White matter fibres dissection in the human brain

PhD ThesisIntroduction: lesion to white matter fibres can induce permanent neurological deficits due to the induction of disconnection syndromes. Knowledge of white matter fibre anatomy is therefore relevant to the neurosurgeon in order to minimise the risk of causing neurological damage when approaching lesions in eloquent areas of the brain. Aim: to investigate the 3D anatomy of white matter fibres with particular attention to the associative tracts, including short arcuate fibres and intralobar fibres. The results obtained will be used to provide insights in brain connectivity, delineating networks important for specific brain functions. Methods: The Klingler technique for white matter dissection was followed. Brain specimens were collected and prepared at the Newcastle Brain Tissue Resource, Newcastle University. Brains were initially fixed in 10% formalin for at least 4 weeks. After removing the pia-mater and arachnoid, the brains were frozen at -15C° for 2 weeks. The water crystallisation induced by the freezing process separates the white matter fibres, facilitating the dissection of the tracts. Dissection was performed with wooden spatulas and blunt metallic dissectors, removing the cortex and exposing the white matter. The short associative (U-shaped) fibres were initially exposed. Long associative, commissural and projection fibres were demonstrated as the dissection proceeded. Results: five papers form the main body of the present work: 1) “Raymond de Vieussens and his contribution to the study of white matter anatomy”. This historical paper reviewed the history of white matter dissection, focusing on the work of Raymond de Vieussens, who gave the first account of the centrum ovale and of the continuity of the corticospinal tract from the centrum ovale to the brainstem. 2) “The white matter of the human cerebrum: part I The occipital lobe by Heinrich Sachs “ ; 3) “Intralobar fibres of the occipital lobe: A post mortem dissection study”. These joint papers were dedicated to the white matter anatomy of the occipital lobe. A rich network of association fibres, arranged around the ventricular wall, was demonstrated. A new white matter tract, connecting the cuneus to the lingula, was also described. Our original data I II were compared to the atlas of occipital fibres produced by the German anatomist Heinrich Sachs. 4) “White matter connections of the Supplementary Motor Area (SMA) in humans”. This study demonstrated that the SMA shows a wide range of connections with motor, language and limbic areas. Features of the SMA syndrome (akinesia and mutism) can be better understood on the basis of these findings. 5) “Anatomical connections of the Subgenual Cingulate Region” (SCG). This study showed that the SCG is at the centre of a large network, connecting prefrontal, limbic and mesotemporal regions. The connectivity of this region can help explain the clinical effect of neuromodulaton of the SCG in Deep Brain Stimulation for neuropsychiatric disorders. Conclusions: Klingler dissection provided original data about the connections of different brain regions that are relevant to neurosurgical practice, along with the description of a new white matter tract, connecting the cuneus to the lingula

Designing Situated Vocabularies to Counter Social Polarizations: A Case Study of Nolo Neighbourhood, Milan

Many neighbourhoods are currently serving as laboratories where new methods are being explored for collaboratively redesigning cities and tackling the social, environmental, and cultural issues affecting them. These redesign processes are often supported by local communities who increasingly develop bottom-up initiatives to innovate and preserve the neighbourhood’s "common goods." This is certainly the case of Nolo, an area in the city of Milan (Italy) that has recently undergone an urban regeneration process thanks to the presence of a proactive community of actors living and working in the neighbourhood. Despite effective social innovation practices enacted by part of the local community, several "voices" in Nolo - mainly belonging to marginalized communities - are still excluded from the current process of urban regeneration. This lack of attention is rather problematic for the whole community, as it is leading to increasing rather than mitigating social polarization. To address this issue, we approached Nolo and its community through a participatory design experimentation, generating a series of collaborative platforms to enable those marginalized voices - humans as well as non-humans - to be heard, to enter into agonistic conversations with one another, and to question what they (should) all care about. What this (still ongoing) experimentation is currently showing is that to co-design collaborative platforms to counter polarization needs to be carefully balanced, negotiating between all the actors involved and acknowledging their thick entanglements to finally unravel how they radically inter-depend on one another. This kind of "ontologizing" practice is currently proving to be pivotal to counter “antagonisms” (and, therefore, mitigate social polarizations), and re-framing them in "agonistic" terms. This article reports how we operated this “ontologizing” practice in a particularly debated area of the neighbourhood by embracing the perspective of marginalized actors, encouraging them to collaborative and transformative actions for their own situated context

Co-designing Contents With Situated Stakeholders: An In-Field Process in Nolo (Milan)

Neighborhoods today emerges as “design incubators” as they are characterized by the proactivity of local actors — such as citizens, shopkeepers, associations, informal groups — acting at the core of the design process by developing brand-new and tailor-made solutions and at the same time provide environmental, economic, and social beneficial transformation in an inclusive and democratic way. This work presents considerations from a two-years initiative named Off Campus Nolo (OCN), a living lab promoted by the Politecnico di Milano that opened its doors in the Nolo neighborhood (Milan). With its rich set of contents (activities, projects, and events) the experience of OCN demonstrates how creating a bridge to transfer the academic skills on a neighborhood-community level can improve the quality of actions to be developed, also exploring new ways of spreading the knowledge from the academia and prompting new forms of social innovation within neighborhood communities

Isolating the Role of Bone Lacunar Morphology on Static and Fatigue Fracture Progression through Numerical Simulations

Currently, the onset of bone damage and the interaction of cracks with the surrounding micro-architecture are still black boxes. With the motivation to address this issue, our research targets isolating lacunar morphological and densitometric effects on crack advancement under both static and cyclic loading conditions by implementing static extended finite element models (XFEM) and fatigue analyses. The effect of lacunar pathological alterations on damage initiation and progression is evaluated; the results indicate that high lacunar density considerably reduces the mechanical strength of the specimens, resulting as the most influencing parameter among the studied ones. Lacunar size has a lower effect on mechanical strength, reducing it by 2%. Additionally, specific lacunar alignments play a key role in deviating the crack path, eventually slowing its progression. This could shed some light on evaluating the effects of lacunar alterations on fracture evolution in the presence of pathologies

Dating the formation of the counter-rotating stellar disc in the spiral galaxy NGC 5719 by disentangling its stellar populations

We present the results of the VLT/VIMOS integral-field spectroscopic observations of the inner 28"x28" (3.1 kpc x 3.1 kpc) of the interacting spiral NGC 5719, which is known to host two co-spatial counter-rotating stellar discs. At each position in the field of view, the observed galaxy spectrum is decomposed into the contributions of the spectra of two stellar and one ionised-gas components. We measure the kinematics and the line strengths of the Lick indices of the two stellar counter-rotating components. We model the data of each stellar component with single stellar population models that account for the alpha/Fe overabundance. We also derive the distribution and kinematics of the ionised-gas disc, that is associated with the younger, less rich in metals, more alpha-enhanced, and less luminous stellar component. They are both counter-rotating with respect the main stellar body of the galaxy. These findings prove the scenario where gas was accreted first by NGC 5719 onto a retrograde orbit from the large reservoir available in its neighbourhoods as the result of the interaction with its companion NGC 5713, and subsequently fuelled the in situ formation of the counter-rotating stellar disc.Comment: 5 pages, 4 figures. Accepted for publication in MNRAS letters. Reference list update

Knocking down metabotropic glutamate receptor 1 improves survival and disease progression in the SOD1G93A mouse model of amyotrophic lateral sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disease reflecting degeneration of upper and lower motoneurons (MNs). The cause of ALS and the mechanisms of neuronal death are still largely obscure, thus impairing the establishment of efficacious therapies. Glutamate (Glu)-mediated excitotoxicity plays a major role in MN degeneration in ALS. We recently demonstrated that the activation of Group I metabotropic Glu autoreceptors, belonging to both type 1 and type 5 receptors (mGluR1 and mGluR5), at glutamatergic spinal cord nerve terminals, produces excessive Glu release in mice over-expressing human superoxide-dismutase carrying the G93A point mutation (SOD1G93A), a widely used animal model of human ALS. To establish whether these receptors are implicated in ALS, we generated mice expressing half dosage of mGluR1 in the SOD1G93A background (SOD1G93AGrm1crv4/+), by crossing the SOD1G93A mutant mouse with the Grm1crv4/+ mouse, lacking mGluR1 because of a spontaneous recessive mutation. SOD1G93AGrm1crv4/+ mice showed prolonged survival probability, delayed pathology onset, slower disease progression and improved motor performances compared to SOD1G93A mice. These effects were associated to reduction of mGluR5 expression, enhanced number of MNs, decreased astrocyte and microglia activation, normalization of metallothionein and catalase mRNA expression, reduced mitochondrial damage, and decrease of abnormal Glu release in spinal cord of SOD1G93AGrm1crv4/+compared to SOD1G93A mice. These results demonstrate that a lower constitutive level of mGluR1 has a significant positive impact on mice with experimental ALS, thus providing the rationale for future pharmacological approaches to ALS by selectively blocking Group I metabotropic Glu receptors

Evaluation of oxidative stress effects on different macromolecules in adult growth hormone deficiency

Adult growth hormone deficiency (GHD) is being increasingly recognized to cause premature mortality exacerbated by oxidative stress. A case-control observational study has been performed with the primary objective of evaluating new parameters of oxidative stress and macromolecular damage in adult GHD subjects: serum nitrotryptophan; Total Antioxidant Capacity expressed as LAG time; urinary hexanoil-lysine; urinary dityrosine and urinary 8-OH-deoxyguanosine. GHD was diagnosed using Growth Hormone-Releasing Hormone 50\u3bcg iv+arginine 0,5 g/Kg test, with a peak GH response <9 \u3bcg /L when BMI was <30 kg/m2 or <4 \u3bcg/L when BMI was >30 kg/m2. Patients affected by adult GHD were divided into three groups, total GHD (n = 26), partial GHD (n = 25), and controls (n = 29). Total Antioxidant Capacity, metabolic and hormonal parameters have been determined in separate plasma samples; nitrotryptophan in serum samples; hexanoil-lysine, dityrosine, 8-OH-deoxyguanosine in urine samples. Assessment of hexanoil-lysine exhibited a trend to increase in comparing total GHD vs partial and controls, although not significant. Values of 8-OH-deoxyguanosine did not significantly differ among the three groups. Significant lower levels of dityrosine in partial GHD vs total and controls were found. No significant difference in nitrotriptophan serum levels was found, while significantly greater values of Total Antioxidant Capacity were showed in total and partial GHD vs controls. Thus, our result confirm that oxidative stress is increased both in partial and total adult GHD. The lack of compensation by antioxidants in total GHD may be connected to the complications associated to this rare disorder

Dendritic cell vaccination in metastatic melanoma turns \u201cnon-T cell inflamed\u201d into \u201cT-cell inflamed\u201d tumors

Dendritic cell (DC)-based vaccination effectively induces anti-tumor immunity, although in the majority of cases this does not translate into a durable clinical response. However, DC vaccination is characterized by a robust safety profile, making this treatment a potential candidate for effective combination cancer immunotherapy. To explore this possibility, understanding changes occurring in the tumor microenvironment (TME) upon DC vaccination is required. In this line, quantitative and qualitative changes in tumor-infiltrating T lymphocytes (TILs) induced by vaccination with autologous tumor lysate/homogenate loaded DCs were investigated in a series of 16 patients with metastatic melanoma. Immunohistochemistry for CD4, CD8, Foxp3, Granzyme B (GZMB), PDL1, and HLA class I was performed in tumor biopsies collected before and after DC vaccination. The density of each marker was quantified by automated digital pathology analysis on whole slide images. Co-expression of markers defining functional phenotypes, i.e., Foxp3+ regulatory CD4+ T cells (Treg) and GZMB+ cytotoxic CD8+ T cells, was assessed with sequential immunohistochemistry. A significant increase of CD8+ TILs was found in post-vaccine biopsies of patients who were not previously treated with immune-modulating cytokines or Ipilimumab. Interestingly, along with a maintained tumoral HLA class I expression, after DC vaccination we observed a significant increase of PDL1+ tumor cells, which significantly correlated with intratumoral CD8+ T cell density. This observation might explain the lack of a significant concurrent cytotoxic reactivation of CD8+ T cell, as measured by the numbers of GZMB+ T cells. Altogether these findings indicate that DC vaccination exerts an important role in sustaining or de novo inducing a T cell inflamed TME. However, the strength of the intratumoral T cell activation detected in post-DC therapy lesions is lessened by an occurring phenomenon of adaptive immune resistance, yet the concomitant PDL1 up-regulation. Overall, this study sheds light on DC immunotherapy-induced TME changes, lending the rationale for the design of smarter immune-combination therapies

Management evaluation of metastasis in the brain (MEMBRAIN)—a United Kingdom and Ireland prospective, multicenter observational study

Background:In recent years an increasing number of patients with cerebral metastasis (CM) have been referred to the neuro-oncology multidisciplinary team (NMDT). Our aim was to obtain a national picture of CM referrals to assess referral volume and quality and factors affecting NMDT decision making. Methods:A prospective multicenter cohort study including all adult patients referred to NMDT with 1 or more CM was conducted. Data were collected in neurosurgical units from November 2017 to February 2018. Demographics, primary disease, KPS, imaging, and treatment recommendation were entered into an online database. Results:A total of 1048 patients were analyzed from 24 neurosurgical units. Median age was 65 years (range, 21-93 years) with a median number of 3 referrals (range, 1-17 referrals) per NMDT. The most common primary malignancies were lung (36.5%, n = 383), breast (18.4%, n = 193), and melanoma (12.0%, n = 126). A total of 51.6% (n = 541) of the referrals were for a solitary metastasis and resulted in specialist intervention being offered in 67.5% (n = 365) of cases. A total of 38.2% (n = 186) of patients being referred with multiple CMs were offered specialist treatment. NMDT decision making was associated with number of CMs, age, KPS, primary disease status, and extent of extracranial disease (univariate logistic regression, P < .001) as well as sentinel location and tumor histology (P < .05). A delay in reaching an NMDT decision was identified in 18.6% (n = 195) of cases. Conclusions:This study demonstrates a changing landscape of metastasis management in the United Kingdom and Ireland, including a trend away from adjuvant whole-brain radiotherapy and specialist intervention being offered to a significant proportion of patients with multiple CMs. Poor quality or incomplete referrals cause delay in NMDT decision making