The impact of modifier genes on cone-rod dystrophy heterogeneity: An explorative familial pilot study and a hypothesis on neurotransmission impairment.

Cone-rod dystrophies (CORDs) are a heterogeneous group of inherited retinopathies (IRDs) with more than 30 already known disease-causing genes. Uncertain phenotypes and extended range of intra- and interfamilial heterogenicity make still difficult to determine a precise genotype-phenotype correlation. Here, we used a next-generation sequencing approach to study a Sicilian family with a suspected form of CORD. Affected family members underwent ophthalmological examinations and a proband, blind from 50 years, underwent whole genome and exome sequencing. Variant analysis was enriched by pathway analysis and relevant variants were, then, investigated in other family members and in 100 healthy controls from Messina. CORD diagnosis with an intricate pattern of symptoms was confirmed by ophthalmological examinations. A total of about 50,000 variants were identified in both proband's genome and exome. All affected family members presented specific genotypes mainly determined by mutated GUCY2D gene, and different phenotypical traits, mainly related to focus and color perception. Thus, we looked for possible modifier genes. According to relationship with GUCY2D, predicted functional effects, eye localization, and ocular disease affinity, only 9 variants, carried by 6 genes (CACNG8, PAX2, RXRG, CCDC175, PDE4DIP and LTF), survived the filtering. These genes encode key proteins involved in cone development and survival, and retina neurotransmission. Among analyzed variants, CACNG8c.*6819A>T and the new CCDC175 c.76C>T showed extremely low frequency in the control group, suggesting a key role on disease phenotypes. Such discovery could enforce the role of modifier genes into CORD onset/progression, contributing to improve diagnostic test towards a better personalized medicine.

Multimodal imaging in subclinical best vitelliform macular dystrophy.

BACKGROUND: To analyse multimodal imaging alterations in the subclinical form of best vitelliform macular dystrophy (BVMD). METHODS: The study was designed as an observational, cross-sectional case series. Eleven eyes of 7 subclinical patients with BVMD and 12 age-matched and sex-matched controls were included. Multimodal imaging included fundus blue-light autofluorescence, near-infrared autofluorescence (NIR-AF), structural optical coherence tomography (OCT) and OCT angiography (OCTA). The quantitative analysis included the calculation of the following parameters: vessel density (VD), vessel tortuosity (VT), vessel dispersion (Vdisp), vessel rarefaction (VR), foveal avascular zone (FAZ) area, reflectivity of the outer retinal bands and choriocapillaris porosity (CCP). RESULTS: Mean best-corrected visual acuity was 0.0±0.0 LogMAR in both groups. The round central hypoautofluorescent alteration on NIR-AF corresponded to a significant reflectivity attenuation of the outer retinal bands on structural OCT (0.55±0.18 vs 0.75±0.08; p<0.001). VD, VT, VR and Vdisp were normal compared with controls (all p>0.05). The FAZ area turned out to be significantly restricted at the level of the deep capillary plexus in subclinical BVMD eyes (p<0.001). Furthermore, quantitative OCTA revealed a significant central increase of CCP, compared with controls (18.25±2.43 vs 4.58±1.36; p<0.001). CONCLUSIONS: The subclinical stage of BVMD is characterised by significant alterations of the outer retinal bands and the choriocapillaris. Quantitative multimodal imaging assessment suggests that subclinical BVMD is affected by the functional impairment of the outer retinal structures, leading to an alteration in melanin and growth factor production.

Acute Central Serous Chorioretinopathy Subtypes as Assessed by Multimodal Imaging.

Purpose: To differentiate acute central serous chorioretinopathy (CSC) subtypes by multimodal imaging. Methods: The research was designed as a prospective, interventional study. Naive patients with acute CSC were followed for 24 months. Overall, 96 CSC patients (96 eyes) and 210 controls (210 eyes) were included. Multimodal imaging allowed the study to classify CSC into retinal pigment epithelium-related CSC (RPE-CSC) and choroidal-related CSC (choroidal-CSC) subtypes. The RPE-CSC type was characterized by normal choroidal thickness (CT) in association with disseminated RPE alterations. The choroidal-CSC type was distinguished by identifying a pachychoroid. All the patients underwent eplerenone or verteporfin photodynamic therapy (PDT). Patients developing macular neovascularization (MNV) underwent anti-VEGF injections. Quantitative measurements included central macular thickness (CMT), choroidal thickness (CT), Sattler layer thickness (SLT) and Haller layer thickness (HLT). Results: Considering the CSC patients as a whole, baseline BCVA was 0.18 ± 0.25 LogMAR, increasing to 0.13 ± 0.21 LogMAR after 24 months (P < 0.01), whereas baseline CMT improved from 337 ± 126 µm to 244 ± 84 µm after 24 months (P < 0.01). We found the following subdivision of CSC eyes: RPE-CSC type (45%) and choroidal-CSC type (55%). Overall, MNV were detected in 18 eyes (19%), 13 eyes (72%) in the RPE-CSC subgroup and five eyes (28%) in the choroidal-CSC subgroup. Forty eyes responded to eplerenone (57% of RPE-CSC and 47% of choroidal-CSC), whereas 38 eyes required PDT (43% of RPE-CSC and 53% of choroidal-CSC). Conclusions: Acute CSC includes two main clinical manifestations, displaying differing features concerning retinal and choroidal involvement. Translational Relevance: This study identified two clinically different acute CSC subtypes on the basis of quantitative pachychoroid cutoff values.

Structural OCT Parameters Associated with Treatment Response and Macular Neovascularization Onset in Central Serous Chorioretinopathy.

INTRODUCTION: This study aimed to assess quantitative factors associated with treatment response and macular neovascularization (MNV) onset in central serous chorioretinopathy (CSC) through an artificial intelligence-based approach. METHODS: The study was designed as an interventional, prospective case series with a planned follow-up of 36 months. We included only eyes demonstrating the first episode of CSC. All the patients underwent eplerenone or photodynamic therapy (PDT) treatment. Eyes developing MNV underwent anti-VEGF injections. We developed an artificial intelligence-based model to assess predictive quantitative structural optical coherence tomography (OCT) factors related to treatment response and onset of MNV. Main outcome measures were best-correct visual acuity (BCVA), central macular thickness (CMT), retinal thickness (RT), retinal pigment epithelium (RPE) thickness, choroidal thickness, Sattler's layer thickness (SLT), Haller's layer thickness, retinal and choroidal hyperreflective foci (HF), and MNV. RESULTS: We included 96 naïve CSC eyes (96 patients). Baseline BCVA was 0.18 ± 0.25 logMAR, which increased to 0.16 ± 0.27 logMAR after 3 years (p > 0.05). Baseline CMT was 337 ± 126 µm, which improved to 229 ± 40 µm after 3 years (p < 0.01). We observed good response to eplerenone in 40/78 (51%) eyes, whereas 38/78 (49%) eyes underwent PDT. The artificial intelligence model showed choroidal HF and age as determining factors of good response to eplerenone or PDT. RPE thickness < 36 µm, RT < 300 µm, and SLT < 50 µm increased probability of 50% of having MNV. CONCLUSIONS: CSC response to eplerenone or PDT is influenced by choroidal HF and patient age. RPE and SLT represent relevant factors for onset of MNV.

Vitreomacular traction quantitative cutoffs for the assessment of resolution after ocriplasmin intravitreal treatment.

This study aimed to assess optical coherence tomography (OCT) parameters associated with vitreomacular traction (VMT) resolution after ocriplasmin intravitreal injection and also associated with the development of vitreomacular complications. Study designed was a retrospective case series. Structural OCT images were acquired at baseline and over the follow-up after treatment. We developed a mathematical model to provide quantitative parameters associated with VMT resolution. Moreover, we adopted the same model to assess the quantitative parameters associated with development of further vitreomacular complications or with the worsening of the coexisting condition. Main outcome measures were BCVA, central macular thickness (CMT), VMT reflectivity, VMT size, VMT resolution, epiretinal membrane (ERM), macular holes. 73 eyes of 73 VMT patients (mean age 73 ± 9 years) were recruited. The mean follow-up duration was 2.6 ± 1.1 years. Mean baseline BCVA was 0.38 ± 0.18 LogMAR, improving to 0.26 ± 0.20 at the end of the follow-up (p < 0.01). Baseline CMT was 431 ± 118 µm, improving to 393 ± 122 µm at the end of the follow-up (p < 0.01). 38/73 eyes (52%) showed only VMT, whereas 35/73 eyes (48%) also showed coexisting alterations at baseline. VMT resolved in 40/73 eyes (55% of cases). Our model disclosed VMT reflectivity as the most involved parameter in VMT resolution. VMT size showed less influence on the success of ocriplasmin treatment. ERM was negatively associated with VMT resolution. Moreover, VMT reflectivity values and ERM represented the most important parameters for the onset of vitreomacular complications.

New insights into cortico-basal-cerebellar connectome: clinical and physiological considerations.

The current model of the basal ganglia system based on the 'direct', 'indirect' and 'hyperdirect' pathways provides striking predictions about basal ganglia function that have been used to develop deep brain stimulation approaches for Parkinson's disease and dystonia. The aim of this review is to challenge this scheme in light of new tract tracing information that has recently become available from the human brain using MRI-based tractography, thus providing a novel perspective on the basal ganglia system. We also explore the implications of additional direct pathways running from cortex to basal ganglia and between basal ganglia and cerebellum in the pathophysiology of movement disorders.

The cortico-rubral and cerebello-rubral pathways are topographically organized within the human red nucleus.

The Red Nucleus (RN) is a large nucleus located in the ventral midbrain: it is subdivided into a small caudal magnocellular part (mRN) and a large rostral parvocellular part (pRN). These distinct structural regions are part of functionally different networks and show distinctive connectivity features: the mRN is connected to the interposed nucleus, whilst the pRN is mainly connected to dentate nucleus, cortex and inferior olivary complex. Despite functional neuroimaging studies suggest RN involvement in complex motor and higher order functions, the pRN and mRN cannot be distinguished using conventional MRI. Herein, we employ high-quality structural and diffusion MRI data of 100 individuals from the Human Connectome Project repository and constrained spherical deconvolution tractography to perform connectivity-based segmentation of the human RN. In particular, we tracked connections of RN with the inferior olivary complex, the interposed nucleus, the dentate nucleus and the cerebral cortex. We found that the RN can be subdivided according to its connectivity into two clusters: a large ventrolateral one, mainly connected with the cerebral cortex and the inferior olivary complex, and a smaller dorsomedial one, mainly connected with the interposed nucleus. This structural topography strongly reflects the connectivity patterns of pRN and mRN respectively. Structural connectivity-based segmentation could represent a useful tool for the identification of distinct subregions of the human red nucleus on 3T MRI thus allowing a better evaluation of this subcortical structure in healthy and pathological conditions.

Mapping the structural connectivity between the periaqueductal gray and the cerebellum in humans.

The periaqueductal gray is a mesencephalic structure involved in modulation of responses to stressful stimuli. Structural connections between the periaqueductal gray and the cerebellum have been described in animals and in a few diffusion tensor imaging studies. Nevertheless, these periaqueductal gray-cerebellum connectivity patterns have yet to be fully investigated in humans. The objective of this study was to qualitatively and quantitatively characterize such pathways using high-resolution, multi-shell data of 100 healthy subjects from the open-access Human Connectome Project repository combined with constrained spherical deconvolution probabilistic tractography. Our analysis revealed robust connectivity density profiles between the periaqueductal gray and cerebellar nuclei, especially with the fastigial nucleus, followed by the interposed and dentate nuclei. High-connectivity densities have been observed between vermal (Vermis IX, Vermis VIIIa, Vermis VIIIb, Vermis VI, Vermis X) and hemispheric cerebellar regions (Lobule IX). Our in vivo study provides for the first time insights on the organization of periaqueductal gray-cerebellar pathways thus opening new perspectives on cognitive, visceral and motor responses to threatening stimuli in humans.

Structural connectivity-based topography of the human globus pallidus: Implications for therapeutic targeting in movement disorders.

BACKGROUND: Understanding the topographical organization of the cortico-basal ganglia circuitry is of pivotal importance because of the spreading of techniques such as DBS and, more recently, MR-guided focused ultrasound for the treatment of movement disorders. A growing body of evidence has described both direct cortico- and dento-pallidal connections, although the topographical organization in vivo of these pathways in the human brain has never been reported. OBJECTIVE: To investigate the topographical organization of cortico- and dento-pallidal pathways by means of diffusion MRI tractography and connectivity based parcellation. METHODS: High-quality data from 100 healthy subjects from the Human Connectome Project repository were utilized. Constrained spherical deconvolution-based tractography was used to reconstruct structural cortico- and dento-pallidal connectivity. Connectivity-based parcellation was performed with a hypothesis-driven approach at three different levels: functional regions (limbic, associative, sensorimotor, and other), lobes, and gyral subareas. RESULTS: External globus pallidus segregated into a ventral associative cluster, a dorsal sensorimotor cluster, and a caudal "other" cluster on the base of its cortical connectivity. Dento-pallidal connections clustered only in the internal globus pallidus, where also associative and sensorimotor clusters were identified. Lobar parcellation revealed the presence in the external globus pallidus of dissociable clusters for each cortical lobe (frontal, parietal, temporal, and occipital), whereas in internal globus pallidus only frontal and parietal clusters were found out. CONCLUSION: We mapped the topographical organization of both internal and external globus pallidus according to cortical and cerebellar connections. These anatomical data could be useful in DBS, radiosurgery and MR-guided focused ultrasound targeting for treating motor and nonmotor symptoms in movement disorders. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Endogenous orientation of visual attention in auditory space.

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.

Claustral structural connectivity and cognitive impairment in drug naïve Parkinson's disease.

The claustrum is a thin grey matter structure which is involved in a wide brain network. Previous studies suggested a link between claustrum and Parkinson's Disease (PD), showing how α-synuclein pathology may affect claustral neurons as well as how α-synuclein immunoreactivity may correlate with the onset of cognitive dysfunctions. Our aim is to investigate, via diffusion MRI, claustral structural network changes in drug naïve PD patients, with the goal to understand whether such changes may contribute to cognitive decline in PD. 15 drug naïve PD patients and 15 age-matched controls were enrolled; MR protocol was performed on a 3T scanner. Whole brain probabilistic tractography was obtained using Constrained Spherical Deconvolution (CSD) diffusion model. Connectivity matrices were estimated based on a robust anatomical parcellation of structural T1w images. In PD group, impaired subnetworks were correlated with psychological examinations. We found decreased claustral connectivity in PD patients compared to controls, especially with areas mainly involved in visuomotor and attentional systems. Moreover, we found a positive correlation between MoCA and density of pathways connecting ipsilaterally claustrum to left (r = 0.578, p = 0.021) and right (r = 0.640, p = 0.020) Pars Orbitalis. Our results support the hypothesis of claustral involvement in cognitive decline in drug naïve PD patients.

White Matter Tissue Quantification at Low b-Values Within Constrained Spherical Deconvolution Framework.

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 Limbic and Sensorimotor Pathways of the Human Amygdala: A Structural Connectivity Study.

The amygdala plays a key role in gathering social cues to context-appropriate responses that require refined motor behavior, involving either direct or indirect connections with sensorimotor-related areas. Although, several studies investigated the structural and functional limbic connectivity of the amygdala both in animals and in humans, less is known about the limbic modulation on sensorimotor-related areas. However, recent evidences suggest the amygdala as a possible cornerstone in the limbic-motor interface. Herein, we used high-resolution diffusion data of the Massachusetts General Hospital-University of Southern California (MGH-USC) Adult Diffusion Dataset, constrained spherical deconvolution-based signal modeling and probabilistic tractography aimed at identifying and reconstructing the connectivity patterns linking the amygdala to the limbic- and sensorimotor-related areas. As regards the limbic network, our results showed that the amygdala has high probability to be connected with the fusiform gyrus and the lateral orbitofrontal cortex. On the other hand, our connectomic analysis revealed a close interplay between the amygdala and the inferior parietal lobule, followed by the postcentral gyrus, the precentral gyrus and the paracentral lobule. The findings of the present study are in line with previous literature and reinforce the idea of the existence of a limbic-motor interface, which is likely to be involved in the emotional modulation of complex functions such as spatial perception and movement computation. Considering that these pathways may play an important role, not on in physiological conditions, but also in pathological context, further studies should be fostered in order to confirm the existence of a limbic-motor interface and its precise functional meaning.

MRI patient selection for endovascular thrombectomy in acute ischemic stroke: correlation between pretreatment diffusion weighted imaging and outcome scores.

INTRODUCTION: Eligibility for endovascular treatment (EVT) in patients with acute ischemic stroke (AIS) depends, amongst other factors, on CT- or MR-based scores. The aim of this study was to investigate the role of Alberta Stroke Program Early CT score based on diffusion weighted imaging (MR-ASPECT) in the assessment of brain damage pre-EVT, patient selection for EVT and outcome. MATERIALS AND METHODS: We included in this study patients with National Institute of Health stroke score (NIHSS) at admission ≥ 8, MR-ASPECT ≥ 5 and anterior AIS, who were treated with EVT in our hospital. All patients were clinically evaluated at admission, post-EVT, discharge and at 3-month follow-up. We used MR-ASPECT to establish infarct core extension at admission. We evaluated ASPECT score at admission (CT-ASPECT-IN), 24 h after EVT and at discharge, NIHSS, modified Ranking Scale (mRS), Thrombolysis in Cerebral Infarction scale (TICI), onset-to-intervention-delay (OTID) and Collateral Circulation Score (CCS). RESULTS: 68 patients (mean age 78 ± 11.9 years) were included in this study. 54.4 and 64.7% of patients had strong clinical improvement after 24 h from EVT and at discharge, respectively. NIHSS evaluated 24 h after EVT correlated with CCS, TICI and OTID. We observed a favourable outcome (mRS 0-2) in 52.9% of patients at 3-month follow-up. MR-ASPECT score correlated with post-EVT outcome better than CT-ASPECT-IN scores. CONCLUSION: MR-ASPECT score based on diffusion weighted imaging is useful for the selection of patients with AIS that can have a favourable outcome from EVT. A prompt EVT has huge impact on patient outcome.

Microstructural investigation of masticatory muscles: a pre- and post-treatment diffusion tensor imaging study in a bruxism case.

We evaluated, by means of a non-invasive procedure based on MRI, the masticatory muscular microstructure in a 55-year-old-female patient affected by bruxism. The patient underwent MR examination before and after 1 month of splint therapy, when she mentioned the complete disappearance of all symptoms. By means of diffusion tensor imaging we observed changes at microstructural level of masticatory muscular complex. We conclude that diffusion tensor imaging may be a useful instrument both to perform panoramic reconstruction of the masticatory muscle complex and to investigate microstructural modifications related to the pain relief in bruxism.

Early Corneal Innervation and Trigeminal Alterations in Parkinson Disease: A Pilot Study.

PURPOSE: To describe corneal innervation and trigeminal alterations in drug-naive patients with Parkinson disease (PD). METHODS: A case series study was conducted by recruiting 3 early drug-naive patients with PD, 2 men and 1 woman (age: 72, 68, and 66, respectively). Ophthalmologic assessment included Ocular Surface Disease Index questionnaire, visual acuity by the logarithm of the minimum angle of resolution score, pupillary light reflexes, extrinsic ocular movements, corneal sensitivity, and slit-lamp examination. Corneal innervation parameter changes were evaluated in vivo using the Confoscan 4 confocal microscope, and they were compared with a control data set. The Heidelberg Retina Tomograph 3 (HRT3) has been used to assess retinal alterations in our patients, if compared with normal range values provided by the HRT3. Moreover, 3T magnetic resonance imaging (MRI) analysis of water diffusion property changes of trigeminal nerves was performed. All data were analyzed and compared with 2 control data sets made by 14 age-matched controls. RESULTS: Patients with PD showed profound alterations of corneal innervation and of trigeminal diffusion MRI parameters, compared with controls. Strong differences (PD vs. controls) were found for deep nerve tortuosity (Kallinikos mean 19.94 vs. 2.13) and the number of beadings (mean 34.2 vs. 15.5). HRT3 retinal evaluation revealed less structural changes compared with the normal range. Diffusion MRI showed profound changes of white matter diffusion properties (PD vs. controls), with fractional anisotropy decrement (mean 0.3029 vs. 0.3329) and mean diffusivity increment (mean 0.00127 vs. 0.00106). CONCLUSIONS: Corneal innervation changes might occur earlier in patients with PD than in retinal ones. Confocal corneal innervation analysis might provide possible early biomarkers for a better PD evaluation and for its earlier diagnosis.

Biased Visuospatial Attention in Cervical Dystonia.

OBJECTIVES: There is increasing evidence of non-motor, sensory symptoms, mainly involving the spatial domain, in cervical dystonia (CD). These manifestations are likely driven by dysfunctional overactivity of the parietal cortex during the execution of a sensory task. Few studies also suggest the possibility that visuospatial attention might be specifically affected in patients with CD. Therefore, we asked whether non-motor manifestations in CD might also comprise impairment of higher level visuospatial processing. METHODS: To this end, we investigated visuospatial attention in 23 CD patients and 12 matched healthy controls (for age, gender, education, and ocular dominance). The patients were identified according to the dystonia pattern type (laterocollis vs. torticollis). Overall, participants were right-handers, and the majority of them was right-eye dominant. Visuospatial attention was assessed using a line bisection task. Participants were asked to bisect horizontal lines, using their right or left hand. RESULTS: Participants bisected more to the left of true center when using their left hand to perform the task than when using their right hand. However, overall, torticollis patients produced a significantly greater leftward deviation than controls. CONCLUSIONS: These data are consistent with preliminary findings suggesting the presence of biased spatial attention in patients with idiopathic cervical dystonia. The presence of an attentional bias in patients with torticollis seem to indicate that alterations of attentional circuits might be implicated in the pathophysiology of this type of CD. (JINS, 2018, 24, 23-32).

Lipofibromatous hamartoma of the median nerve: 3T MRI evaluation by constrained spherical deconvolution analysis.

In this study we described a case of lipofibromatous hamartoma involving the median nerve. We adopted diffusion tensor imaging and constrained spherical deconvolution-based tractography to reconstruct the affected median nerve. Moreover, we extracted diffusion-based parameters reflecting axonal integrity loss of median nerve fibres. Our data showed that constrained spherical deconvolution-based tractography outperformed the diffusion tensor imaging-based method, allowing the detection of the entire median nerve, including its branches, thus offering a robust method to investigate the involvement of the median nerve in pathological conditions. All clinical and technical implications are extensively described.

Is There a Future for Non-invasive Brain Stimulation as a Therapeutic Tool?

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.

A Connectomic Analysis of the Human Basal Ganglia Network.

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.