Much of our present understanding of the function and operation of the basal ganglia rests on models of anatomical connectivity derived from tract-tracing approaches in rodents and primates. However, the last years have been characterized by promising step forwards in the in vivo investigation and comprehension of brain connectivity in humans. The aim of this review is to revise the current knowledge on basal ganglia circuits, highlighting similarities and differences across species, in order to widen the current perspective on the intricate model of the basal ganglia system. This will allow us to explore the implications of additional direct pathways running from cortex to basal ganglia and between basal ganglia and cerebellum recently described in animals and humans.

The red nucleus (RN) is a large subcortical structure located in the ventral midbrain. Although it originated as a primitive relay between the cerebellum and the spinal cord, during its phylogenesis the RN shows a progressive segregation between a magnocellular part, involved in the rubrospinal system, and a parvocellular part, involved in the olivocerebellar system. Despite exhibiting distinct evolutionary trajectories, these two regions are strictly tied together and play a prominent role in motor and non-motor behavior in different animal species. However, little is known about their function in the human brain. This lack of knowledge may have been conditioned both by the notable differences between human and non-human RN and by inherent difficulties in studying this structure directly in the human brain, leading to a general decrease of interest in the last decades. In the present review, we identify the crucial issues in the current knowledge and summarize the results of several decades of research about the RN, ranging from animal models to human diseases. Connecting the dots between morphology, experimental physiology and neuroimaging, we try to draw a comprehensive overview on RN functional anatomy and bridge the gap between basic and translational research.

Purpose: To evaluate feasibility, toxicities, and clinical response in Stage IV patients treated with palliative “metabolism-guided” lattice technique. Patients and Methods: From June 2020 to December 2021, 30 consecutive clinical stage IV patients with 31 bulky lesions were included in this study. All patients received palliative irradiation consisting of a spatially fractionated high radiation dose delivered in spherical deposits (vertices, Vs) within the bulky disease. The Vs were placed at the edges of tumor areas with different metabolisms at the PET exam following a non-geometric arrangement. Precisely, the Vs overlapped the interfaces between the tumor areas of higher ¹⁸F-FDG uptake (>75% SUV max) and areas with lower ¹⁸F-FDG uptake. A median dose of 15 Gy/1 fraction (range 10–27 Gy in 1/3 fractions) was delivered to the Vs. Within 7 days after the Vs boost, all the gross tumor volume (GTV) was homogeneously treated with hypo-fractionated radiation therapy (RT). Results: The rate of symptomatic response was 100%, and it was observed immediately after lattice RT delivery in 3/30 patients, while 27/30 patients had a symptomatic response within 8 days from the end of GTV irradiation. Radiation-related acute grade ≥1 toxicities were observed in 6/30 (20%) patients. The rate of overall clinical response was 89%, including 23% of complete remission. The 1-year overall survival rate was 86.4%. Conclusions: “Metabolism-guided” lattice radiotherapy is feasible and well-tolerated, being able to yield very impressive results both in terms of symptom relief and overall clinical response rate in stage IV bulky disease patients. These preliminary results seem to indicate that this kind of therapy could emerge as the best therapeutic option for this patient setting.

The current model of basal ganglia circuits has been introduced almost two decades ago and has settled the basis for our understanding of basal ganglia physiology and movement disorders. Although many questions are yet to be answered, several efforts have been recently made to shed new light on basal ganglia function. The traditional concept of “direct” and “indirect” pathways, obtained from axonal tracing studies in non-human primates and post-mortem fiber dissection in the human brain, still retains a remarkable appeal but is somehow obsolete. Therefore, a better comprehension of human structural basal ganglia connectivity in vivo, in humans, is of uttermost importance given the involvement of these deep brain structures in many motor and non-motor functions as well as in the pathophysiology of several movement disorders. By using diffusion magnetic resonance imaging and tractography, we have recently challenged the traditional model of basal ganglia network by showing the possible existence, in the human brain, of cortico-pallidal, cortico-nigral projections, which could be mono- or polysynaptic, and an extensive subcortical network connecting the cerebellum and basal ganglia. Herein, we aimed at reconstructing the basal ganglia connectome providing a quantitative connectivity analysis of the reconstructed pathways. The present findings reinforce the idea of an intricate, not yet unravelled, network involving the cerebral cortex, basal ganglia and cerebellum. Our findings may pave the way for a more comprehensive and holistic pathophysiological model of basal ganglia circuits.

Palliative radiotherapy has a great role in the treatment of large tumor masses. However, treating a bulky disease could be difficult, especially in critical anatomical areas. In daily clinical practice, short course hypofractionated radiotherapy is delivered in order to control the symptomatic disease. Radiation fields generally encompass the entire tumor mass, which is homogeneously irradiated. Recent technological advances enable delivering a higher radiation dose in small areas within a large mass. This goal, previously achieved thanks to the GRID approach, is now achievable using the newest concept of LATTICE radiotherapy (LT-RT). This kind of treatment allows exploiting various radiation effects, such as bystander and abscopal effects. These events may be enhanced by the concomitant use of immunotherapy, with the latter being ever more successfully delivered in cancer patients. Moreover, a critical issue in the treatment of large masses is the inhomogeneous intratumoral distribution of well-oxygenated and hypo-oxygenated areas. It is well known that hypoxic areas are more resistant to the killing effect of radiation, hence the need to target them with higher aggressive doses. This concept introduces the “oxygen-guided radiation therapy” (OGRT), which means looking for suitable hypoxic markers to implement in PET/CT and Magnetic Resonance Imaging. Future treatment strategies are likely to involve combinations of LT-RT, OGRT, and immunotherapy. In this paper, we review the radiobiological rationale behind a potential benefit of LT-RT and OGRT, and we summarize the results reported in the few clinical trials published so far regarding these issues. Lastly, we suggest what future perspectives may emerge by combining immunotherapy with LT-RT/OGRT.