This work led us to propose a stepped-care model of psychotherapies for OUD which provided information to assist clinicians in decision-making regarding the selection of psychotherapeutic strategies according to patients’ OUD severity.

Background: Police personnel are among the first responders exposed to terrorist attacks, raising in number in the late decades. Due to their profession, they are also exposed to repetitive violence, increasing their vulnerability to PTSD and depression. Objective: Our study aims at comparing the prevalence of PTSD and depression, and the risk factors associated with these conditions among directly and indirectly exposed versus non-exposed police personnel during the Strasbourg Christmas Market terrorist attack. Method: Three months after the attack, participants completed a survey assessing their sociodemographic characteristics, occupational data, degree of exposure, sleep debt around the event, event centrality (CES), and three mental health conditions: PTSD (PCL-5), depression (PHQ-9), and suicide risk (yes/no questions). Results: A total of 475 police personnel responded to the questionnaire: 263 were exposed to the attack (182 of them directly) and 212 were non-exposed. Among directly exposed participants, the prevalences of partial and complete PTSD were 12.6 and 6.6%, and the prevalence of moderate-to-severe depression was 11.5%. Multivariate analysis revealed that direct exposure was associated with a higher risk of PTSD (OR = 2.98 [1.10–8.12], p = .03). Direct exposure was not associated with a higher risk of depression (OR = 0.40 [0.10–1.10], p = .08). A significant sleep debt after the event was not associated with a higher risk of later PTSD (OR = 2.18 [0.81–5.91], p = .13) but was associated with depression (OR = 7.92 [2.40–26.5], p < .001). A higher event centrality was associated with both PTSD and depression (p < .001). Conclusions: Police personnel directly exposed to the Strasbourg Christmas Market terrorist attack were at higher risk of PTSD but not depression. Efforts to prevent and treat PTSD should focus on directly exposed police personnel. However, general mental health should be monitored for every personnel member.

Background: Stressful events during a pandemic are a major cause of serious health problems, such as burnout, depression and posttraumatic stress disorder (PTSD) among health care workers (HCWs). During three years, HCWs, on the frontline to fight the COVID-19 pandemic, have been at an increased risk of high levels of stress, anxiety, depression, burnout and PTSD. Regarding potential psychological interventions, Eye Movement Desensitization & Reprocessing (EMDR) is a structured, strongly recommended therapy based on its well-known efficacy in reducing PTSD symptoms and anxiety. Objectives: This study, designed as a trial within a cohort (TwiC), aims to 1) estimate the prevalence of depression, burnout and PTSD in a sample of HCWs after experiencing the COVID-19 emergency (cohort part) and 2) assess the efficacy and acceptability of ‘EMDR + usual care’ for HCWs from the cohort who report significant psychological symptoms (trial part). Methods: The study, designed as a TwiC, consists of a prospective cohort study (n = 3000) with an embedded, pragmatic, randomized open-label superiority trial with two groups (n = 900). Participants included in the trial part are HCWs recruited for the cohort with significant symptoms on at least one psychological dimension (depression, burnout, PTSD) at baseline, 3 months or 6 months, determined by using the Patient Health Questionnaire (PHQ-9), Professional Quality of Life (ProQOL) scale, and PTSD Checklist for the DSM-5 (PCL-5). The intervention consists of 12 separate EMDR sessions with a certified therapist. The control group receives usual care. The trial has three primary outcomes: changes in depression, burnout and PTSD scores from randomization to 6 months. All participants are followed up for 12 months. Conclusions: This study provides empirical evidence about the impact of the COVID-19 pandemic and the mental health burden it places on HCWs and assesses the effectiveness of EMDR as a psychological intervention. Trial registration NCT04570202

Purpose STAT2 is both an effector and negative regulator of type I interferon (IFN-I) signalling. We describe the characterization of a novel homozygous missense STAT2 substitution in a patient with a type I interferonopathy. Methods Whole-genome sequencing (WGS) was used to identify the genetic basis of disease in a patient with features of enhanced IFN-I signalling. After stable lentiviral reconstitution of STAT2-null human fibrosarcoma U6A cells with STAT2 wild type or p.(A219V), we performed quantitative polymerase chain reaction, western blotting, immunofluorescence, and co-immunoprecipitation to functionally characterize the p.(A219V) variant. Results WGS identified a rare homozygous single nucleotide transition in STAT2 (c.656C > T), resulting in a p.(A219V) substitution, in a patient displaying developmental delay, intracranial calcification, and up-regulation of interferon-stimulated gene (ISG) expression in blood. In vitro studies revealed that the STAT2 p.(A219V) variant retained the ability to transduce an IFN-I stimulus. Notably, STAT2 p.(A219V) failed to support receptor desensitization, resulting in sustained STAT2 phosphorylation and ISG up-regulation. Mechanistically, STAT2 p.(A219V) showed defective binding to ubiquitin specific protease 18 (USP18), providing a possible explanation for the chronic IFN-I pathway activation seen in the patient. Conclusion Our data indicate an impaired negative regulatory role of STAT2 p.(A219V) in IFN-I signalling and that mutations in STAT2 resulting in a type I interferonopathy state are not limited to the previously reported R148 residue. Indeed, structural modelling highlights at least 3 further residues critical to mediating a STAT2-USP18 interaction, in which mutations might be expected to result in defective negative feedback regulation of IFN-I signalling.

Do you want to know what an anti-chiece Latin square is? Or what a non-consecutive toroidal modular Latin square is? We invented a ton of new types of Latin squares, some inspired by existing Sudoku variations. We can’t wait to introduce them to you and answer important questions, such as: do they even exist? If so, under what conditions? What are some of their interesting properties? And how do we generate them?

Araç-yaya kazalarında yüksek yaralanma ve hatta ölüm riskleri göz önüne alındığında, yayalar araç pasif güvenliği kapsamında savunmasız kullanıcılar olarak değerlendirilmektedir. Bu kapsamda, otomobil üreticileri, özellikle son yirmi yılda, araçta bulunanların ve yayaların yaralanmasını (ve buna bağlı ölümleri) en aza indirmek maksadı ile ürünlerine birçok yeni özellik dâhil etmişlerdir. Yine de, her yıl yüzbinlerce insan trafik kazaları neticesinde hayatını kaybetmektedir. Bu noktadan hareketle, yaya yaralanmaları (ve güvenliği) konusu küresel çapta yankı uyandıran bir güvenlik sorunu haline gelmiş ve yaya dostu araç tasarımlarına olan ilgi (farkındalık) de artmıştır. Otomobil araç tampon sistemi, çarpışmanın ürettiği darbe enerjisini emmeyi ve bir dereceye kadar yolcuyu, yayayı ve araç gövdesini korumayı amaçlayan kritik bir araç bileşendir. Bu çalışmada, otomobil araç tampon tasarımının yaya güvenliği üzerindeki etkisini daha iyi anlamak için sistematik bir literatür taraması yaklaşımından faydalanılmıştır. Bu kapsamda, tasarımın, malzeme seçiminin ve geometri değişikliklerinin araç tampon sisteminin performansı üzerindeki etkisi yaya güvenliği dikkate alınarak incelenmiştir. Yaya dostu araç tampon tasarımlarında kullanılan güncel yaklaşımlar ortaya koyulmuş ve tartışılmıştır.