Loss of Motor Cortical Inputs to the Red Nucleus after CNS Disorders in Nonhuman Primates.

The premotor (PM) and primary motor (M1) cortical areas broadcast voluntary motor commands through multiple neuronal pathways, including the corticorubral projection that reaches the red nucleus (RN). However, the respective contribution of M1 and PM to corticorubral projections as well as changes induced by motor disorders or injuries are not known in nonhuman primates. Here, we quantified the density and topography of axonal endings of the corticorubral pathway in RN in intact monkeys, as well as in monkeys subjected to either cervical spinal cord injury (SCI), Parkinson's disease (PD)-like symptoms or primary motor cortex injury (MCI). Twenty adult macaque monkeys of either sex were injected with the biotinylated dextran amine anterograde tracer either in PM or in M1. We developed a semiautomated algorithm to reliably detect and count axonal boutons within the magnocellular and parvocellular (pRN) subdivisions of RN. In intact monkeys, PM and M1 preferentially target the medial part of the ipsilateral pRN, reflecting its somatotopic organization. Projection of PM to the ipsilateral pRN is denser than that of M1, matching previous observations for the corticotectal, corticoreticular, and corticosubthalamic projections (Fregosi et al., 2018, 2019; Borgognon et al., 2020). In all three types of motor disorders, there was a uniform and strong decrease (near loss) of the corticorubral projections from PM and M1. The RN may contribute to functional recovery after SCI, PD, and MCI, by reducing direct cortical influence. This reduction possibly privileges direct access to the final output motor system, via emphasis on the direct corticospinal projection.SIGNIFICANCE STATEMENT We measured the corticorubral projection density arising from the PM or the M1 cortices in adult macaques. The premotor cortex sent denser corticorubral projections than the primary motor cortex, as previously observed for the corticotectal, corticoreticular, and corticosubthalamic projections. The premotor cortex may thus exert more influence than primary motor cortex onto subcortical structures. We next asked whether the corticorubral motor projections undergo lesion-dependent plasticity after either cervical spinal cord injury, Parkinson's disease-like symptoms, or primary motor cortex lesion. In all three types of pathology, there was a strong decrease of the corticorubral motor projection density, suggesting that the red nucleus may contribute to functional recovery after such motor system disorders based on a reduced direct cortical influence.

Hippocampal, Whole Midbrain, Red Nucleus, and Ventral Tegmental Area Volumes Are Increased by Selective Breeding for High Voluntary Wheel-Running Behavior.

Uncovering relationships between neuroanatomy, behavior, and evolution are important for understanding the factors that control brain function. Voluntary exercise is one key behavior that both affects, and may be affected by, neuroanatomical variation. Moreover, recent studies suggest an important role for physical activity in brain evolution. We used a unique and ongoing artificial selection model in which mice are bred for high voluntary wheel-running behavior, yielding four replicate lines of high runner (HR) mice that run ∼3-fold more revolutions per day than four replicate nonselected control (C) lines. Previous studies reported that, with body mass as a covariate, HR mice had heavier whole brains, non-cerebellar brains, and larger midbrains than C mice. We sampled mice from generation 66 and used high-resolution microscopy to test the hypothesis that HR mice have greater volumes and/or cell densities in nine key regions from either the midbrain or limbic system. In addition, half of the mice were given 10 weeks of wheel access from weaning, and we predicted that chronic exercise would increase the volumes of the examined brain regions via phenotypic plasticity. We replicated findings that both selective breeding and wheel access increased total brain mass, with no significant interaction between the two factors. In HR compared to C mice, adjusting for body mass, both the red nucleus (RN) of the midbrain and the hippocampus (HPC) were significantly larger, and the whole midbrain tended to be larger, with no effect of wheel access nor any interactions. Linetype and wheel access had an interactive effect on the volume of the periaqueductal gray (PAG), such that wheel access increased PAG volume in C mice but decreased volume in HR mice. Neither linetype nor wheel access affected volumes of the substantia nigra, ventral tegmental area, nucleus accumbens, ventral pallidum (VP), or basolateral amygdala. We found no main effect of either linetype or wheel access on neuronal densities (numbers of cells per unit area) for any of the regions examined. Taken together, our results suggest that the increased exercise phenotype of HR mice is related to increased RN and hippocampal volumes, but that chronic exercise alone does not produce such phenotypes.

Spatial profiles provide sensitive MRI measures of the midbrain micro- and macrostructure.

The midbrain is the rostral-most part of the brainstem. It contains numerous nuclei and white matter tracts, which are involved in motor, auditory and visual processing, and changes in their structure and function have been associated with aging, as well as neurodegenerative disorders. Current tools for estimating midbrain subregions and their structure with MRI require high resolution and multi-parametric quantitative MRI measures. We propose an approach that relies on morphology to calculate profiles along the midbrain and show these profiles are sensitive to the underlying macrostructure of the midbrain. First, we show that the midbrain structure can be sampled, within subject space, along three main axes of the left and right midbrain, producing profiles that are similar across subjects. We use two data sets with different field strengths, that contain R1, R2* and QSM maps and show that the profiles are highly correlated both across subjects and between datasets. Next, we compare profiles of the midbrain that sample ROIs, and show that the profiles along the first two axes sample the midbrain in a way that reliably separates the main structures, i.e., the substantia nigra, the red nucleus, and periaqueductal gray. We further show that age differences which are localized to specific nuclei, are reflected in the profiles. Finally, we generalize the same approach to calculate midbrain profiles on a third clinically relevant dataset using HCP subjects, with metrics such as the diffusion tensor and semi-quantitative data such as T1w/T2w maps. Our results suggest that midbrain profiles, both of quantitative and semi-quantitative estimates are sensitive to the underlying macrostructure of the midbrain. The midbrain profiles are calculated in native space, and rely on simple measurements. We show that it is robust and can be easily expanded to different datasets, and as such we hope that it will be of great use to the community and to the study of the midbrain in particular.

Tractographic and Microstructural Analysis of the Dentato-Rubro-Thalamo-Cortical Tracts in Children Using Diffusion MRI.

The dentato-rubro-thalamo-cortical tract (DRTC) is the main outflow pathway of the cerebellum, contributing to a finely balanced corticocerebellar loop involved in cognitive and sensorimotor functions. Damage to the DRTC has been implicated in cerebellar mutism syndrome seen in up to 25% of children after cerebellar tumor resection. Multi-shell diffusion MRI (dMRI) combined with quantitative constrained spherical deconvolution tractography and multi-compartment spherical mean technique modeling was used to explore the frontocerebellar connections and microstructural signature of the DRTC in 30 healthy children. The highest density of DRTC connections were to the precentral (M1) and superior frontal gyri (F1), and from cerebellar lobules I-IV and IX. The first evidence of a topographic organization of anterograde projections to the frontal cortex at the level of the superior cerebellar peduncle (SCP) is demonstrated, with streamlines terminating in F1 lying dorsomedially in the SCP compared to those terminating in M1. The orientation dispersion entropy of DRTC regions appears to exhibit greater contrast than that shown by fractional anisotropy. Analysis of a separate reproducibility cohort demonstrates good consistency in the dMRI metrics described. These novel anatomical insights into this well-studied pathway may prove to be of clinical relevance in the surgical resection of cerebellar tumors.

Tractography of the ansa lenticularis in the human brain.

The aim of this study was to make a thorough investigation of the trajectory of the ansa lenticularis (AL) and its subcomponents using high-resolution fiber-tracking tractography. The subcomponents of the AL were reconstructed from one region of interest (ROI) in the area of the globus pallidus combined with another ROI in the red nucleus, substantia nigra, subthalamic nucleus, or thalamus. This fiber-tracking protocol was tested in an HCP-1065 template, 35 healthy subjects from Massachusetts General Hospital (MGH), and 20 healthy subjects from the human connectome project (HCP) using generalized q-sampling imaging (GQI)-based tractography. Quantitative anisotropy and fractional anisotropy were also computed for the AL subcomponents. The subcomponents of the AL could be reconstructed in the HCP-1065 template, 35 MGH healthy subjects, and 20 HCP healthy subjects. The AL descends from the globus pallidus and joins the ansa peduncularis for a short distance, subdividing later into fibers that continue separately to the red nucleus, substantia nigra, subthalamic nucleus, and thalamus. The study demonstrated the trajectory of the ansa lenticularis and its subcomponents using GQI-based tractography, improving our understanding of the anatomical connectivity between the globus pallidus and the thalamo-subthalamic region in the human brain. One Sentence Summary The investigation of the ansa lenticularis and its subcomponents using high-resolution diffusion images based tractography.

Neural Signals in Red Nucleus during Reactive and Proactive Adjustments in Behavior.

The ability to adjust behavior is an essential component of cognitive control. Much is known about frontal and striatal processes that support cognitive control, but few studies have investigated how motor signals change during reactive and proactive adjustments in motor output. To address this, we characterized neural signals in red nucleus (RN), a brain region linked to motor control, as male and female rats performed a novel variant of the stop-signal task. We found that activity in RN represented the direction of movement and was strongly correlated with movement speed. Additionally, we found that directional movement signals were amplified on STOP trials before completion of the response and that the strength of RN signals was modulated when rats exhibited cognitive control. These results provide the first evidence that neural signals in RN integrate cognitive control signals to reshape motor outcomes reactively within trials and proactivity across them.SIGNIFICANCE STATEMENT Healthy human behavior requires the suppression or inhibition of errant or maladaptive motor responses, often called cognitive control. While much is known about how frontal brain regions facilitate cognitive control, less is known about how motor regions respond to rapid and unexpected changes in action selection. To address this, we recorded from neurons in the red nucleus, a motor region thought to be important for initiating movement in rats performing a cognitive control task. We show that red nucleus tracks motor plans and that selectivity was modulated on trials that required shifting from one motor response to another. Collectively, these findings suggest that red nucleus contributes to modulating motor behavior during cognitive control.

Early red nucleus atrophy in relapse-onset multiple sclerosis.

No study has investigated red nucleus (RN) atrophy in multiple sclerosis (MS) despite cerebellum and its connections are elective sites of MS-related pathology. In this study, we explore RN atrophy in early MS phases and its association with cerebellar damage (focal lesions and atrophy) and physical disability. Thirty-seven relapse-onset MS (RMS) patients having mean age of 35.6 ± 8.5 (18-56) years and mean disease duration of 1.1 ± 1.5 (0-5) years, and 36 age- and sex-matched healthy controls (HC) were studied. Cerebellar and RN lesions and volumes were analyzed on 3 T-MRI images. RMS did not differ from HC in cerebellar lobe volumes but significantly differed in both right (107.84 ± 13.95 mm3 vs. 99.37 ± 11.53 mm3 , p = .019) and left (109.71 ± 14.94 mm3 vs. 100.47 ± 15.78 mm3 , p = .020) RN volumes. Cerebellar white matter lesion volume (WMLV) inversely correlated with both right and left RN volumes (r = -.333, p = .004 and r = -.298, p = .010, respectively), while no correlation was detected between RN volumes and mean cortical thickness, cerebellar gray matter lesion volume, and supratentorial WMLV (right RN: r = -.147, p = .216; left RN: r = -.153, p = .196). Right, but not left, RN volume inversely correlated with midbrain WMLV (r = -.310, p = .008), while no correlation was observed between whole brainstem WMLV and either RN volumes (right RN: r = -.164, p = .164; left RN: r = -.64, p = .588). Finally, left RN volume correlated with vermis VIIb (r = .297, p = .011) and right interposed nucleus (r = .249, p = .034) volumes. We observed RN atrophy in early RMS, likely resulting from anterograde axonal degeneration starting in cerebellar and midbrain WML. RN atrophy seems a promising marker of neurodegeneration and/or cerebellar damage in RMS.

Automated segmentation of deep brain nuclei using convolutional neural networks and susceptibility weighted imaging.

The advent of susceptibility-sensitive MRI techniques, such as susceptibility weighted imaging (SWI), has enabled accurate in vivo visualization and quantification of iron deposition within the human brain. Although previous approaches have been introduced to segment iron-rich brain regions, such as the substantia nigra, subthalamic nucleus, red nucleus, and dentate nucleus, these methods are largely unavailable and manual annotation remains the most used approach to label these regions. Furthermore, given their recent success in outperforming other segmentation approaches, convolutional neural networks (CNN) promise better performances. The aim of this study was thus to evaluate state-of-the-art CNN architectures for the labeling of deep brain nuclei from SW images. We implemented five CNN architectures and considered ensembles of these models. Furthermore, a multi-atlas segmentation model was included to provide a comparison not based on CNN. We evaluated two prediction strategies: individual prediction, where a model is trained independently for each region, and combined prediction, which simultaneously predicts multiple closely located regions. In the training dataset, all models performed with high accuracy with Dice coefficients ranging from 0.80 to 0.95. The regional SWI intensities and volumes from the models' labels were strongly correlated with those obtained from manual labels. Performances were reduced on the external dataset, but were higher or comparable to the intrarater reliability and most models achieved significantly better results compared to multi-atlas segmentation. CNNs can accurately capture the individual variability of deep brain nuclei and represent a highly useful tool for their segmentation from SW images.

Red nucleus IL-33 facilitates the early development of mononeuropathic pain in male rats by inducing TNF-α through activating ERK, p38 MAPK, and JAK2/STAT3.

BACKGROUND: Our recent studies have identified that the red nucleus (RN) dual-directionally modulates the development and maintenance of mononeuropathic pain through secreting proinflammatory and anti-inflammatory cytokines. Here, we further explored the action of red nucleus IL-33 in the early development of mononeuropathic pain. METHODS: In this study, male rats with spared nerve injury (SNI) were used as mononeuropathic pain model. Immunohistochemistry, Western blotting, and behavioral testing were used to assess the expressions, cellular distributions, and actions of red nucleus IL-33 and its related downstream signaling molecules. RESULTS: IL-33 and its receptor ST2 were constitutively expressed in the RN in naive rats. After SNI, both IL-33 and ST2 were upregulated significantly at 3 days and peaked at 1 week post-injury, especially in RN neurons, oligodendrocytes, and microglia. Blockade of red nucleus IL-33 with anti-IL-33 neutralizing antibody attenuated SNI-induced mononeuropathic pain, while intrarubral administration of exogenous IL-33 evoked mechanical hypersensitivity in naive rats. Red nucleus IL-33 generated an algesic effect in the early development of SNI-induced mononeuropathic pain through activating NF-κB, ERK, p38 MAPK, and JAK2/STAT3, suppression of NF-κB, ERK, p38 MAPK, and JAK2/STAT3 with corresponding inhibitors markedly attenuated SNI-induced mononeuropathic pain or IL-33-evoked mechanical hypersensitivity in naive rats. Red nucleus IL-33 contributed to SNI-induced mononeuropathic pain by stimulating TNF-α expression, which could be abolished by administration of inhibitors against ERK, p38 MAPK, and JAK2/STAT3, but not NF-κB. CONCLUSIONS: These results suggest that red nucleus IL-33 facilitates the early development of mononeuropathic pain through activating NF-κB, ERK, p38 MAPK, and JAK2/STAT3. IL-33 mediates algesic effect partly by inducing TNF-α through activating ERK, p38 MAPK and JAK2/STAT3.

Sensitivity-Specificity of Tau and Amyloid ß Positron Emission Tomography in Frontotemporal Lobar Degeneration.

OBJECTIVE: To examine associations between tau and amyloid ß (Aß) molecular positron emission tomography (PET) and both Alzheimer-related pathology and 4-repeat tau pathology in autopsy-confirmed frontotemporal lobar degeneration (FTLD). METHODS: Twenty-four patients had [18 F]-flortaucipir-PET and died with FTLD (progressive supranuclear palsy [PSP], n = 10; corticobasal degeneration [CBD], n = 10; FTLD-TDP, n = 3; and Pick disease, n = 1). All but 1 had Pittsburgh compound B (PiB)-PET. Braak staging, Aß plaque and neurofibrillary tangle counts, and semiquantitative tau lesion scores were performed. Flortaucipir standard uptake value ratios (SUVRs) were calculated in a temporal meta region of interest (meta-ROI), entorhinal cortex and cortical/subcortical regions selected to match the tau lesion analysis. Global PiB SUVR was calculated. Autoradiography was performed in 1 PSP patient, with digital pathology used to quantify tau burden. RESULTS: Nine cases (37.5%) had Aß plaques. Global PiB SUVR correlated with Aß plaque count, with 100% specificity and 50% sensitivity for diffuse plaques. Twenty-one (87.5%) had Braak stages I to IV. Flortaucipir correlated with neurofibrillary tangle counts in entorhinal cortex, but entorhinal and meta-ROI SUVRs were not elevated in Braak IV or primary age-related tauopathy. Flortaucipir uptake patterns differed across FTLD pathologies and could separate PSP and CBD. Flortaucipir correlated with tau lesion score in red nucleus and midbrain tegmentum across patients, but not in cortical or basal ganglia regions. Autoradiography demonstrated minimal uptake of flortaucipir, although flortaucipir correlated with quantitative tau burden across regions. INTERPRETATION: Molecular PET shows expected correlations with Alzheimer-related pathology but lacks sensitivity to detect mild Alzheimer pathology in FTLD. Regional flortaucipir uptake was able to separate CBD and PSP. ANN NEUROL 2020;88:1009-1022.

Synaptic Changes in Parkinson Disease Assessed with in vivo Imaging.

OBJECTIVE: Parkinson disease is characterized by motor and nonmotor symptoms, reduced striatal dopamine signaling, and loss of dopamine neurons in the substantia nigra. It is now known that the pathological process in Parkinson disease may begin decades before the clinical diagnosis and include a variety of neuronal alterations in addition to the dopamine system. METHODS: This study examined the density of all synapses with synaptic vesicle glycoprotein 2A (SV2A) in Parkinson disease subjects with mild bilateral disease (n = 12) and matched normal controls (n = 12) using in vivo high-resolution positron emission tomographic imaging as well as postmortem autoradiography in an independent sample with Parkinson disease (n = 15) and normal controls (n = 13) in the substantia nigra and putamen. RESULTS: A group-by-brain region interaction effect (F10, 22 = 3.52, p = 0.007) was observed in the primary brain areas with in vivo SV2A binding. Post hoc analyses revealed that the Parkinson disease group exhibited lower SV2A in the substantia nigra (-45%; p < 0.001), red nucleus (-31%; p = 0.03), and locus coeruleus (-17%; p = 0.03). Exploratory analyses also revealed lower SV2A binding in clinically relevant cortical areas. Using autoradiography, we confirmed lower SV2A in the substantia nigra (-17%; p < 0.005) and nonsignificant findings in the putamen (-4%; p = 0.06). INTERPRETATION: This work provides the first evidence of synaptic loss in brainstem nuclei involved in the pathogenesis of Parkinson disease in living patients. SV2A imaging holds promise for understanding synaptic changes central to the disease. Ann Neurol 2020;87:329-338.

Coexistence of dentatorubral-pallidoluysian atrophy and Parkinson's disease: An autopsy case report.

We report an autopsy case of a 56-year-old male patient with the coexistence of dentatorubral-pallidoluysian atrophy (DRPLA) and Parkinson's disease (PD). He presented with gait instability and dysarthria for 10 years. The removed brain showed general atrophy (988 g) with depigmentation of the substantia nigra. The neocortex and deep gray matter, including the red nucleus, subthalamic nuclei, and globus pallidus, were atrophic, and grumose degeneration of the cerebellar dentate nucleus was observed. Polyglutamine- and p62-positive neuronal inclusions were present and widespread in the areas mentioned above. Interestingly, this case also had brainstem-predominant PD pathology with α-synuclein-positive Lewy bodies and Lewy neurites. Generalized white matter atrophy with patchy loss of astrocytes in the white matter suggested glial dysfunction by elongated CAG repeats in the atrophin 1 gene (atrophin 1). Polymerase chain reaction (PCR) fragment analysis revealed increased CAG repeats (61) on atrophin 1 encoding atrophin 1. The patient had a family history of DRPLA, including his daughter, who was confirmed positive on genetic testing (CAG repeat: 65). His father, brother, and niece were suspected of having the disease. Clinicopathologically, all of the above findings are consistent with the coexistence of DRPLA and PD. So far, various overlapping neurodegenerative disorders have been reported, but the coexistence of DRPLA and PD has never been demonstrated in the published literature. Even though the exact time of PD development is unknown in this case, PD might develop after DRPLA, and the overwhelming symptoms of DRPLA might mask those of PD. Here, we report a clinicopathologically definite case of the coexistence of DRPLA and PD. White matter degeneration with patchy loss of astrocytes was another remarkable finding of this case.

Reconstruction of the corticorubral tract in the human brain using diffusion tensor tractography.

The corticorubral tract (CRT) facilitates fine motor coordination. However, no diffusion tensor tractography (DTT) study has been conducted although a few studies have reported on the cortical connection of the red nucleus. In this study, we investigated the DTT reconstruction method and DTT characteristics of the CRT in normal subjects. Thirty-six right-handed normal subjects were recruited. Diffusion tensor images were scanned using a 1.5 T MRI scanner. For analysis of the CRT, the seed region of interest (ROI) was placed on the red nucleus of the midbrain, and the target ROI was placed on the primary sensorimotor cortex. Values of fractional anisotropy (FA), mean diffusivity (MD), and tract volume (TV) of the CRT were obtained for both hemispheres. Among the 72 cerebral hemispheres of the 36 normal subjects, the neural tract between the red nucleus and the primary sensorimotor cortex was reconstructed in 66 hemispheres (92%). The reconstructed CRT, which originated from the primary sensorimotor cortex, descended through the posterior portion of the centrum semiovale, the corona radiata and posterior limb of the internal capsule, and terminated at the red nucleus. Analysis of the FA, MD, and TV values revealed no significant differences between the right and left hemispheres (p > 0.05). We describe the method of DTT reconstruction and the imaging parameters of the CRT in the brain of normal subjects. We believe that the DTT method and associated parameter results for the CRT in normal subjects will be useful in future neuroscience studies.

Dynamic Interaction between Cortico-Brainstem Pathways during Training-Induced Recovery in Stroke Model Rats.

Reorganization of residual descending motor circuits underlies poststroke recovery. We previously clarified a causal relationship between the cortico-rubral tract and intensive limb use-induced functional recovery after internal capsule hemorrhage (ICH). However, other descending tracts, such as the cortico-reticular tract, might also be involved in rehabilitation-induced compensation. To investigate whether rehabilitation-induced recovery after ICH involves a shift in the compensatory circuit from the cortico-rubral tract to the cortico-reticular tract, we established loss of function of the cortico-rubral tract or/and cortico-reticular tract using two sets of viral vectors comprising the Tet-on system and designer receptors exclusively activated by the designer drug system. We used an ICH model that destroyed almost 60% of the corticofugal fibers. Anterograde tracing in rehabilitated rats revealed abundant sprouting of axons from the motor cortex in the red nucleus but not in the medullary reticular formation during the early phase of recovery. This primary contribution of the cortico-rubral tract was demonstrated by its selective blockade, whereas selective cortico-reticular tract silencing had little effect. Interestingly, cortico-rubral tract blockade from the start of rehabilitation induced an obvious increase of axon sprouting in the reticular formation with substantial functional recovery. Additional cortico-reticular tract silencing under the cortico-rubral tract blockade significantly worsened the recovered forelimb function. Furthermore, the alternative recruitment of the cortico-reticular tract was gradually induced by intensive limb use under cortico-rubral tract blockade, in which cortico-reticular tract silencing caused an apparent motor deficit. These findings indicate that individual cortico-brainstem pathways have dynamic compensatory potency to support rehabilitative functional recovery after ICH.SIGNIFICANCE STATEMENT This study aimed to clarify the interaction between the cortico-rubral and the cortico-reticular tract during intensive rehabilitation and functional recovery after capsular stroke. Pathway-selective disturbance by two sets of viral vectors revealed that the cortico-rubral tract was involved in rehabilitation-induced recovery of forelimb function from an early phase after internal capsule hemorrhage, but that the cortico-reticular tract was not. The sequential disturbance of both tracts revealed that the cortico-reticular tract was recruited and involved in rehabilitation-induced recovery when the cortico-rubral tract failed to function. Our data demonstrate a dynamic compensatory action of individual cortico-brainstem pathways for recovery through poststroke rehabilitation.

The Amsterdam Ultra-high field adult lifespan database (AHEAD): A freely available multimodal 7 Tesla submillimeter magnetic resonance imaging database.

Normative databases allow testing of novel hypotheses without the costly collection of magnetic resonance imaging (MRI) data. Here we present the Amsterdam Ultra-high field adult lifespan database (AHEAD). The AHEAD consists of 105 7 Tesla (T) whole-brain structural MRI scans tailored specifically to imaging of the human subcortex, including both male and female participants and covering the entire adult life span (18-80 yrs). We used these data to create probability maps for the subthalamic nucleus, substantia nigra, internal and external segment of the globus pallidus, and the red nucleus. Data was acquired at a submillimeter resolution using a multi-echo (ME) extension of the second gradient-echo image of the MP2RAGE sequence (MP2RAGEME) sequence, resulting in complete anatomical alignment of quantitative, R1-maps, R2*-maps, T1-maps, T1-weighted images, T2*-maps, and quantitative susceptibility mapping (QSM). Quantitative MRI maps, and derived probability maps of basal ganglia structures are freely available for further analyses.

Advanced Imaging and Direct Targeting of the Motor Thalamus and Dentato-Rubro-Thalamic Tract for Tremor: A Systematic Review.

Direct targeting methods for stereotactic neurosurgery in the treatment of essential tremor have been the subject of active research over the past decade but have not yet been systematically reviewed. We present a clinically oriented topic review based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses Group guidelines. Our focus is studies using advanced magnetic resonance imaging (MRI) techniques (ultrahigh-field structural MRI, diffusion-weighted imaging, diffusion-tensor tractography, and functional MRI) for patient specific, in vivo identification of the ventral intermediate nucleus and the dentato-rubro-thalamic tract.

Focused Ultrasound Thalamotomy with Dentato-Rubro-Thalamic Tractography in Patients with Spinal Cord Stimulators and Cardiac Pacemakers.

Magnetic resonance image-guided high-intensity focused ultrasound (MRgFUS)-based thermal ablation of the ventral intermediate nucleus of the thalamus (VIM) is a minimally invasive treatment modality for essential tremor (ET). Dentato-rubro-thalamic tractography (DRTT) is becoming increasingly popular for direct targeting of the presumed VIM ablation focus. It is currently unclear if patients with implanted pulse generators (IPGs) can safely undergo MRgFUS ablation and reliably acquire DRTT suitable for direct targeting. We present an 80-year-old male with a spinal cord stimulator (SCS) and an 88-year-old male with a cardiac pacemaker who both underwent MRgFUS for medically refractory ET. Clinical outcomes were measured using the Clinical Rating Scale for Tremor (CRST). DRTT was successfully created and imaging parameter adjustments did not result in any delay in procedural time in either case. In the first case, 7 therapeutic sonications were delivered. The patient improved immediately and durably with a 90% CRST-disability improvement at 6-week follow-up. In our second case, 6 therapeutic sonications were delivered with durable, 75% CRST-disability improvement at 6 weeks. These are the first cases of MRgFUS thalamotomy in patients with IPGs. DRTT targeting and MRgFUS-based thermal ablation can be safely performed in these patients using a 1.5-T MRI.

Red nucleus IL-6 mediates the maintenance of neuropathic pain by inducing the productions of TNF-α and IL-1ß through the JAK2/STAT3 and ERK signaling pathways.

We previously reported that interleukin (IL)-6 in the red nucleus (RN) is involved in the maintenance of neuropathic pain induced by spared nerve injury (SNI), and exerts a facilitatory effect via Janus-activated kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) and extracellular signal-regulated kinase (ERK) signal transduction pathways. The present study aimed at investigating the roles of tumor necrosis factor-α (TNF-α) and IL-1ß in RN IL-6-mediated maintenance of neuropathic pain and related signal transduction pathways. Being similar to the elevation of RN IL-6 three weeks after SNI, increased protein levels of both TNF-α and IL-1ß were also observed in the contralateral RN three weeks after the nerve injury. The upregulations of TNF-α and IL-1ß were closely correlative with IL-6 and suppressed by intrarubral injection of a neutralizing antibody against IL-6. Administration of either the JAK2 antagonist AG490 or the ERK antagonist PD98059 to the RN of rats with SNI remarkably increased the paw withdrawal threshold (PWT) and inhibited the up-regulations of local TNF-α and IL-1ß. Further experiments indicated that intrarubral injection of exogenous IL-6 in naive rats apparently lowered the PWT of the contralateral hindpaw and boosted the local expressions of TNF-α and IL-1ß. Pretreatment with AG490 could block IL-6-induced tactile hypersensitivity and suppress the up-regulations of both TNF-α and IL-1ß. However, injection of PD98059 in advance only inhibited the upregulation of IL-1ß, but not TNF-α. These findings indicate that RN IL-6 mediates the maintenance of neuropathic pain by inducing the productions of TNF-α and IL-1ß. IL-6 induces the expression of TNF-α through the JAK2/STAT3 pathway, and the production of IL-1ß through the JAK2/STAT3 and ERK pathways.

Distribution of brain iron accrual in adolescence: Evidence from cross-sectional and longitudinal analysis.

To track iron accumulation and location in the brain across adolescence, we repurposed diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) data acquired in 513 adolescents and validated iron estimates with quantitative susceptibility mapping (QSM) in 104 of these subjects. DTI and fMRI data were acquired longitudinally over 1 year in 245 male and 268 female, no-to-low alcohol-consuming adolescents (12-21 years at baseline) from the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) study. Brain region average signal values were calculated for susceptibility to nonheme iron deposition: pallidum, putamen, dentate nucleus, red nucleus, and substantia nigra. To estimate nonheme iron, the corpus callosum signal (robust to iron effects) was divided by regional signals to generate estimated R2 (edwR2 for DTI) and R2 * (eR2 * for fMRI). Longitudinal iron deposition was measured using the normalized signal change across time for each subject. Validation using baseline QSM, derived from susceptibility-weighted imaging, was performed on 46 male and 58 female participants. Normalized iron deposition estimates from DTI and fMRI correlated with age in most regions; both estimates indicated less iron in boys than girls. QSM results correlated highly with DTI and fMRI results (adjusted R2 = 0.643 for DTI, 0.578 for fMRI). Cross-sectional and longitudinal analyses indicated an initial rapid increase in iron, notably in the putamen and red nucleus, that slowed with age. DTI and fMRI data can be repurposed for identifying regional brain iron deposition in developing adolescents as validated with high correspondence with QSM.

Collaboration of Cerebello-Rubral and Cerebello-Striatal Loops in a Motor Preparation Task.

In this study, we used fMRI to identify brain regions associated with concentration (sustained attention) during a motor preparation task. In comparison with a non-concentration task, increased activities were observed (P < 0.05, FWE-corrected P values) in cerebellar lobules VI and VII, motor cortex, pre-supplementary motor area (pre-SMA), thalamus, red nucleus (RN), and caudate nucleus (CN). Moreover, analysis of effective connectivity inter-areal (psychophysiological interactions) showed that during preparation, concentration-related brain activity increase was dependent on Cerebello-thalamo-pre-SMA-RN and Pre-SMA-CN-thalamo-M1 loops. We postulate that, while pre-SMA common to both loops is specifically involved in the movement preparation and readiness for voluntary movement through the striatum, the cerebellar lobule VI in conjunction with RN, likely through a cerebellar-rubro-olivary-cerebellar loop, might be implicated in concentration-related optimization of upcoming motor performances.