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.

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.

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).

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.

Visual System Involvement in Patients with Newly Diagnosed Parkinson Disease.

Purpose To assess intracranial visual system changes of newly diagnosed Parkinson disease in drug-naïve patients. Materials and Methods Twenty patients with newly diagnosed Parkinson disease and 20 age-matched control subjects were recruited. Magnetic resonance (MR) imaging (T1-weighted and diffusion-weighted imaging) was performed with a 3-T MR imager. White matter changes were assessed by exploring a white matter diffusion profile by means of diffusion-tensor imaging-based parameters and constrained spherical deconvolution-based connectivity analysis and by means of white matter voxel-based morphometry (VBM). Alterations in occipital gray matter were investigated by means of gray matter VBM. Morphologic analysis of the optic chiasm was based on manual measurement of regions of interest. Statistical testing included analysis of variance, t tests, and permutation tests. Results In the patients with Parkinson disease, significant alterations were found in optic radiation connectivity distribution, with decreased lateral geniculate nucleus V2 density (F, -8.28; P < .05), a significant increase in optic radiation mean diffusivity (F, 7.5; P = .014), and a significant reduction in white matter concentration. VBM analysis also showed a significant reduction in visual cortical volumes (P < .05). Moreover, the chiasmatic area and volume were significantly reduced (P < .05). Conclusion The findings show that visual system alterations can be detected in early stages of Parkinson disease and that the entire intracranial visual system can be involved. © RSNA, 2017 Online supplemental material is available for this article.

Constrained Spherical Deconvolution Tractography Reveals Cerebello-Mammillary Connections in Humans.

According to the classical view, the cerebellum has long been confined to motor control physiology; however, it has now become evident that it exerts several non-somatic features other than the coordination of movement and is engaged also in the regulation of cognition and emotion. In a previous diffusion-weighted imaging-constrained spherical deconvolution (CSD) tractography study, we demonstrated the existence of a direct cerebellum-hippocampal pathway, thus reinforcing the hypothesis of the cerebellar role in non-motor domains. However, our understanding of limbic-cerebellar interconnectivity in humans is rather sparse, primarily due to the intrinsic limitation in the acquisition of in vivo tracing. Here, we provided tractographic evidences of connectivity patterns between the cerebellum and mammillary bodies by using whole-brain CSD tractography in 13 healthy subjects. We found both ipsilateral and contralateral connections between the mammillary bodies, cerebellar cortex, and dentate nucleus, in line with previous studies performed in rodents and primates. These pathways could improve our understanding of cerebellar role in several autonomic functions, visuospatial orientation, and memory and may shed new light on neurodegenerative diseases in which clinically relevant impairments in navigational skills or memory may become manifest at early stages.

Validation of a novel classification model of psychogenic nonepileptic seizures by video-EEG analysis and a machine learning approach.

The aim of this study was to validate a novel classification for the diagnosis of PNESs. Fifty-five PNES video-EEG recordings were retrospectively analyzed by four epileptologists and one psychiatrist in a blind manner and classified into four distinct groups: Hypermotor (H), Akinetic (A), Focal Motor (FM), and with Subjective Symptoms (SS). Eleven signs and symptoms, which are frequently found in PNESs, were chosen for statistical validation of our classification. An artificial neural network (ANN) analyzed PNES video recordings based on the signs and symptoms mentioned above. By comparing results produced by the ANN with classifications given by examiners, we were able to understand whether such classification was objective and generalizable. Through accordance metrics based on signs and symptoms (range: 0-100%), we found that most of the seizures belonging to class A showed a high degree of accordance (mean±SD=73%±5%); a similar pattern was found for class SS (80% slightly lower accordance was reported for class H (58%±18%)), with a minimum of 30% in some cases. Low agreement arose from the FM group. Seizures were univocally assigned to a given class in 83.6% of seizures. The ANN classified PNESs in the same way as visual examination in 86.7%. Agreement between ANN classification and visual classification reached 83.3% (SD=17.8%) accordance for class H, 100% (SD=22%) for class A, 83.3% (SD=21.2%) for class SS, and 50% (SD=19.52%) for class FM. This is the first study in which the validity of a new PNES classification was established and reached in two different ways. Video-EEG evaluation needs to be performed by an experienced clinician, but later on, it may be fed into ANN analysis, whose feedback will provide guidance for differential diagnosis. Our analysis, supported by the ML approach, showed that this model of classification could be objectively performed by video-EEG examination.

Optic radiations evaluation in patients affected by high-grade gliomas: a side-by-side constrained spherical deconvolution and diffusion tensor imaging study.

INTRODUCTION: The need to improve surgical efficacy in patients affected by high-grade gliomas has led to development of advanced pre-surgical MRI-based techniques such as tractography. This study investigates pre-surgical planning of optic radiations (ORs) in patients affected by occipito-temporo-parietal high-grade gliomas, by means of constrained spherical deconvolution (CSD) and diffusion tensor imaging (DTI) tractography. METHODS: Twelve patients with occipito-temporo-parietal high-grade gliomas were recruited and analyzed using a 3 T MRI scanner. Diffusion-weighted imaging (DWI) was conducted with 64 gradient diffusion directions. OR alterations were assessed qualitatively and quantitatively to evaluate the effectiveness of CSD- and DTI-based pre-surgical planning. RESULTS: CSD-based tractography provided better qualitative evaluation of affected white matter tracts when compared to DTI; by thresholding tractographic probabilistic maps coming from all reconstructions, we detected, at the highest cutoff level, OR involvement in 75 % of patients (vs 41.67 % of patients with probabilistic DTI). Quantitative analysis of diffusion parameters revealed a statistically significant decrease in fractional anisotropy (FA) in the affected side following CSD-based reconstructions; on the contrary, DTI-based reconstructions did not show any significant quantitative alteration. CONCLUSION: Our results showed improvement in pre-surgical planning of high-grade gliomas involving ORs with use of CSD-based tractography. This technique provided more useful information regarding the white matter spatial relationship with brain neoplasm and its involvement in the glioma, when compared to DTI. Using CSD model for OR evaluation may optimize safe surgical resection margins, helping to reduce risk of post-operative visual deficits.

Diffusion tensor imaging parameters' changes of cerebellar hemispheres in Parkinson's disease.

INTRODUCTION: Studies with diffusion tensor imaging (DTI) analysis have produced conflicting information about the involvement of the cerebellar hemispheres in Parkinson's disease (PD). We, thus, used a new approach for the analysis of DTI parameters in order to ascertain the involvement of the cerebellum in PD. METHODS: We performed a fiber tract-based analysis of cerebellar peduncles and cerebellar hemispheres in 16 healthy subjects and in 16 PD patients with more than 5 years duration of disease, using a 3T MRI scanner and a constrained spherical deconvolution (CSD) approach for tractographic reconstructions. In addition, we performed statistical analysis of DTI parameters and fractional anisotropy (FA) XYZ direction samplings. RESULTS: We found a statistically significant decrement of FA values in PD patients compared to controls (p < 0.05). In addition, extrapolating and analyzing FA XYZ direction samplings for each patient and each control, we found that this result was due to a stronger decrement of FA values along the Y axis (antero-posterior direction) (p < 0.01); FA changes along X and Z axes were not statistically significant (p > 0.05). We confirmed also no statistically significant differences of FA and apparent diffusion coefficient (ADC) for cerebellar peduncles in PD patients compared to healthy controls. CONCLUSIONS: The DTI-based cerebellar abnormalities in PD could constitute an advance in the knowledge of this disease. We demonstrated a statistically significant reduction of FA in cerebellar hemispheres of PD patients compared to healthy controls. Our work also demonstrated that the use of more sophisticated approaches in the DTI parameter analysis could potentially have a clinical relevance.

Cognitive processess and cognitive reserve in multiple sclerosis.

Multiple Sclerosis (MS) is characterized by motor, cognitive, and neuropsychiatric symptoms, which can occur independently. While MS is traditionally considered an inflammatory disease of the white matter, degeneration of gray matter is increasingly recognized as an important contributor to the progressive cognitive decline. A protective factor against the progression of cognitive dysfunction in MS could be the cognitive reserve, defined as resistance to brain dysfunction. Aim of the present study is to evaluate the role of cognitive reserve for different aspects of cognitive dysfunction of patients with MS. We found that patients with MS and lower cognitive reserve have poorer neuropsychological performance and slower information speed processing. These findings support the notion that intellectual reserve may protect some aspects of cognitive function in patients with MS.

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.

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.

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.

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.

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.