Intrinsically organized resting state networks in the human spinal cord

Spontaneous fluctuations in functional magnetic resonance imaging (fMRI) signals of the brain have repeatedly been observed when no task or external stimulation is present. These fluctuations likely reflect baseline neuronal activity of the brain and correspond to functionally relevant resting-state networks (RSN). It is not known however, whether intrinsically organized and spatially circumscribed RSNs also exist in the spinal cord, the brain’s principal sensorimotor interface with the body. Here, we use recent advances in spinal fMRI methodology and independent component analysis to answer this question in healthy human volunteers. We identified spatially distinct RSNs in the human spinal cord that were clearly separated into dorsal and ventral components, mirroring the functional neuroanatomy of the spinal cord and likely reflecting sensory and motor processing. Interestingly, dorsal (sensory) RSNs were separated into right and left components, presumably related to ongoing hemibody processing of somatosensory information, whereas ventral (motor) RSNs were bilateral, possibly related to commissural interneuronal networks involved in central pattern generation. Importantly, all of these RSNs showed a restricted spatial extent along the spinal cord and likely conform to the spinal cord’s functionally relevant segmental organization. Although the spatial and temporal properties of the dorsal and ventral RSNs were found to be significantly different, these networks showed significant interactions with each other at the segmental level. Together, our data demonstrate that intrinsically highly organized resting-state fluctuations exist in the human spinal cord and are thus a hallmark of the entire central nervous system.Functional magnetic resonance imaging (fMRI) has been used to study the functional connectivity of the human brain, with spontaneous fluctuations in the resting-state fMRI signal (1–3) attracting much attention in the past few years (for review, see refs. 4–6). Brain regions showing temporally coherent spontaneous fluctuations constitute several anatomically consistent “resting state networks” (RSNs), such as visual, auditory, sensory-motor, executive control, and default mode networks (7–11). Consequently, analyses of RSNs are rapidly emerging as a powerful tool for in vivo mapping of neural circuitry in the human brain and one such approach for exploring RSNs is independent component analysis (ICA) (12–14). ICA decomposes the data into spatially independent and temporally coherent source signals/components. The advantage of ICA over more traditional seed-based approaches (15) is that it is a model-free, data-driven multiple-regression approach, i.e., within the ICA framework we can account for multiple underlying signal contributions (artifactual or neuronal in origin) simultaneously and thereby disentangle these different contributions to the measured observations (16). To date, ICA has been used not only to characterize brain connectivity in healthy adults (7, 10, 17), but also to assess the development of brain connectivity at various stages of (18, 19) as well as across the lifespan (20) and to investigate connectivity alterations in clinical populations (21–24).Here, we use this approach to investigate the intrinsic organization of RSNs in the human spinal cord. The spinal cord is the first part of the central nervous system (CNS) involved in the transmission of somatosensory information from the body periphery to the brain, as well as the last part of the CNS involved in relaying motor signals to the body periphery. This functional separation is also evident in the anatomical organization of the spinal cord, with the ventral part of gray matter involved in motor function and the dorsal part involved in somatosensory processing. The corresponding pairs of ventral and dorsal nerve roots convey information to and from the body periphery with a rostro-caudal topographical arrangement for both sensory (dermatomes) and motor innervation (myotomes).Although such a precise anatomical layout would suggest clear organizational principles for intrinsic spinal cord networks (similar to e.g., the visual and auditory RSNs in the brain), it is not known whether spatially consistent RSNs exist in the spinal cord. Distinct spatial maps due to cardiac and respiratory noise sources have been revealed by single subject ICA (25–27), and a seed-based approach demonstrated correlations between ventral horns and between dorsal horns (28), but no group patterns of circumscribed motor or sensory networks have yet been found; also only a few investigations of task-based functional connectivity have been performed (29–31). One reason for the apparent lack of relevant data is that fMRI is more challenging to perform in the spinal cord than in the brain (32, 33). The difficulties faced are mostly due to its small cross-sectional area (∼1 cm², necessitating the use of small voxel sizes, which leads to a low signal-to-noise ratio), magnetic susceptibility differences in tissues adjacent to the cord, e.g., vertebral bodies and spinous processes (causing signal loss and image distortion), as well as the influence of physiological noise (obscuring neuronally induced signal changes).Here, we used recent improvements in spinal fMRI [i.e., acquisition techniques that mitigate magnetic susceptibility differences (34), validated procedures for physiological noise reduction (35, 36) and techniques that allow voxel-wise group analyses (37, 38)] to overcome these difficulties and investigate the organizational principles of RSNs in the human spinal cord. We hypothesized that dorsal and ventral regions of the spinal cord would show different patterns of resting activity and furthermore investigated whether the segmental organization of the spinal cord would be evident in the rostro-caudal spatial layout of spinal RSNs.     

Integrated strategy for improving functional connectivity mapping using multiecho fMRI

Functional connectivity analysis of resting state blood oxygen level–dependent (BOLD) functional MRI is widely used for noninvasively studying brain functional networks. Recent findings have indicated, however, that even small (≤1 mm) amounts of head movement during scanning can disproportionately bias connectivity estimates, despite various preprocessing efforts. Further complications for interregional connectivity estimation from time domain signals include the unaccounted reduction in BOLD degrees of freedom related to sensitivity losses from high subject motion. To address these issues, we describe an integrated strategy for data acquisition, denoising, and connectivity estimation. This strategy builds on our previously published technique combining data acquisition with multiecho (ME) echo planar imaging and analysis with spatial independent component analysis (ICA), called ME-ICA, which distinguishes BOLD (neuronal) and non-BOLD (artifactual) components based on linear echo-time dependence of signals—a characteristic property of BOLD signal changes. Here we show for 32 control subjects that this method provides a physically principled and nearly operator-independent way of removing complex artifacts such as motion from resting state data. We then describe a robust estimator of functional connectivity based on interregional correlation of BOLD-independent component coefficients. This estimator, called independent components regression, considerably simplifies statistical inference for functional connectivity because degrees of freedom equals the number of independent coefficients. Compared with traditional connectivity estimation methods, the proposed strategy results in fourfold improvements in signal-to-noise ratio, functional connectivity analysis with improved specificity, and valid statistical inference with nominal control of type 1 error in contrasts of connectivity between groups with different levels of subject motion.     

Modular origins of high-amplitude cofluctuations in fine-scale functional connectivity dynamics

The topology of structural brain networks shapes brain dynamics, including the correlation structure of brain activity (functional connectivity) as estimated from functional neuroimaging data. Empirical studies have shown that functional connectivity fluctuates over time, exhibiting patterns that vary in the spatial arrangement of correlations among segregated functional systems. Recently, an exact decomposition of functional connectivity into frame-wise contributions has revealed fine-scale dynamics that are punctuated by brief and intermittent episodes (events) of high-amplitude cofluctuations involving large sets of brain regions. Their origin is currently unclear. Here, we demonstrate that similar episodes readily appear in silico using computational simulations of whole-brain dynamics. As in empirical data, simulated events contribute disproportionately to long-time functional connectivity, involve recurrence of patterned cofluctuations, and can be clustered into distinct families. Importantly, comparison of event-related patterns of cofluctuations to underlying patterns of structural connectivity reveals that modular organization present in the coupling matrix shapes patterns of event-related cofluctuations. Our work suggests that brief, intermittent events in functional dynamics are partly shaped by modular organization of structural connectivity.

Structural and functional brain networks exhibit complex topology, and functional brain networks display rich temporal dynamics (1–3). The topological organization of structural connectivity (SC; the connectome) is characterized by broad degree distributions, hubs linked into cores and rich clubs, and multiscale modularity (4–6). Functional connectivity (FC), as measured with resting-state functional MRI (fMRI), displays consistent system-level architecture (7–9) as well as fluctuating dynamics (10–12) and complex spatiotemporal state transitions (13, 14). Resting brain dynamics exhibit metastable behavior. The lack of a fixed attractor allows for exploration of a large repertoire of network states and configurations (15–17).Recent work has uncovered fine-scale dynamics of FC as measured with fMRI during rest and passive movie watching (18, 19). The approach leverages an exact decomposition of averaged FC estimates into patterns of edge cofluctuations resolved at the timescale of single image frames (20). These studies reveal that ongoing activity is punctuated by brief, intermittent, high-amplitude bursts of brain-wide cofluctuations of the blood-oxygenation level–dependent (BOLD) signal. The approach is reminiscent of an earlier approach proposed for electroencephalography (EEG) data in which an exact frame-wise analysis of modeled and human scalp EEG data using the Hilbert transform revealed brief large-scale desynchronous bursts (21). In the BOLD literature, episodes of high-amplitude cofluctuations, referred to as “events,” drive long-time estimates of FC and represent patterns with consistent topography across time and across individuals (18, 19, 22). The occurrence of events appears unrelated to nonneuronal physiological processes, head motion, or acquisition artifacts. A better understanding of how events originate may illuminate the basis for individual differences in FC and its variation across cognitive state, development, and disorders. Here, we aim to provide a generative model for the origin of events in neuronal time series and uncover potential structural bases for their emergence in fine-scale dynamics.The relationship of structure to function has been a central objective of numerous empirical and computational studies, leveraging cellular population recordings (23, 24), electrophysiological (25), and neuroimaging techniques (26–28). While there is broad consensus that “structure shapes function” on long timescales (29, 30), relating specific dynamic features to the topology of the underlying structural network is an open problem. Computational models have made important contributions to understanding how SC (31, 32), time delays, and noisy fluctuations (33) contribute to patterns of FC as estimated over long and short timescales. Model implementations range from biophysically based neural mass models to much simpler phase oscillators such as the Kuramoto model (34). Despite their overt simplicity, phase oscillator models can generate a wide range of complex synchronization and coordination states, and they reproduce patterns of empirical FC (35), including temporal dynamics at intermediate timescales (36). These modeled dynamics reproduce ongoing fluctuations between integrated (less modular) and segregated (more modular) network states (37, 38), a key characteristic of empirical fMRI resting-state dynamics (39).Here, we pursue a computational modeling approach that seeks to relate high-amplitude cofluctuations to whole-brain network structure. We simulate spontaneous BOLD signal dynamics on an empirical SC matrix of the human cerebral cortex using an implementation of a coupled phase oscillator model incorporating phase delays, the Kuramoto–Sakaguchi (KS) model (40). The KS model is well suited for this purpose because its parsimonious parametrization allows for drawing specific links between network structure and synchronization patterns. The KS model also allows simulation focused on a specific frequency band of interest so that it can more closely replicate the oscillatory behavior of neural populations often found in the gamma band (41). We find that over broad parameter ranges, BOLD signals exhibit significant high-amplitude network-wide fluctuations strongly resembling intermittent events observed in empirical data. Model dynamics reproduce several key characteristics of empirical events, including their strong contribution to long-time averages of FC as well as recurrent patterns across time. Simulated events are significantly related to network structure. They fall into distinct clusters aligned with different combinations of modules in underlying SC. Disruption of structural modules largely abolishes the occurrence of events in BOLD dynamics. These findings suggest a modular origin of high-amplitude cofluctuations in fine-scale FC dynamics.     

Increased functional connectivity indicates the severity of cognitive impairment in multiple sclerosis

Correlations in spontaneous brain activity provide powerful access to large-scale organizational principles of the CNS. However, making inferences about cognitive processes requires a detailed understanding of the link between these couplings and the structural integrity of the CNS. We studied the impact of multiple sclerosis, which leads to the severe disintegration of the central white matter, on functional connectivity patterns in spontaneous cortical activity. Using a data driven approach based on the strength of a salient pattern of cognitive pathology, we identified distinct networks that exhibit increases in functional connectivity despite the presence of strong and diffuse reductions of the central white-matter integrity. The default mode network emerged as a core target of these connectivity modulations, showing enhanced functional coupling in bilateral inferior parietal cortex, posterior cingulate, and medial prefrontal cortex. These findings imply a complex and diverging relation of anatomical and functional connectivity in early multiple sclerosis and, thus, add an important observation for understanding how cognitive abilities and CNS integrity may be reflected in the intrinsic covariance of functional signals.     

Melatonin regulates matrix metalloproteinases after traumatic experimental spinal cord injury

Abstract:  The matrix metalloproteinases (MMPs) are important enzymes that regulate developmental processes, maintain normal physiology in adulthood and have reparative roles at specific stages after an insult to the nervous system. MMPs, particularly MMP-9/gelatinase B, promote early inflammation and barrier disruption after spinal cord injury (SCI). Recently, we have reported that the pineal secretory product melatonin exerts important anti-inflammatory effects in an experimental model of SCI induced by the application of vascular clips (force of 24 g) to the dura after a four-level T5–T8 laminectomy. However, no reports are available on the relationship between the activity of MMPs and melatonin's anti-inflammatory effects. The aim of the present study was to evaluate whether the protective effect of melatonin observed in SCI is related to the regulation of MMP-9 and MMP-2 in mice. Biochemical and zymographic methods were used to analyze MMP-9 and -2 expression and activities in spinal cord tissue from SCI-treated mice at 24 hr after the trauma. Our studies reveal that melatonin reduced SCI and lipid peroxidation in spinal cord at 24 hr after SCI. Melatonin also diminished proMMP-9 and -2 activities that were induced in the spinal cord tissues at 24 hr after SCI. The reduced activities of MMP-9 and -2 were associated with depressed expression of TNF-α. We propose that melatonin's ability to reduce SCI in mice is also related to a reduction in MMP-9 and MMP-2 activity and expression.     

Brain-wide functional connectivity of face patch neurons during rest

The brain is a highly organized, dynamic system whose network architecture is often assessed through resting functional magnetic resonance imaging (fMRI) functional connectivity. The functional interactions between brain areas, including those observed during rest, are assumed to stem from the collective influence of action potentials carried by long-range neural projections. However, the contribution of individual neurons to brain-wide functional connectivity has not been systematically assessed. Here we developed a method to concurrently measure and compare the spiking activity of local neurons with fMRI signals measured across the brain during rest. We recorded spontaneous activity from neural populations in cortical face patches in the macaque during fMRI scanning sessions. Individual cells exhibited prominent, bilateral coupling with fMRI fluctuations in a restricted set of cortical areas inside and outside the face patch network, partially matching the pattern of known anatomical projections. Within each face patch population, a subset of neurons was positively coupled with the face patch network and another was negatively coupled. The same cells showed inverse correlations with distinct subcortical structures, most notably the lateral geniculate nucleus and brainstem neuromodulatory centers. Corresponding connectivity maps derived from fMRI seeds and local field potentials differed from the single unit maps, particularly in subcortical areas. Together, the results demonstrate that the spiking fluctuations of neurons are selectively coupled with discrete brain regions, with the coupling governed in part by anatomical network connections and in part by indirect neuromodulatory pathways.

Normal brain function entails a complex interplay among neural networks operating at multiple spatial and temporal scales (1, 2). In the last decades, functional magnetic resonance imaging (fMRI) has enabled researchers to noninvasively study the structure and organization of these neural networks through resting state fMRI (rs-fMRI). This analysis uses the covariation of spontaneous fluctuations across the brain to identify functionally connected regions (3, 4) that together constitute a functional network (5, 6). Importantly, the networks revealed by this analysis often resemble those derived from task-based studies, such as those involving motor action (6), cognitive operation (7), or perceptual experience (8).Despite the widespread use of fMRI-based functional connectivity in humans, its neural basis has not been studied systematically in animals, where local neural circuit activity can be assessed via invasive methodologies. The absence of research in this area can be understood, in part, by the significant challenges associated with concurrently measuring neural and fMRI signals. In the macaque, a few studies have used simultaneous measurement of neural and fMRI signals to study spontaneous activity, for example, comparing spontaneous field potential fluctuations to regional fMRI activity (9) or to global fMRI fluctuations (10). One experiment went further by mapping the brain-wide coupling of spontaneous field potential events linked to particular cognitive operations (11). These studies, though inherently limited by the different spatiotemporal scales of neural and hemodynamic signals (12), have been valuable for assessing how local neural information is coupled with activity elsewhere in the brain.The contribution of individual neurons in functional connectivity is unclear. The observed spatiotemporal correlations are probably constrained by the pattern of axonal connections, which permit the direct exchange of signals across remote brain areas. However, the relationship between functional connectivity and anatomical connections is imprecise (13, 14). Moreover, the functional connectivity of individual neurons, such as those populating an rs-fMRI voxel, has not been studied. Cortical neurons, like fMRI voxels, exhibit large-amplitude, slow fluctuations in their spiking over time scales of many seconds (15). Do these spiking fluctuations underlie the spatiotemporal correlations measured with rs-fMRI? If so, how would the functional connectivity computed from a given neuron compare to that of a neighboring neuron, to the local field potential (LFP), and to locally measured fMRI signal obtained from the same tissue? Ideally, these questions would be best addressed in the context of an fMRI network whose neurophysiology and anatomy are well studied.The face patch system in the macaque is a network of regions in the inferior temporal cortex defined by its selective visual responses to faces (16, 17). These face patches are composed of circumscribed clusters of cells that have been implicated in the structural analysis of faces (18–21). Previous work has investigated the anatomical (22, 23) and fMRI functional (8) connectivity of face patches to demonstrate a highly interconnected network. Based on these results, one might expect that the neurons within individual nodes of this network would show activity correlations with a restricted set of areas and most strongly with other face patches. However, in some modes of visual stimulation this is not the case. For example, during the viewing of naturalistic movies, face patch neurons exhibited varied patterns of correlated activity with visually driven networks, with neighboring neurons often yielding highly distinct correlation maps (24, 25). These results prompt the question of whether neurons in a face patch population would show a restricted and homogeneous pattern of functional connectivity across the brain at rest or whether they would exhibit a high level of diversity in their brain-wide functional connectivity.In the present study, we investigated the resting state functional connectivity of individual neurons by recording from local neural populations in the anterior fundus (AF) and anterior medial (AM) face patches. Concurrent single unit recordings and fMRI were carried out in darkness inside the scanner bore, with animals at rest and not performing any task. We created brain-wide correlation maps by comparing ongoing spiking fluctuations of isolated neurons with fMRI time courses across the brain, in a method akin to seed-based fMRI functional connectivity. The results revealed prominent fMRI coupling across a restricted set of cortical areas, with the strongest correlations observed with voxels in the face patch network, V4, TEO, and the ventral premotor cortex. Neurons within each local population and across the two face patches exhibited a high level of overlap in their pattern of functional connectivity. Unexpectedly, the same neurons showed a strong inverse correlation with the lateral geniculate nucleus (LGN) and brainstem neuromodulatory centers, a feature that was absent in corresponding maps computed from the LFP or fMRI seed voxel derived from the same recording locations.     

Similarity in functional brain connectivity at rest predicts interpersonal closeness in the social network of an entire village

People often have the intuition that they are similar to their friends, yet evidence for homophily (being friends with similar others) based on self-reported personality is inconsistent. Functional connectomes—patterns of spontaneous synchronization across the brain—are stable within individuals and predict how people tend to think and behave. Thus, they may capture interindividual variability in latent traits that are particularly similar among friends but that might elude self-report. Here, we examined interpersonal similarity in functional connectivity at rest—that is, in the absence of external stimuli—and tested if functional connectome similarity is associated with proximity in a real-world social network. The social network of a remote village was reconstructed; a subset of residents underwent functional magnetic resonance imaging. Similarity in functional connectomes was positively related to social network proximity, particularly in the default mode network. Controlling for similarities in demographic and personality data (the Big Five personality traits) yielded similar results. Thus, functional connectomes may capture latent interpersonal similarities between friends that are not fully captured by commonly used demographic or personality measures. The localization of these results suggests how friends may be particularly similar to one another. Additionally, geographic proximity moderated the relationship between neural similarity and social network proximity, suggesting that such associations are particularly strong among people who live particularly close to one another. These findings suggest that social connectivity is reflected in signatures of brain functional connectivity, consistent with the common intuition that friends share similarities that go beyond, for example, demographic similarities.

Human social networks exhibit a high degree of homophily, such that individuals who are close together in their social network (i.e., friends or friends of friends, rather than people further removed from one another in social ties) tend to be exceptionally similar to one another with respect to physical and demographic traits, such as age, gender, and ethnicity (1). Yet, a common intuition is that friends are similar to each other in ways that go beyond readily observable and relatively coarse characteristics, such as demographics. The most common method to assess such similarities is the administration of self-report surveys measuring how people tend to think and behave (i.e., personality). However, past research has found no evidence, or only relatively weak evidence, for a relationship between similarity in personality and social network proximity (e.g., refs. 2 and 3).A separate body of research using functional MRI (fMRI) has shown that patterns of functional brain connectivity at rest comprise person-specific “fingerprints” that capture interindividual variability in a wide range of social, cognitive, and behavioral tendencies and capacities (4–10). These resting-state “functional connectomes” have also been shown to be predictive of individual differences in self-reported personality (11). Given that functional connectomes are predictive of an array of cognitive and behavioral phenotypes, interindividual similarities in functional connectomes may reflect similarities in how friends, and more generally people close to one another in their social network, think and behave. Such similarities may include those that are not sufficiently captured by widely used self-report surveys, such as measures of personality. Thus, fMRI can provide a window into the types of latent similarities that are associated with friendship. This approach is particularly promising given recent research integrating task-based fMRI and social network analysis, which has shown, for example, that when viewing videos, friends, and more generally, people closer together in their real-world social network, have exceptionally similar neural responses, which could be indicative of similarities in how friends attend to (12), understand (13), and interpret (14) the world (15, 16). Taken together with other recent work (17), these findings highlight the promise of integrating social network analysis and tools from cognitive neuroscience to improve our understanding of how individuals shape and are shaped by the real-world social networks in which they are embedded.Here, we tested if patterns of neural responding at rest (e.g., individuals’ functional connectomes) are associated with proximity between individuals in the social network of an entire village (Fig. 1). Specifically, we tested the hypothesis that greater similarity in individuals’ functional connectomes would be associated with greater proximity between those individuals in the social network. Given the large body of research demonstrating that links between interpersonal similarity in a number of cognitive, affective, and behavioral outcomes and social network proximity disappear beyond three or four “degrees of separation” (18–26), we focused our analyses on people four or fewer “degrees of separation” from one another in the village’s social network (Materials and Methods). We also tested if such relationships would persist after controlling not only for similarities in demographic characteristics but also for similarities in self-reported personality (i.e., the Big Five personality traits: extraversion, neuroticism, agreeableness, conscientiousness, and openness/intellect), which are thought to capture stable individual differences in people’s cognitive, affective, and behavioral tendencies (27). Although self-report personality questionnaires capture much variation in how people tend to think and behave, there is considerable variance in such tendencies that is unaccounted for by such questionnaires (28) and that may be encoded in individuals’ functional connectomes. Here, we tested if similarity in such latent traits is associated with proximity in a friendship network. Additionally, we examined which brain networks were particularly strongly associated with social network proximity to inform interpretations of the psychological significance of these results, as well as predictions for future research. Finally, given the well-established relationship between the physical distance between people and their distance from one another in social ties, we tested if geographic distance moderates the relationship between neural similarity and social network proximity.Open in a separate windowFig. 1.Social network characterization. Residents of a rural village located on a small island completed a survey in which they indicated their social ties with other individuals in their community. The complete social network (n = 798) of the village was reconstructed using this data, and a subset of residents (red nodes; n = 64) participated in the fMRI study. Lines (“edges”) indicate the existence of a reciprocated or unreciprocated social tie between individuals. For visualization purposes, unweighted edges were used to depict social ties. However, in our analyses, edges were weighted by individuals’ ratings of emotional closeness with one another (Materials and Methods).     

慢性脊髓压迫减压后脊髓缺血再灌注损伤的动物实验研究

目的探讨慢性脊髓压迫减压后是否存在再灌注损伤,以及脊髓压迫程度与再灌注损伤的关系。方法选择新西兰兔96只,随机分成A、B、C、D4组,每组又分为2个亚组,每个亚组12只。A组为假手术组,B组椎管内占位50%,C组为椎管内占位60%,D组为椎管内占位70%。B1、C1、D1组不取螺钉,B2、C2、D2组取出螺钉后6h分别进行改良Tarlov评分及MDA含量、GSH-px活性、SOD活性测定,TUNEL阳性细胞计数。结果 Tarlov评分A组显著高于B、C、D组（P均〈0.05）;B1、C1、D1组Tarlov评分依次减低（P均〈0.05）,B2、C2组Tarlov评分高于B1、C1组（P均〈0.05）。C1、D1组与A1组比较,D2组与D1组比较,MDA表达明显增高（P〈0.05或〈0.01）。C1组、D1组与A1组比较,D2组与D1组比较,SOD和GSH-px活性降低明显（P〈0.05或〈0.01）。结论慢性脊髓压迫减压后可以出现缺血再灌注损伤,且脊髓压迫程度越重,再灌注损伤越显著。     

Intraoperative finding and management of complete spinal cord transection after thoracolumbar traumatic fracture-dislocation: A case report

Rationale:We report the first case of the management of spinal cord transection due to thoracolumbar fracture-dislocation in human beings. There are several case reports of cord transection, but only radiological findings have been reported; we report intraoperative findings and management.Patient concerns:A 53-year-old man presented to the hospital after falling. He had no motor power or sensation below T10 (below the umbilicus area) dermatome level. American Spinal Injury Association (ASIA) impairment scale was grade A. Magnetic resonance imaging and computed tomography demonstrated a fracture and translation of the vertebral body at the T11-T12 level and anterior displacement of T11 on T12, with complete disruption of the spinal cord.Diagnosis:Complete spinal cord resection due to T11-T12 fracture-dislocation.Interventions:We performed spinal fusion with pedicle screw instrumentation (T10-L1) and autobone graft and decompression and repaired the dural sac to prevent cerebrospinal fluid leakage. There was no neurological recovery either immediately or 4 years post-operation at follow-up.Conclusion:To the best of our knowledge, this report is the first on the intraoperative finding and management of the complete transection of the spinal cord in thoracolumbar spine injury. Perfect fusion is required to facilitate rehabilitation and daily living, prevent neurogenesis, and prevent unnecessary pain such as phantom pain.     

Melatonin treatment protects against spinal cord injury induced functional and biochemical changes in rat urinary bladder

Oxidative stress induced by spinal cord injury (SCI) has deleterious effects on the function of several organ systems including the urinary bladder. In this study, we investigated the possible protective actions of melatonin on SCI-induced oxidative damage and urinary bladder dysfunction. Wistar albino rats (n = 24) were divided randomly as control, vehicle- or melatonin (10 mg/kg, ip)-treated SCI groups. To induce SCI, a standard weight-drop method that induced a moderately severe injury at T10 was used. Injured animals were given either vehicle or melatonin 15 min postinjury. One week postinjury, each rat was neurologically examined and then decapitated; blood samples were taken to evaluate neuron-specific enolase (NSE) and soluble protein 100β (S-100β). Spinal cord (SC) and urinary bladder samples were taken for functional studies and histological examination or stored for the measurement of malondialdehyde (MDA), glutathione (GSH) and nerve growth factor (NGF) levels and caspase-3 activity. Isometric contractions in bladder strips were induced by carbachol. In the SCI rats, decreased contractile responses of the bladder strips were found to be restored by melatonin treatment. Serum S-100β levels and NSE activities and tissue MDA levels and caspase-3 activities, all of which were elevated in the vehicle-treated SCI animals as compared to the control values, were reversed by melatonin treatment. On the other hand, reduced GSH and NGF levels due to SCI were restored by melatonin treatment. Furthermore, melatonin treatment improved histological findings. These findings suggest that melatonin reduces SCI-induced tissue injury and improves bladder functions through its effects on oxidative stress and NGF.     

Metabolic connectivity mapping reveals effective connectivity in the resting human brain

Directionality of signaling among brain regions provides essential information about human cognition and disease states. Assessing such effective connectivity (EC) across brain states using functional magnetic resonance imaging (fMRI) alone has proven difficult, however. We propose a novel measure of EC, termed metabolic connectivity mapping (MCM), that integrates undirected functional connectivity (FC) with local energy metabolism from fMRI and positron emission tomography (PET) data acquired simultaneously. This method is based on the concept that most energy required for neuronal communication is consumed postsynaptically, i.e., at the target neurons. We investigated MCM and possible changes in EC within the physiological range using “eyes open” versus “eyes closed” conditions in healthy subjects. Independent of condition, MCM reliably detected stable and bidirectional communication between early and higher visual regions. Moreover, we found stable top-down signaling from a frontoparietal network including frontal eye fields. In contrast, we found additional top-down signaling from all major clusters of the salience network to early visual cortex only in the eyes open condition. MCM revealed consistent bidirectional and unidirectional signaling across the entire cortex, along with prominent changes in network interactions across two simple brain states. We propose MCM as a novel approach for inferring EC from neuronal energy metabolism that is ideally suited to study signaling hierarchies in the brain and their defects in brain disorders.Complex cognition emerges by integrating upstream sensory information with feedback signaling from higher cortical regions (1–4). Networks related to sensory processing or cognition reliably occur in the human brain even at rest (5, 6). These networks are identified by synchronous signal fluctuations, or functional connectivity (FC), among brain regions when neuronal activity is recorded by functional magnetic resonance imaging (fMRI). In recent years, various FC patterns have emerged as reliable indicators of different brain states, because they have been found to adapt to recent behavior or cognition (7–12) and to be disrupted in patients suffering from specific psychiatric disorders (13, 14). Further knowledge about important aspects of cognition and diseases could be gained from a better distinction between feedback and feedforward communication. Our understanding of the signaling hierarchy in different brain states remains incomplete, however.Although FC captures correlations among neuronal signals, only effective connectivity (EC) describes the influence exerted by one neuronal system over another (15). Recent approaches to modeling EC during different brain states appear promising (16, 17), but face problems inherent to fMRI. First, EC is estimated directly from the time-varying fluctuations or cross-spectra of the observed fMRI signal, and thus is prone to confounds from different hemodynamic responses across groups, particularly when studying patient populations (15, 17). Second, analyses are usually restricted to a limited number of brain regions, owing to the need for complex computations. Here we propose a novel approach integrating FC with simultaneously measured energy metabolism from positron emission tomography (PET) to derive a voxel-wise, whole-brain mapping of EC in humans.Energy consumption is an essential aspect of neuronal communication. Consistently across species, the greatest amount of energy metabolism is dedicated to signaling, with the remaining part dedicated to housekeeping functions (18). Up to 75% of signaling-related energy is consumed postsynaptically, i.e., at the target neurons (19–22). Scaled to the systems level, we assume that an increase in local metabolism reflects an increase in afferent EC from source regions. We hypothesize that the spatial profile of this relationship is expressed in terms of spatial correlations between metabolic activity and long-range FC, which we term metabolic connectivity mapping (MCM). We simultaneously acquired fMRI and PET data for the glucose analog ¹⁸F-fludeoxyglucose (FDG) during two different brain states, as reported previously (10). In individual subject space, we performed spatial correlation analyses of voxel FC and FDG to test whether the metabolic profile indicates the target area of communication between functionally connected regions (Fig. 1).Fig. 1.MCM reveals EC in the human brain. (A) FC reveals undirected pathways of synchronous fMRI signal fluctuations between two regions, X and Y. For each subject, FC is calculated as the temporal correlation, [r] between the cluster time series. In our example, ...Vision is the only sensation that can be interrupted volitionally in a natural way. Opening the eyes is a fundamental behavior for directing attention to the external world, i.e., changing from an interoceptive state to an exteroceptive state (3, 23, 24). Current knowledge of the signaling hierarchy in the extended visual system has emerged from animal and tracer studies. These data reveal reciprocal (bottom-up and top-down) connections along the ventral and dorsal visual stream (25), including top-down projections from frontal back to early visual cortices (3, 4, 26, 27). To test this signaling hierarchy in humans, we scanned healthy human subjects in two brain states, lying with either eyes closed or eyes open in darkness, and calculated EC using our integrated approach. Consistent with previously reported data, MCM revealed persistent and bidirectional interactions between visual stream areas during both the “eyes closed” and “eyes open” conditions, but frontal top-down modulation of early visual areas only during the eyes open condition.In the present study, we used FDG to inform undirected FC from fMRI with a directional measure of postsynaptic neuronal activity. Our results indicate that the integrated measure of MCM serves as a proxy for EC in brain states. Our approach might be particularly useful for investigating other signaling hierarchies in higher cognition or in brain disorders involving, e.g., hippocampal-cortical circuits in Alzheimer’s disease (28) or fronto-midbrain interactions in major depression (29).     

Mitochondrial regulatory mechanisms in spinal cord injury: A narrative review

Spinal cord injury is a severe central nervous system injury that results in the permanent loss of motor, sensory, and autonomic functions below the level of injury with limited recovery. The pathological process of spinal cord injury includes primary and secondary injuries, characterized by a progressive cascade. Secondary injury impairs the ability of the mitochondria to maintain homeostasis and leads to calcium overload, excitotoxicity, and oxidative stress, further exacerbating the injury. The defective mitochondrial function observed in these pathologies accelerates neuronal cell death and inhibits regeneration. Treatment of spinal cord injury by preserving mitochondrial biological function is a promising, although still underexplored, therapeutic strategy. This review aimed to explore mitochondrial-based therapeutic advances after spinal cord injury. Specifically, it briefly describes the characteristics of spinal cord injury. It then broadly discusses the drugs used to protect the mitochondria (e.g., cyclosporine A, acetyl-L-carnitine, and alpha-tocopherol), phenomena associated with mitochondrial damage processes (e.g., mitophagy, ferroptosis, and cuproptosis), mitochondrial transplantation for nerve cell regeneration, and innovative mitochondrial combined protection therapy.     

逆行灌注白藜芦醇对猪脊髓缺血再灌注损伤的神经保护作用

目的 探讨逆行灌注白藜芦醇(resveratrol,Res)对猪脊髓缺血再灌注(ischemia-reperfusion,I/R)损伤的神经保护作用.方法 将18只西藏小型猪按“随机数字表法”随机分为3组:手术对照组(I/R组,n=6);冷液(cold saline,CL)逆灌组(CL组,n=6);Res逆灌组(CL+Res组,n=6).I/R组:常温阻断降主动脉70 min;CL组:阻断前游离出副半奇静脉,阻断降主动脉70 min,同时经副半奇静脉逆行灌注低温(4℃)9 g/L氯化钠溶液,灌注流速为16.65 mL/min;CL+Res组:阻断降主动脉70 min,同时经副半奇静脉逆行灌注含Res 10 mg/kg的低温(4℃)9 g/L氯化钠溶液.于术后6、24、48 h行神经功能评分,术后48 h取L2～L4段脊髓,免疫组化法和Western Blot检测Bax及Bcl-2蛋白表达变化.结果 18只西藏小型猪全部存活.术后6、24、48 h各组行为学评分均降低,I/R组低于CL+Res组、CL组,CL+Res组高于CL组,差异有统计学意义(F=26.341、18.553、9.637,P＜0.05).将主动脉阻断后各组实验动物的鼻咽温度和椎管温度均有下降,I/R组、CL+Res组和CL组分别在阻断70 min和再灌注20 min时降至最低.再灌注后,I/R组的鼻咽温度和椎管温度逐渐回升,至再灌注60 min时与阻断前相近(P=0.293、0.115);而CL组和CL+Res组回升不明显,在再灌注60 min时仍明显低于阻断前(P＜0.01).Western Blot检测结果与免疫组化结果一致:Bcl-2蛋白表达水平在CL+Res组与CL组均高于I/R组,差异有统计学意义(P＜0.05);且CL+Res组高于CL组,差异有统计学意义(P＜0.05).Bax蛋白表达水平在CL+Res组与CL组均低于I/R组,差异有统计学意义(P＜0.05);且CL+Res组低于CL组,差异有统计学意义(P＜0.05).结论 经猪副半奇静脉逆行灌注低温9 g/L氯化钠溶液及Res对脊髓I/R损伤有保护作用,其机制可能是通过下调Bax及上调Bcl-2蛋白的表达,抑制细胞凋亡而发挥作用.     

Mirabegron causes vesical and urethral relaxation in rats with spinal cord injury

The effects of solifenacin and mirabegron on vesical and urethral function were compared in rats with or without spinal cord injury (SCI). Isovolumetric cystometry and urethral pressure recording were initially performed in intact rats. Then, the bladder neck was ligated under urethane anesthesia, after which a catheter was inserted through the bladder dome for isovolumetric cystometry and another catheter was inserted into the urethra to measure urethral pressure. Solifenacin (0.03–3 mg/kg) or mirabegron (0.03–3 mg/kg) was injected intravenously, and bladder and urethral activity were recorded. To create rats with SCI, the spinal cord was transected at the lower thoracic level under isoflurane anesthesia. After 2 weeks, a catheter was inserted through the bladder dome for single cystometry and bladder activity was recorded without anesthesia following intravenous injection of solifenacin or mirabegron. Isovolumetric cystometry revealed a larger decrease in maximum bladder contraction pressure after injection of solifenacin, whereas prolongation of the interval between bladder contractions was greater with mirabegron. In SCI rats, single cystometry showed that solifenacin and mirabegron both increased bladder volume at the first non‐voiding bladder contraction and decreased the maximum bladder contraction pressure. Mirabegron also increased the voided volume and decreased the percentage residual volume without altering bladder capacity. Solifenacin and mirabegron both inhibited bladder contractility, and mirabegron possibly also induced urethral relaxation. Mirabegron may be suitable for patients with overactive bladder and residual urine.     

Beneficial effects of IL-37 after spinal cord injury in mice

IL-37, a member of the IL-1 family, broadly reduces innate inflammation as well as acquired immunity. Whether the antiinflammatory properties of IL-37 extend to the central nervous system remains unknown, however. In the present study, we subjected mice transgenic for human IL-37 (hIL-37tg) and wild-type (WT) mice to spinal cord contusion injury and then treated them with recombinant human IL-37 (rIL-37). In the hIL-37tg mice, the expression of IL-37 was barely detectable in the uninjured cords, but was strongly induced at 24 h and 72 h after the spinal cord injury (SCI). Compared with WT mice, hIL-37tg mice exhibited increased myelin and neuronal sparing and protection against locomotor deficits, including 2.5-fold greater speed in a forced treadmill challenge. Reduced levels of cytokines (e.g., an 80% reduction in IL-6) were observed in the injured cords of hIL-37tg mice, along with lower numbers of blood-borne neutrophils, macrophages, and activated microglia. We treated WT mice with a single intraspinal injection of either full-length or processed rIL-37 after the injury and found that the IL-37–treated mice had significantly enhanced locomotor skills in an open field using the Basso Mouse Scale, as well as supported faster speed on a mechanical treadmill. Treatment with both forms of rIL-37 led to similar beneficial effects on locomotor recovery after SCI. This study presents novel data indicating that IL-37 suppresses inflammation in a clinically relevant model of SCI, and suggests that rIL-37 may have therapeutic potential for the treatment of acute SCI.The inflammatory response plays an essential role in tissue protection after injury or invasion by microorganisms (1, 2). Regardless of the tissue, unless regulated, inflammation can become chronic and result in tissue damage and loss of function (1, 2). This is particularly the case in spinal cord injury (SCI). After spinal cord contusion or compression injury, there is a rapid initiation of inflammation in rodents and in humans (2). This response is orchestrated by endogenous microglial cells and by circulating leukocytes, especially monocytes and neutrophils, which invade the lesion site during the first hours and days after injury (2–4). Although these cells are required for the clearance of cellular and myelin debris, they also release cytokines and cytotoxic factors, which are harmful to neurons, glia, axons, and myelin, resulting in secondary damage to adjacent regions of the spinal cord that had been previously unaffected by the insult (2, 5, 6). Indeed, it is currently well accepted that inflammation is a major contributor to secondary cell death after SCI. The damaging effects of inflammation are more pronounced in the central nervous system (CNS) than in other tissues, because of the limited capacity for axon regeneration and replenishment of damaged neurons and glial cells, which leads to irreversible functional disabilities (7, 8). Therefore, targeting inflammation is a valuable approach to promoting neuroprotection and limiting functional deficits in SCI.Cytokines are key players in the initiation, progression, and suppression of inflammation. Although several members of the IL-1 family are proinflammatory (9, 10), IL-37 has broad suppressive effects on innate inflammation and acquired immunity (11–14). Because a complete ORF for the mouse homolog of IL-37 has not yet been found, it was necessary to generate a strain of transgenic mice expressing human IL-37, designated hIL-37tg mice. These mice are protected against endotoxin shock, colitis, hepatitis, and myocardial infarction (9, 13, 15–18); however, a role for IL-37 after CNS trauma remains unexplored. In the present study, we subjected hIL-37tg mice to SCI and studied subsequent functional impairments in comparison with wild type (WT) mice. We also administered recombinant human IL-37 (rIL-37) to WT mice, to provide a rationale for clinical use of IL-37 as a therapeutic agent. We provide direct evidence for the first time, to our knowledge, that IL-37 exerts marked antiinflammatory properties on the contused spinal cord and confers protection from tissue damage and functional loss.     

High-flow nasal cannula oxygen therapy was effective for dysphagia associated with respiratory muscle paralysis due to cervical spinal cord injury: A case report

Rationale:Respiratory muscle paralysis due to low cervical spinal cord injury (CSCI) can lead to dysphagia. Noninvasive positive airway pressure (PAP) therapy can effectively treat this type of dysphagia. High-flow nasal cannula (HFNC) oxygen therapy can generate a low level of positive airway pressure resembling PAP therapy, it may improve the dysphagia.Patient concerns:The patient was an 87-year-old man without preexisting dysphagia. He suffered a CSCI due to a dislocated C5/6 fracture, without brain injury, and underwent emergency surgery. Postoperatively (day 2), he complained of dysphagia, and the intervention was initiated.Diagnosis:Based on clinical findings, dysphagia in this case, may have arisen due to impaired coordination between breathing and swallowing, which typically occurs in patients with CSCI who have reduced forced vital capacity.Interventions:HFNC oxygen therapy was started immediately after the surgery, and swallowing rehabilitation was started on Day 2. Indirect therapy (without food) and direct therapy (with food) were applied in stages. HFNC oxygen therapy appeared to be effective because swallowing function temporarily decreased when the HFNC oxygen therapy was changed to nasal canula oxygen therapy.Outcomes:Swallowing function of the patient improved and he did not develop aspiration pneumonia.Lessons:HFNC oxygen therapy improved swallowing function in a patient with dysphagia associated with respiratory-muscle paralysis following a CSCI. It may have prolonged the apnea tolerance time during swallowing and may have improved the timing of swallowing. HFNC oxygen therapy can facilitate both indirect and direct early swallowing therapy to restore both swallowing and respiratory function.     

Melatonin reduces stress-activated/mitogen-activated protein kinases in spinal cord injury

Abstract:  Permanent functional deficits following spinal cord injury (SCI) arise from both mechanical injury and from secondary tissue reactions involving inflammation. The mitogen-activated protein kinases (MAPKs) play a critical role in cell signaling and gene expression. MAPK family includes three major members: extracellular signal regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK), representing three different signaling cascades. Moreover, various studies have clearly shown that high-mobility group box 1 (HMGB1) protein is implicated as a putative danger signal involved in the pathogenesis of a variety of inflammatory conditions including autoimmunity, cancer, trauma and hemorrhagic shock, and ischemia-reperfusion injury. Recently, we have reported that the pineal secretory product melatonin exerts important anti-inflammatory effects in an experimental model of SCI induced by the application of vascular clips (force of 24 g) to the dura after a four-level T5–T8 laminectomy. However, no reports are available on the effect of melatonin on MAPK signaling pathways and HMGB1 expression in SCI. The aim of the present study was to evaluate whether the melatonin protective effect observed in SCI is related to the regulation of MAPK signaling pathways and HMGB1 in mice. In this study we demonstrate the efficacy of treatment with the melatonin in SCI in mice in reducing (a) motor recovery, (b) activation of MAPKs p38, JNK and ERK1/2, (c) tumor necrosis factor-α expression, and (d) expression of HMGB1. We propose that melatonin's ability to reduce SCI in mice is also related to a reduction in MAPK signaling pathways and HMGB1 expression.     

Resting-state functional MRI in depression unmasks increased connectivity between networks via the dorsal nexus

To better understand intrinsic brain connections in major depression, we used a neuroimaging technique that measures resting state functional connectivity using functional MRI (fMRI). Three different brain networks—the cognitive control network, default mode network, and affective network—were investigated. Compared with controls, in depressed subjects each of these three networks had increased connectivity to the same bilateral dorsal medial prefrontal cortex region, an area that we term the dorsal nexus. The dorsal nexus demonstrated dramatically increased depression-associated fMRI connectivity with large portions of each of the three networks. The discovery that these regions are linked together through the dorsal nexus provides a potential mechanism to explain how symptoms of major depression thought to arise in distinct networks—decreased ability to focus on cognitive tasks, rumination, excessive self-focus, increased vigilance, and emotional, visceral, and autonomic dysregulation—could occur concurrently and behave synergistically. It suggests that the newly identified dorsal nexus plays a critical role in depressive symptomatology, in effect “hot wiring” networks together; it further suggests that reducing increased connectivity of the dorsal nexus presents a potential therapeutic target.     

Increased incidence of biliary sludge and normal gall bladder contractility in patients with high spinal cord injury

Background—Patients with spinal cordinjury (SCI) have an increased prevalence of gallstones.
Aims—To study prospectively theincidence of gallstones and gall bladder contractility inpatients with SCI.
Patients and methods—Thirty sixconsecutive patients with SCI were studied: 18 patients with SCI abovethoracic 10 neuronal segment (>T10) and 18 patients with SCI below T10(<T10). An equal number each of disease controls (multiple fractures)and healthy controls were also studied. All patients and controlsunderwent serial ultrasonography to detect development of gallstonesand ultrasonographic measurement of gall bladder contractility.
Results—A significantly higher number(9/18) of patients with SCI >T10 developed biliary sludge comparedwith patients with SCI <T10 (2/18), disease controls (2/18), andhealthy controls (1/18) (p<0.05). No patient developed gallstones. Thegall bladder fasting volume was significantly decreased in patientswith SCI >T10 (20.56 ml; 95% confidence intervals (CI) 19.74 to21.38) compared with that in patients with SCI <T10 (27.33 ml, 95%CI 26.17 to 28.49; p<0.05), disease controls (27.92 ml, 95% CI 26.69to 29.15; p<0.05), and healthy controls (28.35 ml, 95% CI 27.25to29.45; p<0.05). Gall bladder contractility was normal in patients withSCI as shown by normal gall bladder residual volume and emptying time.
Conclusions—Patients with SCI aboveT10 have an increased incidence of biliary sludge and a decreased gallbladder fasting volume. Gall bladder contractility is, however, normal.

Keywords:spinal cord injury; biliary sludge; gall bladder