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Occipital nerve decompression is effective in reducing headache symptoms in select patients with migraine and occipital neuralgia. Eligibility for surgery relies on subjective symptoms and responses to nerve blocks and Onabotulinum toxin A (Botox) injections. No validated objective method exists for detecting occipital headache pathologies. The purpose of the study is to explore the potential of high-resolution Magnetic Resolution Imaging (MRI) in identifying greater occipital nerve (GON) pathologies in chronic headache patients. The MRI protocol included three sequences targeting fat-suppressed fluid-sensitive T2-weighted signals. Visualization of the GON involved generating 2-D image slices with sequential rotation to track the nerve course. Twelve patients underwent pre-surgical MRI assessment. MRI identified four main pathologies that were validated against intra-operative examination: GON entanglement by the occipital artery, increased nerve thickness and hyperintensity suggesting inflammation compared to the non-symptomatic contralateral side, early GON branching with rejoining at a distal point, and a connection between the GON and the lesser occipital nerve. MRI possesses the ability to visualize the GON and identify suspected trigger points associated with headache symptoms. This case series highlights MRI's potential to provide objective evidence of nerve pathology. Further research is warranted to establish MRI as a gold standard for diagnosing extracranial contributors in headaches. [ABSTRACT FROM AUTHOR]

A mathematical model-based parcellation of magnetic resonance diffusion tensor images (DTI) has been developed to quantify progressive changes in three types of tissues – grey (GM), white matter (WM), and damaged spinal cord tissue, along with behavioral assessments over a 6 month period following targeted spinal cord injuries (SCI) in monkeys. Sigmoid Gompertz function based fittings of DTI metrics provide early indicators that correlate with, and predict, recovery of hand grasping behavior. Our three tissue pool model provided unbiased, data-driven segmentation of spinal cord images and identified DTI metrics that can serve as reliable biomarkers of severity of spinal cord injuries and predictors of behavioral outcomes. • Mathematical model-based parcellation of magnetic resonance diffusion tensor images. • Longitudinal quantitative evaluation of changes in grey, white matter, and damaged spinal cord tissue after injury. • Sigmoid Gompertz function fittings of DTI and behavioral metrics. • Prediction of hand grasping behavioral recovery. [ABSTRACT FROM AUTHOR]

Primary repair of peripheral nerves is recommended following transection; however, patient management following repair is challenged by a lack of biomarkers to nerve regeneration. Previous studies have demonstrated that diffusion magnetic resonance imaging (MRI) may provide viable biomarkers of nerve regeneration in injury models; though, these methods have not been systematically evaluated in graded partial transections and repairs. Ex vivo diffusion MRI was performed in fixed rat sciatic nerve samples 4 or 12 weeks following partial nerve transection and repair (25% cut = 12, 50% cut = 12 and 75% cut = 11), crush injuries (n = 12), and sham surgeries (n = 9). Behavioral testing and histologic evaluation were performed in the same animals and nerve samples for comparison. Diffusion tractography provided visual characterizations of nerve damage and recovery consistent with the expected degree of injury within each cohort. In addition, quantitative indices from diffusion MRI correlated with both histological and behavioral evaluations, the latter of indicated full recovery for sham and crush nerves and limited recovery in all partially transected/repaired nerves. Nerve recovery between 4 and 12 weeks was statistically significant in partial transections 50% and 75% depth cuts (p = 0.043 and p = 0.022) but not for 25% transections. Our findings suggest that DTI can i) distinguish different degrees of partial nerve transection following surgical repair and ii) map spatially heterogeneous nerve recovery (e.g., due to collateral sprouting) from 4 to 12 weeks in partially transected nerves. [ABSTRACT FROM AUTHOR]

Nerve regeneration after injury must occur in a timely fashion to restore function. Unfortunately, current methods (e.g., electrophysiology) provide limited information following trauma, resulting in delayed management and suboptimal outcomes. Herein, we evaluated the ability of diffusion MRI to monitor nerve regeneration after injury/repair. Sprague-Dawley rats were divided into three treatment groups (sham = 21, crush = 23, cut/repair = 19) and ex vivo diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) was performed 1–12 weeks post-surgery. Behavioral data showed a distinction between crush and cut/repair nerves at 4 weeks. This was consistent with DTI, which found that thresholds based on the ratio of radial and axial diffusivities (RD/AD = 0.40 ± 0.02) and fractional anisotropy (FA = 0.53 ± 0.01) differentiated crush from cut/repair injuries. By the 12th week, cut/repair nerves whose behavioral data indicated a partial recovery were below the RD/AD threshold (and above the FA threshold), while nerves that did not recover were on the opposite side of each threshold. Additional morphometric analysis indicated that DTI-derived normalized scalar indices report on axon density (RD/AD: r = −0.54, p < 1e-3; FA: r = 0.56, p < 1e-3). Interestingly, higher-order DKI analyses did not improve our ability classify recovery. These findings suggest that DTI may provide promising biomarkers for distinguishing successful/unsuccessful nerve repairs and potentially identify cases that require reoperation. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy has transformed breast cancer treatment. However, ICI-induced systemic inflammatory immune-related adverse events (irAE) remain a major clinical challenge. In our current communication, using breast tumor models, we demonstrated that a low salt diet could reduce irAE development following ICI therapy. Importantly, a low salt diet did not change the anti-tumor efficiency. Our current study provides a basis for future clinical trials to verify the role of a low salt diet in long-term immunotherapeutic efficiency in breast cancer patients. Immune checkpoint inhibitor (ICI) therapy has revolutionized the breast cancer treatment landscape. However, ICI-induced systemic inflammatory immune-related adverse events (irAE) remain a major clinical challenge. Previous studies in our laboratory and others have demonstrated that a high-salt (HS) diet induces inflammatory activation of CD4+T cells leading to anti-tumor responses. In our current communication, we analyzed the impact of dietary salt modification on therapeutic and systemic outcomes in breast-tumor-bearing mice following anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) monoclonal antibody (mAb) based ICI therapy. As HS diet and anti-CTLA4 mAb both exert pro-inflammatory activation of CD4+T cells, we hypothesized that a combination of these would lead to enhanced irAE response, while low-salt (LS) diet through blunting peripheral inflammatory action of CD4+T cells would reduce irAE response. We utilized an orthotopic murine breast tumor model by injecting Py230 murine breast cancer cells into syngeneic C57Bl/6 mice. In an LS diet cohort, anti-CTLA4 mAb treatment significantly reduced tumor progression (day 35, 339 ± 121 mm3), as compared to isotype mAb (639 ± 163 mm3, p < 0.05). In an HS diet cohort, treatment with anti-CTLA4 reduced the survival rate (day 80, 2/15) compared to respective normal/regular salt (NS) diet cohort (8/15, p < 0.05). Further, HS plus anti-CTLA4 mAb caused an increased expression of inflammatory cytokines (IFNγ and IL-1β) in lung infiltrating and peripheral circulating CD4+T cells. This inflammatory activation of CD4+T cells in the HS plus anti-CTLA4 cohort was associated with the upregulation of inflammasome complex activity. However, an LS diet did not induce any significant irAE response in breast-tumor-bearing mice upon treatment with anti-CTLA4 mAb, thus suggesting the role of high-salt diet in irAE response. Importantly, CD4-specific knock out of osmosensitive transcription factor NFAT5 using CD4cre/creNFAT5flox/flox transgenic mice caused a downregulation of high-salt-mediated inflammatory activation of CD4+T cells and irAE response. Taken together, our data suggest that LS diet inhibits the anti-CTLA4 mAb-induced irAE response while retaining its anti-tumor efficacy. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]

Comprehensive characterizations of hand grasping behaviors after cervical spinal cord injuries are fundamental for developing rehabilitation strategies to promote recovery in spinal-cord-injured primates. We used the machine-learning-based video analysis software, DeepLabCut, to sensitively quantify kinematic aspects of grasping behavioral deficits in squirrel monkeys with C5-level spinal cord injuries. Three squirrel monkeys were trained to grasp sugar pellets from wells of varying depths before and after a left unilateral lesion of the cervical dorsal column. Using DeepLabCut, we identified post-lesion deficits in kinematic grasping behavior that included changes in digit orientation, increased variance in vertical and horizontal digit movement, and longer time to complete the task. While video-based analyses of grasping behavior demonstrated deficits in fine-scale digit function that persisted through at least 14 weeks post-injury, traditional end-point behavioral analyses showed a recovery of global hand function as evidenced by recovery of the proportion of successful retrievals by approximately 14 weeks post-injury. The combination of traditional end-point and video-based kinematic analyses provides a more comprehensive characterization of grasping behavior and highlights that global grasping performance may recover despite persistent fine-scale kinematic deficits in digit function. Machine-learning-based video analysis of kinematic digit function, in conjunction with traditional end-point behavioral analyses of grasping behavior, provide sensitive and specific indices for monitoring recovery of fine-grained hand sensorimotor behavior after spinal cord injury that can aid future studies that seek to develop targeted therapeutic interventions for improving behavioral outcomes. • Video-based analyses are sensitive in detecting fine-scale abnormal digit behavior. • Global grasping behavior recovered while fine-scale behavior remained abnormal. • A combined use of global and video-based analysis is recommended. • Using end-point and video-based kinematic analyses comprehensively characterizes grasping. • Global digit function recovers by 14 weeks post cervical spinal cord injury. • Deficits in fine-scale digit function persist until at least 14 weeks post injury. [ABSTRACT FROM AUTHOR]

Objective: Management of peripheral nerve injuries requires physicians to rely on qualitative measures from patient history, electromyography, and physical exam. Determining a successful nerve repair can take months to years for proximal injuries, and the resulting delays in clinical decision‐making can lead to a negative impact on patient outcomes. Early identification of a failed nerve repair could prevent permanent muscle atrophy and loss of function. This study aims to test the feasibility of performing diffusion tensor imaging (DTI) to evaluate injury and recovery following repair of wrist trauma. We hypothesize that DTI provides a noninvasive and reliable assessment of regeneration, which may improve clinical decision‐making and alter the clinical course of surgical interventions. Methods: Clinical and MRI measurements from subjects with traumatic peripheral nerve injury, carpal tunnel syndrome, and healthy control subjects were compared to evaluate the relationship between DTI metrics and injury severity. Results: Fractional anisotropy from DTI was sensitive to differences between damaged and healthy nerves, damaged and compressed nerves, and injured and healthy contralateral nerves. Longitudinal measurements in two injury subjects also related to clinical outcomes. Implications of other diffusion measures are also discussed. Interpretation: DTI is a sensitive tool for wrist nerve injuries and can be utilized for monitoring nerve recovery. Across three subjects with nerve injuries, this study has shown how DTI can detect abnormalities between injured and healthy nerves, measure recovery, and determine if re‐operation was successful. Additional comparisons to carpal tunnel syndrome and healthy nerves show that DTI is sensitive to the degree of impairment. [ABSTRACT FROM AUTHOR]

Background: Previous studies in our laboratory have demonstrated that a magnetic resonance imaging method called diffusion tensor imaging (DTI) can differentiate between crush and complete transection peripheral nerve injuries in a rat model ex vivo. DTI measures the directionally dependent effect of tissue barriers on the random diffusion of water molecules. In ordered tissues such as nerves, this information can be used to reconstruct the primary direction of diffusion along fiber tracts, which may provide information on fiber tract continuity after nerve injury and surgical repair.Methods: Sprague-Dawley rats were treated with different degrees of partial transection of the sciatic nerve followed by immediate repair and euthanized after 1 week of recovery. Nerves were then harvested, fixed, and scanned with a 7 Tesla magnetic resonance imaging to obtain DTIand fiber tractography in each sample. Additional behavioral (sciatic function index, foot fault asymmetry) and histological (Toluidine blue staining) assessments were performed for validation.Results: Tractography yielded a visual representation of the degree of injury that correlated with behavioral and histological evaluations.Conclusions: DTI tractography is a noninvasive tool that can yield a visual representation of a partial nerve transection as early as 1 week after surgical repair. [ABSTRACT FROM AUTHOR]

A scalable and versatile methodology for production of vinylated carboxylic compounds with 13C isotopic label in C1 position is described. It allowed synthesis of vinyl acetate-1-13C, which is a precursor for preparation of 13C hyperpolarized ethyl acetate-1-13C, which provides a convenient vehicle for potential in vivo delivery of hyperpolarized acetate to probe metabolism in living organisms. Kinetics of vinyl acetate molecular hydrogenation and polarization transfer from para-hydrogen to 13C via magnetic field cycling were investigated. Nascent proton nuclear spin polarization (% PH) of ca. 3.3 % and carbon-13 polarization (% P13C) of ca. 1.8 % were achieved in ethyl acetate utilizing 50 % para-hydrogen corresponding to ca. 50 % polarization transfer efficiency. The use of nearly 100% para-hydrogen and the improvements of % PH of para-hydrogen-nascent protons may enable production of 13C hyperpolarized contrast agents with % P13C of 20-50 % in seconds using this chemistry. [ABSTRACT FROM AUTHOR]

A scalable and versatile methodology for production of vinylated carboxylic compounds with 13C isotopic label in C1 position is described. It allowed synthesis of vinyl acetate-1-13C, which is a precursor for preparation of 13C hyperpolarized ethyl acetate-1-13C, which provides a convenient vehicle for potential in vivo delivery of hyperpolarized acetate to probe metabolism in living organisms. Kinetics of vinyl acetate molecular hydrogenation and polarization transfer from para-hydrogen to 13C via magnetic field cycling were investigated. Nascent proton nuclear spin polarization (% PH) of ca. 3.3 % and carbon-13 polarization (% P13C) of ca. 1.8 % were achieved in ethyl acetate utilizing 50 % para-hydrogen corresponding to ca. 50 % polarization transfer efficiency. The use of nearly 100% para-hydrogen and the improvements of % PH of para-hydrogen-nascent protons may enable production of 13C hyperpolarized contrast agents with % P13C of 20-50 % in seconds using this chemistry. [ABSTRACT FROM AUTHOR]