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Abstract Traditionally, the frontotemporal arcuate fasciculus (AF) is viewed as a single entity in anatomo-clinical models. However, it is unclear if distinct cortical origin and termination patterns within this bundle correspond to specific language functions. We use track-weighted dynamic functional connectivity, a hybrid imaging technique, to study the AF structure and function in two distinct datasets of healthy subjects. Here we show that the AF can be subdivided based on dynamic changes in functional connectivity at the streamline endpoints. An unsupervised parcellation algorithm reveals spatially segregated subunits, which are then functionally quantified through meta-analysis. This approach identifies three distinct clusters within the AF - ventral, middle, and dorsal frontotemporal AF - each linked to different frontal and temporal termination regions and likely involved in various language production and comprehension aspects. Our findings may have relevant implications for the understanding of the functional anatomy of the AF as well as its contribution to linguistic and non-linguistic functions.

Abstract Neuroimaging studies have allowed for non-invasive mapping of brain networks in brain tumors. Although tumor core and edema are easily identifiable using standard MRI acquisitions, imaging studies often neglect signals, structures, and functions within their presence. Therefore, both functional and diffusion signals, as well as their relationship with global patterns of connectivity reorganization, are poorly understood. Here, we explore the functional activity and the structure of white matter fibers considering the contribution of the whole tumor in a surgical context. First, we find intertwined alterations in the frequency domain of local and spatially distributed resting-state functional signals, potentially arising within the tumor. Second, we propose a fiber tracking pipeline capable of using anatomical information while still reconstructing bundles in tumoral and peritumoral tissue. Finally, using machine learning and healthy anatomical information, we predict structural rearrangement after surgery given the preoperative brain network. The generative model also disentangles complex patterns of connectivity reorganization for different types of tumors. Overall, we show the importance of carefully designing studies including MR signals within damaged brain tissues, as they exhibit and relate to non-trivial patterns of both structural and functional (dis-)connections or activity.

Background: Depression presents with altered energy regulation and neural plasticity. Previous electroencephalography (EEG) studies showed that practice in learning tasks increases power in beta range (13–30 Hz) in healthy subjects but not in those with impaired plasticity. Here, we ascertain whether depression presents with alterations of spectral activity and connectivity before and after a learning task. Methods: We used publicly available resting-state EEG recordings (64 electrodes) from 122 subjects. Based on Beck Depression Inventory (BDI) scores, they were assigned to either a high BDI (hBDI, BDI > 13, N = 46) or a control (CTL, BDI < 7, N = 75) group. We analyzed spectral activity, theta–beta, and theta–gamma phase–amplitude coupling (PAC) of EEG recorded at rest before and after a learning task. Results: At baseline, compared to CTL, hBDI exhibited greater power in beta over fronto-parietal regions and in gamma over the right parieto-occipital area. At post task, power increased in all frequency ranges only in CTL. Theta–beta and theta–gamma PAC were greater in hBDI at baseline but not after the task. Conclusions: The lack of substantial post-task growth of beta power in depressed subjects likely represents power saturation due to greater baseline values. We speculate that inhibitory/excitatory imbalance, altered plasticity mechanisms, and energy dysregulation present in depression may contribute to this phenomenon.

Previous work showed that movements are accompanied by modulation of electroencephalographic (EEG) activity in both beta (13–30 Hz) and gamma (>30 Hz) ranges. The amplitude of beta event-related synchronization (ERS) is not linked to movement characteristics, but progressively increases with motor practice, returning to baseline after a period of rest. Conversely, movement-related gamma ERS amplitude is proportional to movement distance and velocity. Here, high-density EEG was recorded in 51 healthy subjects to investigate whether i) three-hour practice in two learning tasks, one with a motor component and one without, affects gamma ERS amplitude and connectivity during a motor reaching test, and ii) 90-minutes of either sleep or quiet rest have an effect on gamma oscillatory activity. We found that, while gamma ERS was appropriately scaled to the target extent at all testing points, its amplitude decreased after practice, independently of the type of interposed learning, and after both quiet wake and nap, with partial correlations with subjective fatigue scores. During movement execution, connectivity patterns within fronto-parieto-occipital electrodes, over areas associated with attentional networks, decreased after both practice and after 90-minute rest. While confirming the prokinetic nature of movement-related gamma ERS, these findings demonstrated the preservation of gamma ERS scaling to movement velocity with practice, despite constant amplitude reduction. We thus speculate that such decreases, differently from the practice-related increases of beta ERS, are related to reduced attention or working memory mechanisms due to fatigue or a switch of strategy toward automatization of movement execution and do not specifically reflect plasticity phenomena.

Purpose: To determine the best predictor of lesion volume induced by magnetic resonance (MR)-guided focused ultrasound (MRgFUS) thalamotomy in patients with tremor-dominant symptoms in Parkinson’s disease (PD) and essential tremor (ET) patients. Methods: Thirty-six neurological patients with medication-refractory tremor (n°19 PD; n°17 ET) were treated using a commercial MRgFUS brain system (Exablate Neuro 4000, Insightec) integrated with a 1.5 T MRI unit (Sigma HDxt; GE Medical System). Linear regression analysis was used to determine how the demographic, clinical, radiological (Fazekas scale), volumetric (total GM/WM/CSF volume, cortical thickness), and MRgFUS-related parameters [Skull Density Ratio (SDR), n° of transducer elements, n° of sonications, skull area, maximal energy delivered (watt), maximal power delivered (joule), maximal sonication time delivered, maximal mean temperature reached (T°C_max), accumulated thermal dose (ATD)] impact on ventral intermediate (VIM)-thalamotomy-related 3D volumetric lesions of necrosis and edema. Results: The VIM thalamotomy was clinically efficacious in improving the tremor symptoms of all the patients as measured at 1 week after treatment. Multiple regression analysis revealed that T°C_max and n° of transducer elements were the best predictors of the necrosis and edema volumes. Moreover, total WM volume also predicted the size of necrosis. Conclusions: Our study provides new insights into the clinical MRgFUS procedures that can be used to forecast brain lesion size and improve treatment outcomes.

Estimating structural connectivity from diffusion-weighted magnetic resonance imaging is a challenging task, partly due to the presence of false-positive connections and the misestimation of connection weights. Building on previous efforts, the MICCAI-CDMRI Diffusion-Simulated Connectivity (DiSCo) challenge was carried out to evaluate state-of-the-art connectivity methods using novel large-scale numerical phantoms. The diffusion signal for the phantoms was obtained from Monte Carlo simulations. The results of the challenge suggest that methods selected by the 14 teams participating in the challenge can provide high correlations between estimated and ground-truth connectivity weights, in complex numerical environments. Additionally, the methods used by the participating teams were able to accurately identify the binary connectivity of the numerical dataset. However, specific false positive and false negative connections were consistently estimated across all methods. Although the challenge dataset doesn’t capture the complexity of a real brain, it provided unique data with known macrostructure and microstructure ground-truth properties to facilitate the development of connectivity estimation methods.

Background: There is evidence that temporal duration is spatially represented on a horizontal mental timeline (MTL) with relatively short durations represented on the left and long duration on the right side. Most of this evidence comes from the visual domain. Objective: With the present study, we investigated whether temporal duration judgements of visual and auditory stimuli might be affected by spatial biases in time representation. Methods: Participants were asked to estimate the temporal duration of a target with respect to a reference stimulus. Two different exposure times were used for the reference (fast and slow), and three exposure times for the target with respect to the reference (shorter, equal, longer). Two versions of the task were implemented to probe visual and auditory temporal processing. Results: Participants showed enhanced performance when the target had longer duration than the reference independently of the type of task, but they were affected in opposite ways by the reference exposure time, in the two tasks. Best performance was observed for the fast reference in the visual domain and for the slow reference in the auditory one. Discussion: We argue that these findings provide evidence that temporal judgments of visual and auditory stimuli are affected by the duration of the reference stimulus, besides the duration of the target stimulus. Interestingly, they suggest putative leftward and rightward spatial biases in time representation for the visual and auditory domains, respectively, although future studies are necessary to further investigate these initial findings.

Tumors and their location distinctly alter both local and global brain connectivity within the ipsilesional hemisphere of glioma patients.

Agoraphobia is a visuo-vestibular-spatial disorder that may involve dysfunction of the vestibular network, which includes the insular and limbic cortex. We sought to study the neural correlates of this disorder in an individual who developed agoraphobia after surgical removal of a high-grade glioma located in the right parietal lobe, by assessing pre- and post-surgery connectivities in the vestibular network. The patient underwent surgical resection of the glioma located within the right supramarginal gyrus. The resection interested also portions of the superior and inferior parietal lobe. Structural and functional connectivities were assessed through magnetic resonance imaging before and 5 and 7 months after surgery. Connectivity analyses focused on a network comprising 142 spherical regions of interest (4 mm radius) associated with the vestibular cortex: 77 in the left and 65 in the right hemisphere (excluding lesioned regions). Tractography for diffusion-weighted structural data and correlation between time series for functional resting-state data were calculated for each pair of regions in order to build weighted connectivity matrices. Graph theory was applied to assess post-surgery changes in network measures, such as strength, clustering coefficient, and local efficiency. Structural connectomes after surgery showed a decrease of strength in the preserved ventral portion of the supramarginal gyrus (PFcm) and in a high order visual motion area in the right middle temporal gyrus (37dl), and decrease of the clustering coefficient and of the local efficiency in several areas of the limbic, insular cortex, parietal and frontal cortex, indicating general disconnection of the vestibular network. Functional connectivity analysis showed both a decrease in connectivity metrics, mainly in high-order visual areas and in the parietal cortex, and an increase in connectivity metrics, mainly in the precuneus, parietal and frontal opercula, limbic, and insular cortex. This post-surgery reorganization of the vestibular network is compatible with altered processing of visuo-vestibular-spatial information, yielding agoraphobia symptoms. Specifically, post-surgical functional increases of clustering coefficient and local efficiency in the anterior insula and in the cingulate cortex might indicate a more predominant role of these areas within the vestibular network, which could be predictive of the fear and avoiding behavior characterizing agoraphobia.

Aims: To evaluate neurocognitive performance, daily activity and quality of life (QoL), other than usual oncologic outcomes, among patients with brain metastasis ≥5 (MBM) from solid tumors treated with Stereotactic Brain Irradiation (SBI) or Whole Brain Irradiation (WBI). Methods: This multicentric randomized controlled trial will involve the enrollment of 100 patients (50 for each arm) with MBM ≥ 5, age ≥ 18 years, Karnofsky Performance Status (KPS) ≥ 70, life expectancy > 3 months, known primary tumor, with controlled or controllable extracranial disease, baseline Montreal Cognitive Assessment (MoCA) score ≥ 20/30, Barthel Activities of Daily Living score ≥ 90/100, to be submitted to SBI by LINAC with monoisocentric technique and non-coplanar arcs (experimental arm) or to WBI (control arm). The primary endpoints are neurocognitive performance, QoL and autonomy in daily-life activities variations, the first one assessed by MoCa Score and Hopkins Verbal Learning Test-Revised, the second one through the EORTC QLQ-C15-PAL and QLQ-BN-20 questionnaires, the third one through the Barthel Index, respectively. The secondary endpoints are time to intracranial failure, overall survival, retreatment rate, acute and late toxicities, changing of KPS. It will be considered significant a statistical difference of at least 30% between the two arms (statistical power of 80% with a significance level of 95%). Discussion: Several studies debate what is the decisive factor accountable for the development of neurocognitive decay among patients undergoing brain irradiation for MBM: radiation effect on clinically healthy brain tissue or intracranial tumor burden? The answer to this question may come from the recent technological advancement that allows, in a context of a significant time saving, improved patient comfort and minimizing radiation dose to off-target brain, a selective treatment of MBM simultaneously, otherwise attackable only by WBI. The achievement of a local control rate comparable to that obtained with WBI remains the fundamental prerequisite. Trial registration: NCT number: NCT04891471.

Background: Paraneoplastic gastroparesis is a gastrointestinal syndrome that rarely precedes a tumor diagnosis. To increase awareness of this rare clinical entity, we present a case of severe gastroparesis, which was later proven to be associated with a thymoma. Case report: A 55-year old man had the sudden onset of severe abdominal cramps and abdominal distension, early satiety with postprandial nausea, acid regurgitation, belching, and flatulence. He lost about 20 pounds. The physical and imaging examination revealed stomach distension, gastroparesis, and the presence of a solid mass in the anterior mediastinum. Radical surgery was performed to remove the thymoma and, given the high value of Mib-1, the patient was submitted to postoperative chest radiation therapy. After thymectomy, a diagnosis of paraneoplastic myasthenia gravis with subacute autonomic failure was made. Conclusion: Autoimmune gastroparesis should be considered as a potential paraneoplastic syndrome in patients with thymoma, myasthenia gravis, and delayed gastric emptying in the absence of mechanical obstruction.

Aim: To evaluate if hyaluronic acid reduces proctitis episodes with respect to corticosteroids in prostate cancer patients submitted to radical or adjuvant radiotherapy. Methods: A consecutive series of eligible patients received hyaluronic acid enemas as supportive care (experimental group, from January 2013 to June 2015). A historical group (control group), treated from October 2011 to December 2012, received beclomethasone dipropionate suppositories. We registered each patient’s data regarding acute and chronic proctitis. All patients were treated with static-intensity-modulated radiotherapy coupled to a daily set-up verification with orthogonal anterior–posterior/lateral X-ray pairs. Results: A total of 269 patients, 175 in the experimental group and 94 in the control group, was evaluated; 2 Gy/day (up to a total median dose of 80 Gy) and 2.7 Gy/day (up to a total median dose of 67.5 Gy) fractionation schemes were used for 216 and 53 patients, respectively. All patients had a good tolerance to radiotherapy, reporting no G3 or greater proctitis. No significant difference was reported concerning the total rate of proctitis between the two groups but only with respect to its grade: a higher G2 rate within the control group. There was no correlation between daily dose fractionation and toxicity grade. Conclusions: Hyaluronic acid enemas might be effective in reducing the severity of radiation proctitis.

The contribution of structural connectivity to functional connectivity dynamics is still far from being elucidated. Herein, we applied track-weighted dynamic functional connectivity (tw-dFC), a model integrating structural, functional, and dynamic connectivity, on high quality diffusion weighted imaging and resting-state fMRI data from two independent repositories. The tw-dFC maps were analyzed using independent component analysis, aiming at identifying spatially independent white matter components which support dynamic changes in functional connectivity. Each component consisted of a spatial map of white matter bundles that show consistent fluctuations in functional connectivity at their endpoints, and a time course representative of such functional activity. These components show high intra-subject, inter-subject, and inter-cohort reproducibility. We provided also converging evidence that functional information about white matter activity derived by this method can capture biologically meaningful features of brain connectivity organization, as well as predict higher-order cognitive performance.

Old or very old oncological patients represent a heterogeneous and frail population due to concomitant comorbidities. Whether radiotherapy alone or in combination with novel cancer drugs may provide a clear benefit in this setting of patients is still a matter of debate.The aim of our review is to analyze the evaluation process and the different therapeutic possibilities in older cancer patients, focusing on the different and most disparate applications of radiotherapy. We reviewed the most recent literature on radiotherapy in older patients providing clinical evidence of treatment related toxicity, tolerance and outcomes using standard fractionated and/or hypofractionated irradiation alone or in combination with chemotherapy, targeted and immunotherapy.In older cancer patients unfit for systemic therapy or surgery, radiotherapy represents a valid therapeutic approach, both with curative and palliative intents, ensuring excellent patient compliance in terms of local toxicity and adherence to therapy.

We present the case of a patient with vaginal mucosal melanoma who underwent complete remission after immunotherapy and ‘0-7-21’ radiotherapy regimen (24 Gy/3 fractions/21 days). An 80-year-old woman had a biopsy of a voluminous vaginal lesion and received a histological diagnosis of melanoma with angiomatoid aspects. The patient underwent immunotherapy with pembrolizumab 2 mg/kg every 3 weeks and was sent to our attention for planning radiotherapy as the extent of the lesion did not make it susceptible to surgery.Considering the concomitant administration of pembrolizumab, we chose to treat this patient with a modulated intensity radiation therapy technique delivering a hypofractionated dose of 24 Gy in 3 fractions delivered on days 0, 7, and 21. We observed a complete clinical remission of the melanoma 12 months after radiotherapy and she has been alive for 18 months with no clinical signs of local recurrence.

Abstract Background Stereotactic radiosurgery (SRS) is an effective treatment for trigeminal neuralgia (TN). Nevertheless, a proportion of patients will experience recurrence and treatment-related sensory disturbances. In order to evaluate the predictors of efficacy and safety of image-guided non-isocentric radiosurgery, we analyzed the impact of trigeminal nerve volume and the nerve dose/volume relationship, together with relevant clinical characteristics. Methods Two-hundred and ninety-six procedures were performed on 262 patients at three centers. In 17 patients the TN was secondary to multiple sclerosis (MS). Trigeminal pain and sensory disturbances were classified according to the Barrow Neurological Institute (BNI) scale. Pain-free-intervals were investigated using Kaplan Meier analyses. Univariate and multivariate Cox regression analyses were performed to identify predictors. Results The median follow-up period was 38 months, median maximal dose 72.4 Gy, median target nerve volume 25 mm3, and median prescription dose 60 Gy. Pain control rate (BNI I-III) at 6, 12, 24, 36, 48, and 60 months were 96.8, 90.9, 84.2, 81.4, 74.2, and 71.2%, respectively. Overall, 18% of patients developed sensory disturbances. Patients with volume ≥ 30 mm3 were more likely to maintain pain relief (p = 0.031), and low integral dose ( 2.7 mJ; low vs. intermediate: log-rank test, χ2 = 5.02, p = 0.019; low vs. high: log-rank test, χ2 = 6.026, p = 0.014). MS, integral dose, and mean dose were the factors associated with pain recurrence, while re-irradiation and MS were predictors for sensory disturbance in the multivariate analysis. Conclusions The dose to nerve volume ratio is predictive of pain recurrence in TN, and re-irradiation has a major impact on the development of sensory disturbances after non-isocentric SRS. Interestingly, the integral dose may differ significantly in treatments using apparently similar dose and volume constraints.

The subthalamic nucleus (STN) is commonly used as a surgical target for deep brain stimulation in movement disorders such as Parkinson's Disease. Tractography-derived connectivity-based parcellation (CBP) has been recently proposed as a suitable tool for non-invasive in vivo identification and pre-operative targeting of specific functional territories within the human STN. However, a well-established, accurate and reproducible protocol for STN parcellation is still lacking. The present work aims at testing the effects of different tractography-based approaches for the reconstruction of STN functional territories.We reconstructed functional territories of the STN on the high-quality dataset of 100 unrelated healthy subjects and on the test-retest dataset of the Human Connectome Project (HCP) repository. Connectivity-based parcellation was performed with a hypothesis-driven approach according to cortico-subthalamic connectivity, after dividing cortical areas into three groups: associative, limbic and sensorimotor. Four parcellation pipelines were compared, combining different signal modeling techniques (single-fiber vs multi-fiber) and different parcellation approaches (winner takes all parcellation vs fiber density thresholding). We tested these procedures on STN regions of interest obtained from three different, commonly employed, subcortical atlases. We evaluated the pipelines both in terms of between-subject similarity, assessed on the cohort of 100 unrelated healthy subjects, and of within-subject similarity, using a second cohort of 44 subjects with available test-retest data. We found that each parcellation provides converging results in terms of location of the identified parcels, but with significative variations in size and shape. All pipelines obtained very high within-subject similarity, with tensor-based approaches outperforming multi-fiber pipelines. On the other hand, higher between-subject similarity was found with multi-fiber signal modeling techniques combined with fiber density thresholding. We suggest that a fine-tuning of tractography-based parcellation may lead to higher reproducibility and aid the development of an optimized surgical targeting protocol.

Modulation of gamma oscillations recorded from the human motor cortex and basal ganglia appears to play a key role in movement execution. However, there are still major questions to be answered about the specific role of cortical gamma activity in both the planning and execution of movement features such as the scaling of peak velocity and movement time. In this study, we characterized movement-related gamma oscillatory dynamics and its relationship with kinematic parameters based on 256-channels EEG recordings in 64 healthy subjects while performing fast and uncorrected reaching movements to targets located at three distances. In keeping with previous studies, we found that movement-related gamma synchronization occurred during movement execution. As a new finding, we showed that gamma synchronization occurred also before movement onset, with planning and execution phases involving different gamma peak frequencies and topographies. Importantly, the amplitude of gamma synchronization in both planning and execution increased with target distance and predicted peak velocity and movement time. Additional analysis of phase coherence revealed a gamma-coordinated long-range network involving occipital, frontal and central regions during movement execution that was positively related to kinematic features. This is the first evidence in humans supporting the notion that gamma synchronization amplitude and phase coherence pattern can reliably predict peak velocity amplitude and movement time. Therefore, these findings suggest that cortical gamma oscillations have a crucial role for the selection, implementation and control of the appropriate kinematic parameters of goal-directed reaching movements.

BackgroundCerebral arteriovenous malformations (AVMs) are challenging lesions, often requiring multimodal interventions; however, data on the efficacy of stereotactic radiosurgery for cerebral AVMs are limited. This study aimed to evaluate the clinical and radiographic results following robotic radiosurgery, alone or in combination with endovascular treatment, and to investigate factors associated with obliteration and complications in patients with AVM.MethodsWe retrospectively analyzed the clinical and imaging characteristics of 123 patients with AVMs of all Spetzler-Martin grades treated at two institutions by robotic radiosurgery in single-fraction doses (CyberKnife). Embolization was performed before radiosurgery in a subset of patients to attempt to downgrade the lesions. Factors associated with AVM obliteration and complications (toxicity) were identified via univariate and multivariate analyses.ResultsThe median follow-up time was 48.1 months (range, 3.6-123 months). Five patients were lost to follow-up. The obliteration rate in the 59 patients with a follow-up period exceeding four years was 72.8%. Complete obliteration and partial remission were achieved in 67 (56.8%) and 31 (26.3%) cases, respectively, whereas no change was observed in 20 cases (17.8%). Embolization was performed in 54/123 cases (43.9%). Complete and partial obliteration were achieved in 29 (55.7%) and 14 (26.9%) embolized patients, respectively. In the multivariate analysis, the factors associated with obliteration were age (p = .018) and the Spetzler-Martin grade (p = .041). Treatment-induced toxicity (radiation necrosis and/or edema) was observed in 15 cases (12.7%), rebleeding occurred in three cases (2.5%), and the rate of mortality associated with rebleeding was 1.7%.ConclusionsCyberKnife radiosurgery is a valid approach for treating AVMs of all Spetzler-Martin-grades, with satisfactory obliteration rates, low toxicity, and a relatively rare incidence of rebleeding.

The Ventral intermediate nucleus (Vim) of thalamus is the most targeted structure for the treatment of drug-refractory tremors. Since methodological differences across existing studies are remarkable and no gold-standard pipeline is available, in this study, we tested different parcellation pipelines for tractography-derived putative Vim identification.Thalamic parcellation was performed on a high quality, multi-shell dataset and a downsampled, clinical-like dataset using two different diffusion signal modeling techniques and two different voxel classification criteria, thus implementing a total of four parcellation pipelines. The most reliable pipeline in terms of inter-subject variability has been picked and parcels putatively corresponding to motor thalamic nuclei have been selected by calculating similarity with a histology-based mask of Vim. Then, spatial relations with optimal stimulation points for the treatment of essential tremor have been quantified. Finally, effect of data quality and parcellation pipelines on a volumetric index of connectivity clusters has been assessed.We found that the pipeline characterized by higher-order signal modeling and threshold-based voxel classification criteria was the most reliable in terms of inter-subject variability regardless data quality. The maps putatively corresponding to Vim were those derived by precentral and dentate nucleus-thalamic connectivity. However, tractography-derived functional targets showed remarkable differences in shape and sizes when compared to a ground truth model based on histochemical staining on seriate sections of human brain. Thalamic voxels connected to contralateral dentate nucleus resulted to be the closest to literature-derived stimulation points for essential tremor but at the same time showing the most remarkable inter-subject variability. Finally, the volume of connectivity parcels resulted to be significantly influenced by data quality and parcellation pipelines. Hence, caution is warranted when performing thalamic connectivity-based segmentation for stereotactic targeting.

The striatum represents the major hub of the basal ganglia, receiving projections from the entire cerebral cortex and it is assumed to play a key role in a wide array of complex behavioral tasks. Despite being extensively investigated during the last decades, the topographical organization of the striatum is not well understood yet. Ongoing efforts in neuroscience are focused on analyzing striatal anatomy at different spatial scales, to understand how structure relates to function and how derangements of this organization are involved in various neuropsychiatric diseases. While being subdivided at the macroscale level into dorsal and ventral divisions, at a mesoscale level the striatum represents an anatomical continuum sharing the same cellular makeup. At the same time, it is now increasingly ascertained that different striatal compartments show subtle histochemical differences, and their neurons exhibit peculiar patterns of gene expression, supporting functional diversity across the whole basal ganglia circuitry. Such diversity is further supported by afferent connections which are heterogenous both anatomically, as they originate from distributed cortical areas and subcortical structures, and biochemically, as they involve a variety of neurotransmitters. Specifically, the cortico-striatal projection system is topographically organized delineating a functional organization which is maintained throughout the basal ganglia, subserving motor, cognitive and affective behavioral functions. While such functional heterogeneity has been firstly conceptualized as a tripartite organization, with sharply defined limbic, associative and sensorimotor territories within the striatum, it has been proposed that such territories are more likely to fade into one another, delineating a gradient-like organization along medio-lateral and ventro-dorsal axes. However, the molecular and cellular underpinnings of such organization are less understood, and their relations to behavior remains an open question, especially in humans. In this review we aimed at summarizing the available knowledge on striatal organization, especially focusing on how it links structure to function and its alterations in neuropsychiatric diseases. We examined studies conducted on different species, covering a wide array of different methodologies: from tract-tracing and immunohistochemistry to neuroimaging and transcriptomic experiments, aimed at bridging the gap between macroscopic and molecular levels.

Visuospatial attention is asymmetrically distributed with a leftward bias (i.e. pseudoneglect), while evidence for asymmetries in auditory spatial attention is still controversial. In the present study, we investigated putative asymmetries in the distribution of auditory spatial attention and the influence that visual information might have on its deployment. A modified version of the Posner task (i.e. the visuo-audio spatial task [VAST]) was used to investigate spatial processing of auditory targets when endogenous orientation of spatial attention was mediated by visual cues in healthy adults. A line bisection task (LBT) was also administered to assess the presence of a leftward bias in deployment of visuospatial attention. Overall, participants showed rightward and leftward biases in the VAST and the LBT, respectively. In the VAST, sound localization was enhanced by visual cues. Altogether, these findings support the existence of a facilitation effect for auditory targets originating from the right side of space and provide new evidence for crossmodal links in endogenous spatial attention between vision and audition. Keywords: Auditory system, Endogenous spatial attention, Pseudoneglect, Visual system, Visuo-audio task

Stereotactic body radiation therapy in patients with spine metastases maximizes local tumor control and preserves neurologic function. A novel approach could be the use of stereotactic body radiation therapy with simultaneous integrated boost delivering modality. The aim of the present study is to report our experience in the treatment of spine metastases using a frameless radiosurgery system delivering stereotactic body radiation therapy–simultaneous integrated boost technique. The primary endpoints were the pain control and the time to local progression; the secondary ones were the overall survival and toxicity. A total of 20 patients with spine metastases and 22 metastatic sites were treated in our center with stereotactic body radiation therapy–simultaneous integrated boost between December 2007 and July 2018. Stereotactic body radiation therapy–simultaneous integrated boost treatments were delivered doses of 8 to 10 Gy in 1 fraction to isodose line of 50%. The median follow-up was 35 months (range: 12-110). The median time to local progression for all patients was not reached and the actuarial 1-, 2-, and 3-years local free progression rate was 86.36%. In 17 of 20 patients, a complete pain remission was observed and 3 of 20 patients had a partial pain remission (complete pain remission + partial pain remission: 100%). The median overall survival was 38 months (range 12-83). None of the patients experienced neither radiation adverse events (grade 1-4) nor reported pain flair reaction. None of the patients included in our series experienced vertebral compression fracture. Spine radiosurgery with stereotactic body radiation therapy–simultaneous integrated boost is safe. The use of this modality in spine metastases patients provides an excellent local control.

Introduction The clinical relevance of the anatomy and variations of the anterior ethmoidal artery (AEA) is outstanding, considering its role as a landmark in endoscopic surgery, its importance in the therapy of epistaxis, and the high risks related to iatrogenic injuries. Objective To provide an anatomical description of the course and relationships of the AEA, based on direct computed-tomography (CT)-based 3D volume rendering. Methods Direct volume rendering was performed on 18 subjects who underwent (CT) with contrast medium for suspected cerebral aneurism. Results The topographical location of 36 AEAs was assessed as shown: 10 dehiscent (27.8%), 20 intracanal (55.5%), 6 incomplete canals (16.7%). Distances from important topographic landmarks are reported. Conclusion This work demonstrates that direct 3D volume rendering is a valid imaging technique for a detailed description of the anterior ethmoidal artery thus representing a useful tool for head pre-operatory assessments.

Abstract Introduction Sexual desire, arousal, and orgasm are mediated by complex, yet still not fully understood, interactions of the somatic and autonomic nervous systems operating at the central and peripheral levels. Disruption of endocrine, neural, or vascular response, caused by aging, medical illness, neurological diseases, surgery, or drugs, can lead to sexual dysfunctions, thus significantly affecting patients' quality of life. Purpose This narrative review aims at characterizing the involvement of the central nervous system in human sexual behavior. Methods A literature search was conducted using PubMed in its entirety up to June 2018, analyzing the studies dealing with the neurobiological and neurophysiological basis of human sexuality. Results Sexual behavior is regulated by both subcortical structures, such as the hypothalamus, brainstem, and spinal cord, and several cortical brain areas acting as an orchestra to finely adjust this primitive, complex, and versatile behavior. At the central level, dopaminergic and serotonergic systems appear to play a significant role in various factors of sexual response, although adrenergic, cholinergic, and other neuropeptide transmitter systems may contribute as well. Conclusions Providing healthcare professionals with information concerning sexual behavior may overcome useless and sometimes dangerous barriers and improve patient management, since sexual well‐being is considered one of the most important aspects of one's quality of life.

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.

An amendment to this paper has been published and can be accessed via the original article.

Background and objectives: The internal (GPi) and external segments (GPe) of the globus pallidus represent key nodes in the basal ganglia system. Connections to and from pallidal segments are topographically organized, delineating limbic, associative and sensorimotor territories. The topography of pallidal afferent and efferent connections with brainstem structures has been poorly investigated. In this study we sought to characterize in-vivo connections between the globus pallidus and the pedunculopontine nucleus (PPN) via diffusion tractography. Materials and Methods: We employed structural and diffusion data of 100 subjects from the Human Connectome Project repository in order to reconstruct the connections between the PPN and the globus pallidus, employing higher order tractography techniques. We assessed streamline count of the reconstructed bundles and investigated spatial relations between pallidal voxels connected to the PPN and pallidal limbic, associative and sensorimotor functional territories. Results: We successfully reconstructed pallidotegmental tracts for the GPi and GPe in all subjects. The number of streamlines connecting the PPN with the GPi was greater than the number of those joining it with the GPe. PPN maps within pallidal segments exhibited a distinctive spatial organization, being localized in the ventromedial portion of the GPi and in the ventral-anterior portion in the GPe. Regarding their spatial relations with tractography-derived maps of pallidal functional territories, the highest value of percentage overlap was noticed between PPN maps and the associative territory. Conclusions: We successfully reconstructed the anatomical course of the pallidotegmental pathways and comprehensively characterized their topographical arrangement within both pallidal segments. PPM maps were localized in the ventromedial aspect of the GPi, while they occupied the anterior pole and the most ventral portion of the GPe. A better understanding of the spatial and topographical arrangement of the pallidotegmental pathways may have pathophysiological and therapeutic implications in movement disorders.

Several techniques and protocols of non-invasive transcranial brain stimulation (NIBS), including transcranial magnetic and electrical stimuli, have been developed in the past decades. These techniques can induce long lasting changes in cortical excitability by promoting synaptic plasticity and thus may represent a therapeutic option in neuropsychiatric disorders. On the other hand, despite these techniques have become popular, the fragility and variability of the after effects are the major challenges that non-invasive transcranial brain stimulation currentlyfaces. Several factors may account for such a variability such as biological variations, measurement reproducibility, and the neuronal state of the stimulated area. One possible strategy, to reduce this variability is to monitor the neuronal state in real time using EEG and trigger TMS pulses only at pre-defined state. In addition, another strategy under study is to use the spaced application of multiple NIBS protocols within a session to improve the reliability and extend the duration of NIBS effects. Further studies, although time consuming, are required for improving the so far limited effect sizes of NIBS protocols for treatment of neurological or psychiatric disorders.

In the last decades, a number of Diffusion Weighted Imaging (DWI) based techniques have been developed to study non-invasively human brain tissues, especially white matter (WM). In this context, Constrained Spherical Deconvolution (CSD) is recognized as being able to accurately characterize water molecules displacement, as they emerge from the observation of MR diffusion weighted (MR-DW) images. CSD is suggested to be applied on MR-DW datasets consisting of b-values around 3,000 s/mm2 and at least 45 unique diffusion weighting directions. Below such technical requirements, Diffusion Tensor Imaging (DT) remains the most widely accepted model. Unlike CSD, DTI is unable to resolve complex fiber geometries within the brain, thus affecting related tissues quantification. In addition, thanks to CSD, an index called Apparent Fiber Density (AFD) can be measured to estimate intra-axonal volume fraction within WM. In standard clinical settings, diffusion based acquisitions are well below such technical requirements. Therefore, in this study we wanted to extensively compare CSD and DTI model outcomes on really low demanding MR-DW datasets, i.e., consisting of a single shell (b-value = 1,000 s/mm2) and only 30 unique diffusion encoding directions. To this end, we performed deterministic and probabilistic tractographic reconstruction of two major WM pathways, namely the Corticospinal Tract and the Arcuate Fasciculus. We estimated and analyzed tensor based features as well as, for the first time, AFD interpretability in our data. By performing multivariate statistics and tract-based ROI analysis, we demonstrate that WM quantification is affected by both the diffusion model and threshold applied to noisy tractographic maps. Consistently with existing literature, we showed that CSD outperforms DTI even in our scenario. Most importantly, for the first time we address the problem of accuracy and interpretation of AFD in a low-demanding DW setup, and show that it is still a biological meaningful measure for the analysis of intra-axonal volume even in clinical settings.

The last few years have been characterized by a growing interest of the medical and scientific world for the field of consciousness and its related disorders. Medically speaking, consciousness can be defined as the state of awareness of self and environment and the alertness to external stimulation, besides responsiveness to inner need. Transient loss of consciousness can be due to alterations in cerebral blood flow leading to fainting or syncope, migraine, metabolic dysfunctions, unexpected intracranial pressure increases, epileptic seizures, and sleep disorders. Chronic disorders of consciousness are a tragic success of high-technology treatment, in an attempt to maintain or reestablish brain function, which is to be considered as the main goal of therapeutics. Management of vegetative or a minimally conscious state individuals involves charily getting the right diagnosis with an evidence-based prognosis, also taking into account the medical, ethical, and legal key factors of the ideal treatment. This paper is aimed at exploring the wide spectrum of consciousness disorders and their clinical differential diagnosis, with particular regards to those with a negative impact on patient and their caregiver quality of life, including epilepsy, sleep disorders, and vegetative/minimally conscious state.

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 unraveled, 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.

Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are non-invasive methods for stimulating cortical neurons that have been increasingly used in the neurology realm and in the neurosciences applied to movement disorders. In addition, these tools have the potential to be delivered as clinically therapeutic approach. Despite several studies support this hypothesis, there are several limitations related to the extreme variability of the stimulation protocols, clinical enrolment and variability of rTMS and tDCS after effects that make clinical interpretation very difficult. Aim of the present study will be to critically discuss the state of art therapeutically applications of rTMS and tDCS in dystonia.

Neuromodulatory effects of non-invasive brain stimulation (NIBS) have been extensively studied in chronic pain. A hypothetic mechanism of action would be to prevent or revert the ongoing maladaptive plasticity within the pain matrix. In this review, the authors discuss the mechanisms underlying the development of an abnormal plasticity in patients with chronic pain and the putative mechanisms of NIBS in modulating synaptic plasticity in neuropathic pain conditions.

Substantia nigra is an important neuronal structure, located in the ventral midbrain, that exerts a regulatory function within the basal ganglia circuitry through the nigro-striatal pathway. Although its subcortical connections are relatively well known in human brain, very little is known about its cortical connections. The existence of a direct cortico-nigral pathway has been demonstrated in rodents and primates but only hypothesized in humans. In this study, we aimed at evaluating cortical connections of substantia nigra in vivo in human brain, by using probabilistic constrained spherical deconvolution tractography on magnetic resonance diffusion weighted imaging data. We found that substantia nigra is connected with cerebral cortex as a whole, with the most representative connections involving prefrontal cortex, precentral and postcentral gyri and superior parietal lobule. These results may be relevant for the comprehension of the pathophysiology of several neurological disorders involving substantia nigra, such as parkinson’s disease, schizophrenia and pathological addictions.