The USP7-STAT3-granzyme-Par-1 axis regulates allergic inflammation by promoting differentiation of IL-5-producing Th2 cells.

Uncontrolled type 2 immunity by type 2 helper T (Th2) cells causes intractable allergic diseases; however, whether the interaction of CD4+ T cells shapes the pathophysiology of allergic diseases remains unclear. We identified a subset of Th2 cells that produced the serine proteases granzyme A and B early in differentiation. Granzymes cleave protease-activated receptor (Par)-1 and induce phosphorylation of p38 mitogen-activated protein kinase (MAPK), resulting in the enhanced production of IL-5 and IL-13 in both mouse and human Th2 cells. Ubiquitin-specific protease 7 (USP7) regulates IL-4-induced phosphorylation of STAT3, resulting in granzyme production during Th2 cell differentiation. Genetic deletion of Usp7 or Gzma and pharmacological blockade of granzyme B ameliorated allergic airway inflammation. Furthermore, PAR-1+ and granzyme+ Th2 cells were colocalized in nasal polyps from patients with eosinophilic chronic rhinosinusitis. Thus, the USP7-STAT3-granzymes-Par-1 pathway is a potential therapeutic target for intractable allergic diseases.

Suppression of Type I Interferon Signaling in Myeloid Cells by Autoantibodies in Severe COVID-19 Patients.

PURPOSE: Auto-antibodies (auto-abs) to type I interferons (IFNs) have been identified in patients with life-threatening coronavirus disease 2019 (COVID-19), suggesting that the presence of auto-abs may be a risk factor for disease severity. We therefore investigated the mechanism underlying COVID-19 exacerbation induced by auto-abs to type I IFNs. METHODS: We evaluated plasma from 123 patients with COVID-19 to measure auto-abs to type I IFNs. We performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells from the patients with auto-abs and conducted epitope mapping of the auto-abs. RESULTS: Three of 19 severe and 4 of 42 critical COVID-19 patients had neutralizing auto-abs to type I IFNs. Patients with auto-abs to type I IFNs showed no characteristic clinical features. scRNA-seq from 38 patients with COVID-19 revealed that IFN signaling in conventional dendritic cells and canonical monocytes was attenuated, and SARS-CoV-2-specific BCR repertoires were decreased in patients with auto-abs. Furthermore, auto-abs to IFN-α2 from COVID-19 patients with auto-abs recognized characteristic epitopes of IFN-α2, which binds to the receptor. CONCLUSION: Auto-abs to type I IFN found in COVID-19 patients inhibited IFN signaling in dendritic cells and monocytes by blocking the binding of type I IFN to its receptor. The failure to properly induce production of an antibody to SARS-CoV-2 may be a causative factor of COVID-19 severity.

Inhibition of tibialis anterior spinal reflex circuits using frequency-specific neuromuscular electrical stimulation.

BACKGROUND: Neuromuscular electrical stimulation (NMES) can generate muscle contractions and elicit excitability of neural circuits. However, the optimal stimulation frequency for effective neuromodulation remains unclear. METHODS: Eleven able-bodied individuals participated in our study to examine the effects of: (1) low-frequency NMES at 25 Hz, (2) high-frequency NMES at 100 Hz; and (3) mixed-frequency NMES at 25 and 100 Hz switched every second. NMES was delivered to the right tibialis anterior (TA) muscle for 1 min in each condition. The order of interventions was pseudorandomized between participants with a washout of at least 15 min between conditions. Spinal reflexes were elicited using single-pulse transcutaneous spinal cord stimulation applied over the lumbar enlargement to evoke responses in multiple lower-limb muscles bilaterally and maximum motor responses (Mmax ) were elicited in the TA muscle by stimulating the common peroneal nerve to assess fatigue at the baseline and immediately, 5, 10, and 15 min after each intervention. RESULTS: Our results showed that spinal reflexes were significantly inhibited immediately after the mixed-frequency NMES, and for at least 15 min in follow-up. Low-frequency NMES inhibited spinal reflexes 5 min after the intervention, and also persisted for at least 10 min. These effects were present only in the stimulated TA muscle, while other contralateral and ipsilateral muscles were unaffected. Mmax responses were not affected by any intervention. CONCLUSIONS: Our results indicate that even a short-duration (1 min) NMES intervention using low- and mixed-frequency NMES could inhibit spinal reflex excitability of the TA muscle without inducing fatigue.

Neuropil-like islands are a possible pathogenetic link between glioblastoma and gangliocytoma/ganglioglioma in a case of synchronous bilateral brain tumors.

Neuropil-like islands (NIs) are a histologic hallmark of glioneuronal tumors with neuropil-like islands (GTNIs), but GTNIs are presently not considered a homogeneous entity. The essence of GTNI is likely its glial component, and NIs are now considered aberrant neuronal differentiation or metaplasia. The case we report herein is a 41-year-old woman who was synchronously affected by two brain tumors: one was a glioblastoma (glioblastoma multiforme, GBM), of isocitrate dehydrogenase (IDH)-wild type, with NIs in the left parietal lobe, and the other was histologically a composite gangliocytoma (GC)/anaplastic ganglioglioma (GG) with NIs in the right medial temporal lobe. While both tumors were genetically wild type for IDH, histone H3, and v-raf murine sarcoma viral oncogene homolog B1 (BRAF), the former tumor, but not the latter, was mutated for telomerase reverse transcriptase promoter gene (TERT). A recent systematic study using DNA methylation profiling and next-generation sequencing showed that anaplastic GG separate into other WHO tumor types, including IDH-wild-type GBM. It suggested a diagnostic scheme where an anaplastic GG is likely an IDH-wild-type GBM if it is a BRAF wild type, IDH wild type, and TERT promoter mutant tumor. The likely scenario in this patient is that the GBM results from the progression of GC/anaplastic GG due to the superimposed TERT promoter mutation and the propagation of newly generated GBM cells in the contralateral hemisphere. A systematic analysis using DNA methylation profiling and next-generation sequencing was not available in this study, but the common presence of NIs histologically noted in the two tumors could support this scenario. Although a sufficient volume of molecular and genetic testing is sine qua non for the accurate understanding of brain tumors, the importance of histologic observation cannot be overemphasized.

Primary cauda equina lymphoma confirmed by autopsy: A case report.

Compared with those involving the central nervous system, lymphomas involving the peripheral nervous system, namely neurolymphomatosis, are extremely rare. Neurolymphomatosis is classified as primary or secondary; the former is much rarer than the latter. Herein, we present an autopsied case of primary cauda equina lymphoma (PCEL), a type of primary neurolymphomatosis, with a literature review of autopsied cases of PCEL as well as primary neurolymphomatosis other than PCEL (non-PCEL primary neurolymphomatosis). A 70-year-old woman presented with difficulty walking, followed by paraplegia and then bladder and bowel disturbance. On magnetic resonance imaging, the cauda equina was diffusely enlarged and enhanced with gadolinium. The brainstem and cerebellum were also enhanced with gadolinium along their surface. The differential diagnosis of the patient included meningeal tumors (other than lymphomas), lymphomas, or sarcoidosis. The biopsy of the cauda equina was planned for a definite diagnosis, but because the patient deteriorated so rapidly, it was not performed. Eventually, she was affected by cranial nerve palsies. With the definite diagnosis being undetermined, the patient died approximately 1.5 years after the onset of disesase. At autopsy, the cauda equina was replaced by a bulky mass composed of atypical B-lymphoid cells, consistent with diffuse large B-cell lymphoma (DLBCL). The spinal cord was heavily infiltrated, as were the spinal/cranial nerves and subarachnoid space. There was metastasis in the left adrenal. The patient was finally diagnosed postmortem as PCEL with a DLBCL phenotype. To date, there have been a limited number of autopsied cases of PCEL and non-PCEL primary neurolymphomatosis (nine cases in all, including ours). The diagnosis is, without exception, B-cell lymphoma including DLBCL, and the histology features central nervous system parenchymal infiltration, nerve root involvement, and subarachnoid dissemination (lymphomatous meningitis). Metastases are not uncommon. All clinicians and pathologists should be aware of lymphomas primarily involving the peripheral nervous system.

The predominance of "astrocytic" intranuclear inclusions in neuronal intranuclear inclusion disease manifesting encephalopathy-like symptoms: A case series with brain biopsy.

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder represented by eosinophilic intranuclear inclusions (EIIs) and GGC/CGG repeat expansion in the NOTCH2NLC gene. We report here two adult cases of NIID, genetically confirmed, with manifestation of encephalopathy-like symptoms and address the histopathologic findings obtained by brain biopsies, with a focus on "astrocytic" intranuclear inclusions (AIIs). Case 1 presented with paroxysmal restlessness, vertigo, or fever and was later involved in severe dementia and tetraparesis. Case 2 presented with forgetfulness and then with paroxysmal fever and headache. In both cases, delimited areas with gadolinium enhancement on magnetic resonance imaging and corresponding hyperperfusion were detected, leading to brain biopsies of the cortex. On histology, Case 1 showed an abnormal lamination, where the thickness of layers was different from usual. Both neurons and astrocytes showed some dysmorphologic features. Notably, astrocytes rather than neurons harbored EIIs. Case 2 showed a cortex, where neurons tended to be arrayed in a columnar fashion. Astrocytes showed some dysmorphologic features. Notably, much more astrocytes than neurons harbored EIIs. By a double-labeling immunofluorescence study for p62/NeuN and p62/glial fibrillary acidic protein, the predominance of AIIs was confirmed in both cases. Considering the physiological functions of astrocytes for the development and maintenance of the cortex, the encephalopathy-like symptoms, dynamic change of cerebral blood flow, and cortical dysmorphology can reasonably be explained by the dysfunction of EII-bearing astrocytes rather than EII-bearing neurons. This study suggests the presence of a subtype of NIID where AIIs rather than "neuronal" intranuclear inclusions are likely a key player in the pathogenesis of NIID, particularly in cases with encephalopathy-like symptoms. The importance of AIIs ("gliopathy") should be more appreciated in future studies of NIID.

RGMa Signal in Macrophages Induces Neutrophil-Related Astrocytopathy in NMO.

OBJECTIVE: Repulsive guidance molecule-a (RGMa) is a glycosylphosphatidylinositol-linked glycoprotein which has multiple functions including axon growth inhibition and immune regulation. However, its role in the pathophysiology of neuromyelitis optica (NMO) is poorly understood. Perivascular astrocytopathy, which is induced by the leakage of aquaporin-4 (AQP4)-specific IgG into the central nervous system parenchyma, is a key feature of NMO pathology. We investigated the RGMa involvement in the pathology of NMO astrocytopathy, and tested a therapeutic potential of humanized anti-RGMa monoclonal antibody (RGMa-mAb). METHODS: Using a clinically relevant NMO rat model, we evaluated the therapeutic effect of a RGMa-mAb by behavioral testing, immunohistochemistry, and gene expression assay. We further performed in vitro experiments to address the RGMa-signaling in macrophages. RESULTS: In both NMO rats and an NMO-autopsied sample, RGMa was expressed by the spared neurons and astrocytes, whereas its receptor neogenin was expressed by infiltrating macrophages. AQP4-IgG-induced astrocytopathy and clinical exacerbation in NMO rats were ameliorated by RGMa-mAb treatment. RGMa-mAb treatment significantly suppressed neutrophil infiltration, and decreased the expression of neutrophil chemoattractants. Interestingly, neogenin-expressing macrophages accumulated in the lesion expressed CXCL2, a strong neutrophil chemoattractant, and further analysis revealed that RGMa directly regulated CXCL2 expression in macrophages. Finally, we found that our NMO rats developed neuropathic pain, and RGMa-mAb treatment effectively ameliorated the severity of neuropathic pain. INTERPRETATION: RGMa signaling in infiltrated macrophages is a critical driver of neutrophil-related astrocytopathy in NMO lesions, and RGMa-mAb may provide an efficient therapeutic strategy for NMO-associated neuropathic pain and motor deficits in patients with NMO. ANN NEUROL 2022;91:532-547.

Short-and long-latency afferent inhibition of the human leg motor cortex by H-reflex subthreshold electrical stimulation at the popliteal fossa.

In humans, peripheral sensory stimulation inhibits subsequent motor evoked potentials (MEPs) induced by transcranial magnetic stimulation; this process is referred to as short- or long-latency afferent inhibition (SAI or LAI, respectively), depending on the inter-stimulus interval (ISI) length. Although upper limb SAI and LAI have been well studied, lower limb SAI and LAI remain under-investigated. Here, we examined the time course of the soleus (SOL) muscle MEP following electrical tibial nerve (TN) stimulation at the popliteal fossa at ISIs of 20-220 ms. When the conditioning stimulus intensity was three-fold the perceptual threshold, MEP amplitudes were inhibited at an ISI of 220 ms, but not at shorter ISIs. TN stimulation just below the Hoffman (H)-reflex threshold intensity inhibited MEP amplitudes at ISIs of 30, 35, 100, 180 and 200 ms. However, the relationship between MEP inhibition and the P30 latency of somatosensory evoked potentials (SEPs) did not show corresponding ISIs at the SEP P30 latency that maximizes MEP inhibition. To clarify whether the site of afferent-induced MEP inhibition occurs at the cortical or spinal level, we examined the time course of SOL H-reflex following TN stimulation. H-reflex amplitudes were not significantly inhibited at ISIs where MEP inhibition occurred but at an ISI of 120 ms. Our findings indicate that stronger peripheral sensory stimulation is required for lower limb than for upper limb SAI and LAI and that lower limb SAI and LAI are of cortical origin. Moreover, the direct pathway from the periphery to the primary motor cortex may contribute to lower limb SAI.

F-waves induced by motor point stimulation are facilitated during handgrip and motor imagery tasks.

The F-wave is a motor response elicited via the antidromic firings of motor nerves by the electrical stimulation of peripheral nerves, which reflects the motoneuron pool excitability. However, the F-wave generally has low robustness i.e., low persistence and small amplitude. We recently found that motor point stimulation (MPS), which provides the muscle belly with electrical stimulation, shows different neural responses compared to nerve stimulation, e.g., MPS elicits F-waves more robustly than nerve stimulation. Here, we investigated whether F-waves induced by MPS can identify changes in motoneuron pool excitability during handgrip and motor imagery. Twelve participants participated in the present study. We applied MPS on their soleus muscle and recorded F-waves during eyes-open (EO), eyes-closed (EC), handgrip (HG), and motor imagery (MI) conditions. In the EO and EC conditions, participants relaxed with their eyes open and closed, respectively. In the HG, participants matched the handgrip force level to 30% of the maximum voluntary force with visual feedback. In the MI, they performed kinesthetic MI of plantarflexion at the maximal strength with closed eyes. In the HG and MI, the amplitudes of the F-waves induced by MPS were increased compared with those in the EO and EC, respectively. These results indicate that the motoneuron pool excitability was facilitated during the HG and MI conditions, consistent with findings in previous studies. Our findings suggest that F-waves elicited by MPS can be a good tool in human neurophysiology to assess the motoneuron pool excitability during cognitive and motor tasks.

Effects of trunk neuromuscular electrical stimulation on the motor circuits of able-bodied individuals.

Upper- and lower-limb neuromuscular electrical stimulation (NMES) is known to modulate the excitability of the neural motor circuits. However, it remains unclear whether short-duration trunk muscle NMES could achieve similar neuromodulation effects. We assessed motor evoked potentials (MEPs) elicited through transcranial magnetic stimulation of the primary motor cortex representation of the trunk extensor muscles to evaluate corticospinal excitability. Moreover, cervicomedullary motor evoked potentials (CMEPs) were assessed through cervicomedullary junction magnetic stimulation to evaluate subcortical excitability. Twelve able-bodied individuals participated in the MEP study, and another twelve in the CMEP study. During the interventions, NMES was applied bilaterally to activate the erector spinae muscle and produce intermittent contractions (20 s ON/20 s OFF) for a total of 20 min while participants remained seated. Assessments were performed: (i) before; (ii) during (in brief periods when NMES was OFF); and (iii) immediately after the interventions to compare MEP or CMEP excitability. Our results showed that MEP responses were not affected by trunk NMES, while CMEP responses were facilitated for approximately 8 min during the intervention, and returned to baseline before the end of the 20 min stimulating period. Our findings therefore suggest that short-duration NMES of the trunk extensor muscles likely does not affect the corticospinal excitability, but it has a potential to facilitate subcortical neural circuits immediately after starting the intervention. These findings indicate that short-duration application of NEMS may be helpful in rehabilitation to enhance neuromodulation of the trunk subcortical neural motor circuits.

Effects of dimension reduction of hyperspectral images in skin gross pathology.

BACKGROUND: Hyperspectral imaging (HSI) is an emerging modality for the gross pathology of the skin. Spectral signatures of HSI could discriminate malignant from benign tissue. Because of inherent redundancies in HSI and in order to facilitate the use of deep-learning models, dimension reduction is a common preprocessing step. The effects of dimension reduction choice, training scope, and number of retained dimensions have not been evaluated on skin HSI for segmentation tasks. MATERIALS AND METHODS: An in-house dataset of HSI signatures from pigmented skin lesions was prepared and labeled with histology. Eleven different dimension reduction methods were used as preprocessing for tumor margin detection with support vector machines. Cluster-wise principal component analysis (ClusterPCA), a new variant of PCA, was proposed. The scope of application for dimension reduction was also investigated. RESULTS: The components produced by ClusterPCA show good agreement with the expected optical properties of skin chromophores. Random forest importance performed best during classification. However, all methods suffered from low sensitivity and generalization. CONCLUSION: Investigation of more complex reduction and segmentation schemes with emphasis on the nature of HSI and optical properties of the skin is necessary. Insights on dimension reduction for skin tissue could facilitate the development of HSI-based systems for cancer margin detection at gross level.

Muscle synergy patterns as altered coordination strategies in individuals with chronic low back pain: a cross-sectional study.

BACKGROUND: Chronic low back pain (CLBP) is a highly prevalent disease with poorly understood underlying mechanisms. In particular, altered trunk muscle coordination in response to specific trunk tasks remains largely unknown. METHODS: We investigated the muscle synergies during 11 trunk movement and stability tasks in 15 healthy individuals (8 females and 7 males, aged 21. 3 (20.1-22.8) ± 0.6 years) and in 15 CLBP participants (8 females and 7 males, aged 20. 9 (20.2-22.6) ± 0.7 years) by recording the surface electromyographic activities of 12 back and abdominal muscles (six muscles unilaterally). Non-negative matrix factorization was performed to extract the muscle synergies. RESULTS: We found six trunk muscle synergies and temporal patterns in both groups. The high similarity of the trunk synergies and temporal patterns in the groups suggests that both groups share the common feature of the trunk coordination strategy. We also found that trunk synergies related to the lumbar erector spinae showed lower variability in the CLBP group. This may reflect the impaired back muscles that reshape the trunk synergies in the fixed structure of CLBP. Furthermore, the higher variability of trunk synergies in the other muscle regions such as in the latissimus dorsi and oblique externus, which were activated in trunk stability tasks in the CLBP group, represented more individual motor strategies when the trunk tasks were highly demanding. CONCLUSION: Our work provides the first demonstration that individual modular organization is fine-tuned while preserving the overall structures of trunk synergies and temporal patterns in the presence of persistent CLBP.

Evidence for basic units of upper limb muscle synergies underlying a variety of complex human manipulations.

Manipulations require complex upper limb movements in which the central nervous system (CNS) must deal with many degrees of freedom. Evidence suggests that the CNS utilizes motor primitives called muscle synergies to simplify the production of movements. However, the exact neural mechanism underlying muscle synergies to control a wide array of manipulations is not fully understood. Here, we tested whether there are basic units of muscle synergies that can explain a diverse range of manipulations. We measured the electromyographic activities of 20 muscles across the shoulder, elbow, and wrist and fingers during 24 manipulation tasks. As a result, nonnegative matrix factorization identified nine basic units of muscle synergies derived from the upper limb muscles that are shared across all tasks. The high similarity between muscle synergies of each of the 24 tasks and various combinations of nine basic unit muscle synergies in a single and/or merging state provides evidence that the CNS flexibly selects and modifies the degree of contribution of the nine basic units of muscle synergies to overcome different mechanical demands of tasks.NEW & NOTEWORTHY We expanded upon experiments that investigated motor modularity in upper limb movements in humans. The identification of modular features, including distinct functional muscle weightings, during highly variable manipulation tasks supports a hypothetical neural mechanism in which the CNS combines preexisting basic patterns of muscle synergies rather than framing new patterns to deal with behavioral diversity in the upper limb.

Corticospinal excitability and somatosensory information processing of the lower limb muscle during upper limb voluntary or electrically induced muscle contractions.

Neural interactions between upper and lower limbs underlie motor coordination in humans. Specifically, upper limb voluntary muscle contraction can facilitate spinal and corticospinal excitability of the lower limb muscles. However, little remains known on the involvement of somatosensory information in arm-leg neural interactions. Here, we investigated effects of voluntary and electrically induced wrist flexion on corticospinal excitability and somatosensory information processing of the lower limbs. In Experiment 1, we measured transcranial magnetic stimulation (TMS)-evoked motor evoked potentials (MEPs) of the resting soleus (SOL) muscle at rest or during voluntary or neuromuscular electrical stimulation (NMES)-induced wrist flexion. The wrist flexion force was matched to 10% of the maximum voluntary contraction (MVC). We found that SOL MEPs were significantly increased during voluntary, but not NMES-induced, wrist flexion, compared to the rest (P < .001). In Experiment 2, we examined somatosensory evoked potentials (SEPs) following tibial nerve stimulation under the same conditions. The results showed that SEPs were unchanged during both voluntary and NMES-induced wrist flexion. In Experiment 3, we examined the modulation of SEPs during 10%, 20% and 30% MVC voluntary wrist flexion. During 30% MVC voluntary wrist flexion, P50-N70 SEP component was significantly attenuated compared to the rest (P = .003). Our results propose that the somatosensory information generated by NMES-induced upper limb muscle contractions may have a limited effect on corticospinal excitability and somatosensory information processing of the lower limbs. However, voluntary wrist flexion modulated corticospinal excitability and somatosensory information processing of the lower limbs via motor areas.

Short-term facilitation effects elicited by cortical priming through theta burst stimulation and functional electrical stimulation of upper-limb muscles.

Non-invasive theta burst stimulation (TBS) can elicit facilitatory or inhibitory changes in the central nervous system when applied intermittently (iTBS) or continuously (cTBS). Conversely, neuromuscular electrical stimulation (NMES) can activate the muscles to send a sensory volley, which is also known to affect the excitability of the central nervous system. We investigated whether cortical iTBS (facilitatory) or cTBS (inhibitory) priming can affect subsequent NMES-induced corticospinal excitability. A total of six interventions were tested, each with 11 able-bodied participants: cortical priming followed by NMES (iTBS + NMES and cTBS + NMES), NMES only (iTBSsham + NMES and cTBSsham + NMES), and cortical priming only (iTBS + rest and cTBS + rest). After iTBS or cTBS priming, NMES was used to activate right extensor capri radialis (ECR) muscle intermittently for 10 min (5 s ON/5 s OFF). Single-pulse transcranial magnetic stimulation motor evoked potentials (MEPs) and maximum motor response (Mmax) elicited by radial nerve stimulation were compared before and after each intervention for 30 min. Our results showed that associative facilitatory iTBS + NMES intervention elicited greater MEP facilitation that lasted for at least 30 min after the intervention, while none of the interventions alone were effective to produce effects. We conclude that facilitatory iTBS priming can make the central nervous system more susceptible to changes elicited by NMES through sensory recruitment to enhance facilitation of corticospinal plasticity, while cTBS inhibitory priming efficacy could not be confirmed.

Prognostic significance of intrahepatic lymphatic invasion in colorectal liver metastases.

BACKGROUND: Intrahepatic lymphatic invasion is an adverse prognostic factor after hepatectomy for colorectal liver metastases (CLMs). However, most patients in previous reports had liver resection before the era of FOLFOX/FIRI-based chemotherapy. METHODS: Forty-six patients who underwent hepatectomy for CLMs from 2004 to 2020 were evaluated. We histologically evaluated portal invasion, intrahepatic lymphatic invasion, and biliary invasion on hematoxylin-eosin slides. We also collected the following clinicopathologic factors: gender, age, timing, the number and maximum size of CLMs, preoperative tumor markers, neutrophil/lymphocyte ratio, location, and lymph node metastases of primary cancer, and chemotherapy after hepatectomy. A multivariate Cox proportional hazard model was used to define the relationship between overall (OS) or disease-free survival (DFS) and clinicopathologic factors. RESULTS: Histological invasions were portal invasion in 8 (17.4 %), intrahepatic lymphatic invasion in 6 (13.0 %), and biliary invasion in 5 (10.9 %). Chemotherapy for recurrence after hepatectomy (n = 29) was performed in 22 and 14 of those who received FOLFOX/FIRI-based chemotherapy. By multivariate analysis, the number of CLMs (p < 0. 01) and presence of intrahepatic lymphatic invasion (p = 0.02) were independent predictors of recurrence. The number of CLMs (p = 0.02) and prehepatectomy carcinoembryonic antigen level (p = 0.02), but not intrahepatic lymphatic invasion (p = 0.18), were independent predictors of survival using multivariate analysis. CONCLUSIONS: The presence of intrahepatic lymphatic invasion adversely affected patient's DFS, but not OS in patients with CLMs in the era of FOLFOX/FIRI chemotherapy. FOLFOX/FIRI-based chemotherapy might improve OS, even in patients with positive intrahepatic lymphatic invasion.

Flexible Recruitments of Fundamental Muscle Synergies in the Trunk and Lower Limbs for Highly Variable Movements and Postures.

The extent to which muscle synergies represent the neural control of human behavior remains unknown. Here, we tested whether certain sets of muscle synergies that are fundamentally necessary across behaviors exist. We measured the electromyographic activities of 26 muscles, including bilateral trunk and lower limb muscles, during 24 locomotion, dynamic and static stability tasks, and we extracted the muscle synergies using non-negative matrix factorization. Our results show that 13 muscle synergies that may have unique functional roles accounted for almost all 24 tasks by combinations of single and/or merging of synergies. Therefore, our results may support the notion of the low dimensionality in motor outputs, in which the central nervous system flexibly recruits fundamental muscle synergies to execute diverse human behaviors. Further studies are required to validate the neural representation of the fundamental components of muscle synergies.

Interlimb neural interactions in corticospinal and spinal reflex circuits during preparation and execution of isometric elbow flexion.

Although coordinated and simultaneous movement of upper and lower limb muscles is required for activities of daily living, interlimb neural interaction mechanisms and their nature are yet to be fully elucidated. The purpose of this study was to investigate effects of motor preparation and execution of ipsilateral, contralateral, and bilateral upper limb muscle contractions on the excitability of corticospinal and spinal reflex circuits of the lower limb muscles. Fourteen able-bodied individuals were recruited in each study. Experiments were conducted to investigate 1) corticospinal excitability with transcranial magnetic stimulation applied on the primary motor cortex to evoke motor evoked potentials (MEPs) and 2) spinal reflex excitability with transcutaneous spinal cord stimulation applied at the lumbothoracic level to evoke spinal reflexes. Measurements were recorded from multiple right lower limb muscles simultaneously during 1) ipsilateral (right), 2) contralateral (left), and 3) bilateral (right and left) elbow flexion. The results indicate that MEPs in lower limb muscles were facilitated during both preparation and execution of elbow flexion, whereas spinal reflexes were facilitated only during motor execution. Moreover, the extent of facilitation did not differ between right, left, and bilateral contractions. In conclusion, motor preparation for upper limb muscle contractions did not affect spinal circuits but seemed to affect the supraspinal networks controlling lower limb muscles. However, actual contraction (motor execution) of upper limb muscles is required to facilitate spinal reflex circuits controlling the lower limb muscles. Moreover, interlimb remote facilitation in corticospinal and spinal reflex circuits did not depend on whether contralateral or ipsilateral hands were contracted or if they were contracted bilaterally.NEW & NOTEWORTHY We found that upper limb muscle contractions facilitated corticospinal circuits controlling lower limb muscles even during motor preparation, whereas motor execution of the task was required to facilitate spinal circuits. We also found that facilitation did not depend on whether contralateral or ipsilateral hands were contracted or if they were contracted bilaterally. Overall, these findings suggest that training of unaffected upper limbs may be useful to enhance facilitation of affected lower limbs in paraplegic individuals.

Changes in corticospinal excitability during bilateral and unilateral lower-limb force control tasks.

Ankle dorsiflexion force control is essential for performing daily living activities. However, the involvement of the corticospinal pathway during different ankle dorsiflexion tasks is not well understood. The objective of this study was to compare the corticospinal excitability during: (1) unilateral and bilateral; and (2) ballistic and tonic ankle dorsiflexion force control. Fifteen healthy young adults (age: 25.2 ± 2.8 years) participated in this study. Participants performed unilateral and bilateral isometric ankle dorsiflexion force-control tasks, which required matching a visual target (10% of maximal effort) as quickly and precisely as possible during ballistic and tonic contractions. Transcranial magnetic stimulation (TMS) was applied over the primary motor cortex to elicit motor-evoked potentials (MEPs) from the right tibialis anterior during: (i) pre-contraction phase; (ii) ascending contraction phase; (iii) plateau phase (tonic tasks only); and (iv) resting phase (control). Peak-to-peak MEP amplitude was computed to compare the corticospinal excitability during each experimental condition. MEP amplitudes significantly increased during unilateral contraction compared to bilateral contraction in the pre-contraction phase. There were no significant differences in the MEP amplitudes between the ballistic tasks and tonic tasks in any parts of the contraction phase. Although different strategies are required during ballistic and tonic contractions, the extent of corticospinal involvement appears to be similar. This could be because both tasks enhance the preparation for precise force control. Furthermore, our results suggest that unilateral muscle contractions may largely facilitate the central nervous system during movement preparation for unilateral force control compared to bilateral muscle contractions.

On the reflex mechanisms of cervical transcutaneous spinal cord stimulation in human subjects.

Transcutaneous and epidural electrical spinal cord stimulation techniques are becoming more valuable as electrophysiological and clinical tools. Recently, remarkable recovery of the upper limb sensorimotor function during cervical spinal stimulation was demonstrated. In the present study, we sought to elucidate the neural mechanisms underlying the effects of transcutaneous spinal cord stimulation (tSCS) of the cervical spine. We hypothesized that cervical tSCS can be used to selectively activate the sensory route entering the spinal cord and transsynaptically converge on upper limb motor pools. To test this hypothesis, we applied cervical tSCS using paired stimuli (homosynaptic depression) and during passive muscle stretching of the wrist flexor (presynaptic inhibition via Ia afferents), voluntary hand muscle contraction (descending facilitation of motoneuron pool), and muscle-tendon vibration of the wrist (presynaptic inhibition via afferent occlusion). Our results demonstrate significant inhibition of the second evoked response during paired stimulus delivery, inhibition of responses during passive muscle stretching and muscle-tendon vibration, and facilitation during voluntary muscle contraction, which share similarities with responses evoked during lumbosacral tSCS. These results indicate that the route of the stimulation current transmission passes via afferents in the dorsal roots through the spinal cord to activate the motor pools and potentially interneuronal networks projecting to upper limb muscles. Using a novel stimulation paradigm, our study is the first to present evidence of the sensory neuronal pathway of the cervical tSCS propagation. Overall, our work demonstrates the utility and sensitivity of cervical tSCS to engage the sensory pathway projecting to the upper limbs. NEW & NOTEWORTHY Despite therapeutic effects that have been demonstrated previously using noninvasive cervical spinal stimulation, it has been unclear whether, and to what degree, the stimulation can activate the sensory afferent system. Our study presents evidence that cervical transcutaneous spinal cord stimulation can engage the sensory pathways and transsynaptically converge on motor pools projecting to upper limb muscles, demonstrating the utility and sensitivity of cervical spinal stimulation for electrophysiological assessments and neurorehabilitation.