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IL-13 is a central mediator of asthma1–3. Here, we used genome-wide approaches to characterize genes and regulatory elements modulated by IL-13 and other asthma-associated cytokines in airway epithelial cells and showed how they can be used for therapeutic purposes. Using bulk and single cell RNA-seq, we found distinctive responses to IL-13, IL-17, and interferons in human bronchial epithelial basal, ciliated, and secretory cells. H3K27ac ChIP-seq revealed that IL-13 had widespread effects on regulatory elements. Detailed characterization of an enhancer of SPDEF, a transcription factor required for pathologic mucin production, revealed that STAT6 and KLF5 binding sites cooperate to drive IL-13-dependent transcription selectively in secretory cells. Using this enhancer to drive CRISPRi and knockdown either SPDEF or the mucin MUC5AC showed the potential use of this approach for asthma therapeutics. This work identifies numerous genes and regulatory elements involved in cell type-selective cytokine responses and showcases their use for therapeutic purposes.

Cortical layer 1 (L1) interneurons have been proposed as a hub for attentional modulation of underlying cortex, but the transformations that this circuit implements are not known. We combined genetically targeted voltage imaging with optogenetic activation and silencing to study the mechanisms underlying sensory processing in mouse barrel cortex L1. Whisker stimuli evoked precisely timed single spikes in L1 interneurons, followed by strong lateral inhibition. A mild aversive stimulus activated cholinergic inputs and evoked a bimodal distribution of spiking responses in L1. A simple conductance-based model that only contained lateral inhibition within L1 recapitulated the sensory responses and the winner-takes-all cholinergic responses, and correctly predicted that the network would function as a spatial and temporal high-pass filter for excitatory inputs. Our results demonstrate that all-optical electrophysiology can reveal basic principles of neural circuit function in vivo and suggest an intuitive picture for how L1 transforms sensory and modulatory inputs.

Working memory is an essential human trait required for all cognitive activities. Our previous model from Mongillo et al. (1), Mi et al. (2) uses synaptic facilitation to store traces of working memory. Thus memories can be maintained without persistent neural activity. A critical component of this model is a central inhibition which prevents multiple item representations from being active at the same time. We know from experimental studies that multiple genetically-defined interneuron subtypes (e.g. PV, SOM) with different excitability and connectivity properties mediate inhibition in the cortex. The role of these sub-types in working memory however is not known. Here we develop a modified model with these interneuron subtypes, and propose their functional roles in working memory. We make concrete testable predictions about the roles of these groups.

Genetic variants account for approximately half the cases of congenital and early‐onset deafness. Methods and technologies for viral delivery of genes into the inner ear have evolved over the past decade to render gene therapy a viable and attractive approach for treatment. Variants in SYNE4, encoding the protein nesprin‐4, a member of the linker of nucleoskeleton and cytoskeleton (LINC), lead to DFNB76 human deafness. Syne4 −/− mice have severe‐to‐profound progressive hearing loss and exhibit mislocalization of hair cell nuclei and hair cell degeneration. We used AAV9‐PHP.B, a recently developed synthetic adeno‐associated virus, to deliver the coding sequence of Syne4 into the inner ears of neonatal Syne4 −/− mice. Here we report rescue of hair cell morphology and survival, nearly complete recovery of auditory function, and restoration of auditory‐associated behaviors, without observed adverse effects. Uncertainties remain regarding the durability of the treatment and the time window for intervention in humans, but our results suggest that gene therapy has the potential to prevent hearing loss in humans with SYNE4 mutations., Syne4 deficiency leads to hearing loss in humans. In this work, auditory function was rescued in Syne4 knockout mice by a synthetic AAV that enables safe and efficient transduction of hair cells in the cochlea.

The medial prefrontal cortex (mPFC) mediates a variety of complex cognitive functions via its vast and diverse connections with cortical and subcortical structures. Understanding the patterns of synaptic connectivity that comprise the mPFC local network is crucial for deciphering how this circuit processes information and relays it to downstream structures. To elucidate the synaptic organization of the mPFC, we developed a high-throughput optogenetic method for mapping large-scale functional synaptic connectivity. We show that mPFC neurons that project to the basolateral amygdala display unique spatial patterns of local-circuit synaptic connectivity within the mPFC, which distinguish them from the general mPFC cell population. Moreover, the intrinsic properties of the postsynaptic mPFC cell and anatomical position of both cells jointly account for ~7.5% of the variation in probability of connection between mPFC neurons, with anatomical distance and laminar position explaining most of this fraction in variation. Our findings demonstrate a functional segregation of mPFC excitatory neuron subnetworks, and reveal the factors determining connectivity in the mPFC.

Subdivisions of mouse whisker somatosensory thalamus project to cortex in a region-specific and layer-specific manner. However, a clear anatomical dissection of these pathways and their functional properties during whisker sensation is lacking. Here, we use anterograde trans-synaptic viral vectors to identify three specific thalamic subpopulations based on their connectivity with brainstem. The principal trigeminal nucleus innervates ventral posterior medial thalamus, which conveys whisker-selective tactile information to layer 4 primary somatosensory cortex that is highly sensitive to self-initiated movements. The spinal trigeminal nucleus innervates a rostral part of the posterior medial (POm) thalamus, signaling whisker-selective sensory information, as well as decision-related information during a goal-directed behavior, to layer 4 secondary somatosensory cortex. A caudal part of the POm, which apparently does not receive brainstem input, innervates layer 1 and 5A, responding with little whisker selectivity, but showing decision-related modulation. Our results suggest the existence of complementary segregated information streams to somatosensory cortices., The thalamus provides sensory input to the cortex, but many aspects of thalamocortical signaling remain unknown. Here, the authors reveal parallel non-overlapping thalamic pathways with distinct representations of tactile and decision-related information during a goal-directed sensorimotor task.

Complex behavioral phenotyping techniques are becoming more prevalent in the field of behavioral neuroscience, and thus methods for manipulating neuronal activity must be adapted to fit into such paradigms. Here, we present a head-mounted, magnetically activated device for wireless optogenetic manipulation that is compact, simple to construct, and suitable for use in group-living mice in an enriched semi-natural arena over several days. Using this device, we demonstrate that repeated activation of oxytocin neurons in male mice can have different effects on pro-social and agonistic behaviors, depending on the social context. Our findings support the social salience hypothesis of oxytocin and emphasize the importance of the environment in the study of social neuromodulators. Our wireless optogenetic device can be easily adapted for use in a variety of behavioral paradigms, which are normally hindered by tethered light delivery or a limited environment.

The inner ear is a complex structure responsible for hearing and balance, and organ pathology is associated with deafness and balance disorders. To evaluate the role of epigenomic dynamics, we performed whole genome bisulfite sequencing at key time points during the development and maturation of the mouse inner ear sensory epithelium (SE). Our single-nucleotide resolution maps revealed variations in both general characteristics and dynamics of DNA methylation over time. This allowed us to predict the location of non-coding regulatory regions and to identify several novel candidate regulatory factors, such as Bach2, that connect stage-specific regulatory elements to molecular features that drive the development and maturation of the SE. Constructing in silico regulatory networks around sites of differential methylation enabled us to link key inner ear regulators, such as Atoh1 and Stat3, to pathways responsible for cell lineage determination and maturation, such as the Notch pathway. We also discovered that a putative enhancer, defined as a low methylated region (LMR), can upregulate the GJB6 gene and a neighboring non-coding RNA. The study of inner ear SE methylomes revealed novel regulatory regions in the hearing organ, which may improve diagnostic capabilities, and has the potential to guide the development of therapeutics for hearing loss by providing multiple intervention points for manipulation of the auditory system.

Motor neuron–specific microRNA-218 (miR-218) has recently received attention because of its roles in mouse development. However, miR-218 relevance to human motor neuron disease was not yet explored. Here, we demonstrate by neuropathology that miR-218 is abundant in healthy human motor neurons. However, in amyotrophic lateral sclerosis (ALS) motor neurons, miR-218 is down-regulated and its mRNA targets are reciprocally up-regulated (derepressed). We further identify the potassium channel Kv10.1 as a new miR-218 direct target that controls neuronal activity. In addition, we screened thousands of ALS genomes and identified six rare variants in the human miR-218-2 sequence. miR-218 gene variants fail to regulate neuron activity, suggesting the importance of this small endogenous RNA for neuronal robustness. The underlying mechanisms involve inhibition of miR-218 biogenesis and reduced processing by DICER. Therefore, miR-218 activity in motor neurons may be susceptible to failure in human ALS, suggesting that miR-218 may be a potential therapeutic target in motor neuron disease., Target ALS; European Union (European Union); Horizon 2020; European Research Council (ERC), European Union's Seventh Framework Programme (FP7/2007-2013); AFM Telethon; NIH; National Institute of Neurological Disorders and Stroke; NIH/NINDS; United Kingdom, Medical Research Council; Suna and İnan Kıraç Foundation; Legacy Heritage Fund; Bruno and Ilse Frick Foundation for Research on ALS; Teva Pharmaceutical Industries Ltd. as part of the Israeli National Network of Excellence in Neuroscience (NNE); Minna-James-Heineman Stiftung through Minerva; Israel Science Foundation; ALS-Therapy Alliance; Motor Neuron Disease Association (United Kingdom); Thierry Latran Foundation for ALS research; ERA-Net for Research Programmes on Rare Diseases (FP7); IsrALS, Yeda-Sela, Yeda-CEO, Israel Ministry of Trade and Industry; Y. Leon Benoziyo Institute for Molecular Medicine; Kekst Family Institute for Medical Genetics; David and Fela Shapell Family Center for Genetic Disorders Research; Crown Human Genome Center; Nathan, Shirley, Philip and Charlene Vener New Scientist Fund; Julius and Ray Charlestein Foundation; Fraida Foundation; Wolfson Family Charitable Trust; Adelis Foundation; Merck (United Kingdom); ALS Canada Tim E. Noel Postdoctoral Fellowship; Project5 for ALS; Robert Packard Center for ALS Research; University of Missouri Spinal Cord Injury/Disease Research Program; Hope Center for Neurological Disorders; ALS Association ; Biogen; ALS Finding a Cure; Angel Fund; ALS-One; Cellucci Fund; Motor Neurone Disease Association; National Institute for Health Research (NIHR) Biomedical Research Centre

Fear-related disorders are thought to reflect strong and persistent fear memories. The basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) form strong reciprocal synaptic connections that play a key role in acquisition and extinction of fear memories. While synaptic contacts of BLA cells onto mPFC neurons are likely to play a crucial role in this process, the BLA connects with several additional nuclei within the fear circuit that could relay fear-associated information to the mPFC, and the contribution of direct monosynaptic BLA-mPFC inputs is not yet clear. Here we establish an optogenetic stimulation protocol that induces synaptic depression in BLA-mPFC synapses. In behaving mice, optogenetic high-frequency stimulation of BLA inputs to mPFC interfered with retention of cued associations, attenuated previously acquired cue-associated responses in mPFC neurons and facilitated extinction. Our findings demonstrate the contribution of BLA inputs to mPFC in forming and maintaining cued fear associations.

Summary The ability to plan and execute appropriately timed responses to external stimuli is based on a well-orchestrated balance between movement initiation and inhibition. In impulse control disorders involving the prefrontal cortex (PFC) [1], this balance is disturbed, emphasizing the critical role that PFC plays in appropriately timing actions [2–4]. Here, we employed optogenetic and electrophysiological techniques to systematically analyze the functional role of five key subareas of the rat medial PFC (mPFC) and orbitofrontal cortex (OFC) in action control [5–9]. Inactivation of mPFC subareas induced drastic changes in performance, namely an increase (prelimbic cortex, PL) or decrease (infralimbic cortex, IL) of premature responses. Additionally, electrophysiology revealed a significant decrease in neuronal activity of a PL subpopulation prior to premature responses. In contrast, inhibition of OFC subareas (mainly the ventral OFC, i.e., VO) significantly impaired the ability to respond rapidly after external cues. Consistent with these findings, mPFC activity during response preparation predicted trial outcomes and reaction times significantly better than OFC activity. These data support the concept of opposing roles of IL and PL in directing proactive behavior and argue for an involvement of OFC in predominantly reactive movement control. By attributing defined roles to rodent PFC sections, this study contributes to a deeper understanding of the functional heterogeneity of this brain area and thus may guide medically relevant studies of PFC-associated impulse control disorders in this animal model for neural disorders [10–12].

Animals constantly evaluate their environment in order to avoid potential threats and obtain reward in the form of food, shelter and social interactions. In order to appropriately respond to sensory cues from the environment, the brain needs to form and store multiple cue-outcome associations. These can then be used to form predictions of the valence of sounds, smells and other sensory inputs arising from the surroundings. However, these associations must be subject to constant update, as the environment can rapidly change. Failing to adapt to such change can be detrimental to survival. Several systems in the mammalian brain have evolved to perform these important behavioral functions. Among these systems, the amygdala and prefrontal cortex are prominent players. Although the amygdala has been shown to form strong cue-outcome associations, the prefrontal cortex is essential for modifying these associations through extinction and reversal learning, and synaptic plasticity occurring in the strong reciprocal connections between these structures is thought to underlie both adaptive and maladaptive learning. Here we review the synaptic organization of the amygdala-prefrontal circuit, and summarize the physiological and behavioral evidence for its involvement in appetitive and aversive learning.

BackgroundThe mammalian inner ear is a complex morphological structure responsible for hearing and balance, and its pathology is associated with deafness and balance disorders. To evaluate the role of epigenomic dynamics in the development and maturation of mouse inner ear sensory epithelium, we performed whole-genome bisulfite sequencing on inner ear tissue, yielding temporal base-pair resolution methylomes at key developmental time points.ResultsWe found a late accumulation of non-CpG methylation, indicating a similarity between the inner ear sensory epithelium and neuronal tissue. Moreover, annotation of both unmethylated and low methylated regions pointed to regulatory elements active in the inner ear in proximity of and distal from transcriptional units. Finally, we identified differentially methylated regions across the transition periods. An analysis of these regions led us to identify several novel candidate regulatory factors, connecting regulatory elements from specific time points in development to molecular features that drive the development and maturation of the inner ear sensory epithelium. The GJB6 locus putative regulatory region was shown to upregulate distal GJB6 gene expression and a non-coding RNA.ConclusionsOur analysis of inner ear sensory epithelium DNA methylation sheds light on novel regulatory regions in the hearing organ, and may help boost diagnostic capabilities and guide the development of therapeutics for hearing loss, by providing multiple intervention points for manipulation of the auditory system.

A normal motion and segmental interrelationship has been determined as a significant factor in normal function. Yet, the relationship between distal segments and pelvic alignment needs further investigation. The aim of this study was to investigate the interrelationship between distal and proximal lower extremity segments while standing and during induced feet hyperpronation. Changes in alignment of the pelvis and lower extremities were measured at a gait laboratory using the VICON 612 computerized motion analysis system. Thirty-five healthy volunteer subjects were recruited. Four randomized repeated-measure standing modes were used: standing directly on the floor and then on three wedges angled at 10°, 15° and 20° to induce bilateral hyperpronation for 20 seconds. A significant (p

We combined two-photon holographic stimulation of blue light-sensitive opsins with two-photon imaging of red-shifted fluorescence indicators in the intact mouse neocortex to perform cellular-resolution control of neural excitability with minimal crosstalk between imaging and stimulation.

Optogenetic silencing allows time-resolved functional interrogation of defined neuronal populations. However, the limitations of inhibitory optogenetic tools impose stringent constraints on experimental paradigms. The high light power requirement of light-driven ion pumps and their effects on intracellular ion homeostasis pose unique challenges, particularly in experiments that demand inhibition of a widespread neuronal population in vivo. Guillardia theta anion-conducting channelrhodopsins (GtACRs) are promising in this regard, due to their high single-channel conductance and favorable photon-ion stoichiometry. However, GtACRs show poor membrane targeting in mammalian cells, and the activity of such channels can cause transient excitation in the axon due to an excitatory chloride reversal potential in this compartment. Here, we address these problems by enhancing membrane targeting and subcellular compartmentalization of GtACRs. The resulting soma-targeted GtACRs show improved photocurrents, reduced axonal excitation and high light sensitivity, allowing highly efficient inhibition of neuronal activity in the mammalian brain., Current optogenetic inhibition methods like light-controlled ion pumps require high-intensity light and disrupt physiological ion gradients. Here, the authors somatically target the anion-conducting opsin GtACR to eliminate spiking in distal axons and improve photocurrents, thus enhancing its utility.

View references (89) Optogenetic techniques allow versatile, cell type-specific light-based control of cellular activity in diverse set of cells, circuits, and brain structures. Optogenetic actuators are genetically encoded light-sensitive membrane proteins that can be selectively introduced into cellular circuits in the living brain using a variety of genetic approaches. Gene targeting approaches used in optogenetic studies vary greatly in their specificity, their spatial coverage, the level of transgene expression and their potential adverse effects on neuronal cell health. Here, we describe the major gene targeting approaches utilized in optogenetics and provide a simple set of guidelines through which these approaches can be evaluated when designing an in vitro or in vivo optogenetic study. © Springer Science+Business Media LLC 2018.

The inner ear is composed of a complex mixture of cells, which together allow organisms to hear and maintain balance. The cells in the inner ear, which undergo an extraordinary process of development, have only recently begun to be studied on an individual level. As it has recently become clear that individual cells, previously considered to be of uniform character, may differ dramatically from each other, the need to study cell-to-cell variation, along with distinct transcriptional and regulatory signatures, has taken hold in the scientific community. In conjunction with high-throughput technologies, attempts are underway to dissect the inter- and intra-cellular variability of different cell types and developmental states of the inner ear from a novel perspective. Single cell analysis of the inner ear sensory organs holds the promise of providing a significant boost in building an omics network that translates into a comprehensive understanding of the mechanisms of hearing and balance. These networks may uncover critical elements for trans-differentiation, regeneration and/or reprogramming, providing entry points for therapeutics of deafness and vestibular pathologies.

Parkinson's disease (PD) is characterized by dopaminergic (DA) neuron depletion. Early detection of PD may help in selecting the appropriate treatment. Biomarkers of PD have been suggested, however none of these is currently in clinical use. The aim of this study was to identify volatile organic compounds (VOCs) as early biomarkers of PD. Our hypothesis was that during PD progression, specific VOCs are generated that are linked to the biochemical pathways characterizing PD. These VOCs can be detected by GC-MS combined with solid-phase microextraction (SPME) technique. Three groups of rats were studied: DA-lesioned rats injected with 6-hydroxydopamine (HDA; 250μg/rat n=11); control rats injected with saline (n=9), and control rats injected with DSP-4 (n=8), a specific noradrenergic neuron toxin. Blood and striatal tissue homogenate were analyzed. In the blood, 1-octen-3-ol and 2-ethylhexanol were found at significantly higher concentrations in HDA versus sham rats. In the striatal homogenate 1-octen-3-ol and other four compounds were found at significantly lower concentrations in HDA versus sham rats. 1-Octen-3-ol is a cytotoxic compound. These results may lead to the development of an early diagnostic test for PD based on profiling of VOCs in body fluids.

Despite decades of research on neurobiological mechanisms of psychostimulant addiction, the only effective treatment for many addicts is contingency management, a behavioral treatment that uses alternative non-drug reward to maintain abstinence. However, when contingency management is discontinued, most addicts relapse to drug use. The brain mechanisms underlying relapse after cessation of contingency management are largely unknown, and, until recently, an animal model of this human condition did not exist. Here we used a novel rat model, in which the availability of a mutually exclusive palatable food maintains prolonged voluntary abstinence from intravenous methamphetamine self-administration, to demonstrate that the activation of monosynaptic glutamatergic projections from anterior insular cortex to central amygdala is critical to relapse after the cessation of contingency management. We identified the anterior insular cortex-to-central amygdala projection as a new addiction- and motivation-related projection and a potential target for relapse prevention.

Social encounters are associated with varying degrees of emotional arousal and stress. The mechanisms underlying adequate socioemotional balance are unknown. The medial amygdala (MeA) is a brain region associated with social behavior in mice. Corticotropin-releasing factor receptor type-2 (CRF-R2) and its specific ligand urocortin-3 (Ucn3), known components of the behavioral stress response system, are highly expressed in the MeA. Here we show that mice deficient in CRF-R2 or Ucn3 exhibit abnormally low preference for novel conspecifics. MeA-specific knockdown of Crfr2 (Crhr2) in adulthood recapitulated this phenotype. In contrast, pharmacological activation of MeA CRF-R2 or optogenetic activation of MeA Ucn3 neurons increased preference for novel mice. Furthermore, chemogenetic inhibition of MeA Ucn3 neurons elicited pro-social behavior in freely behaving groups of mice without affecting their hierarchal structure. These findings collectively suggest that the MeA Ucn3-CRF-R2 system modulates the ability of mice to cope with social challenges.

Currently there is no general approach for achieving specific optogenetic control of genetically defined cell types in rats, which provide a powerful experimental system for numerous established neurophysiological and behavioral paradigms. To overcome this challenge we have generated genetically restricted recombinase-driver rat lines suitable for driving gene expression in specific cell types, expressing Cre recombinase under the control of large genomic regulatory regions (200-300 kb). Multiple tyrosine hydroxylase (Th)::Cre and choline acetyltransferase (Chat)::Cre lines were produced that exhibited specific opsin expression in targeted cell types. We additionally developed methods for utilizing optogenetic tools in freely moving rats and leveraged these technologies to clarify the causal relationship between dopamine (DA) neuron firing and positive reinforcement, observing that optical stimulation of DA neurons in the ventral tegmental area (VTA) of Th::Cre rats is sufficient to support vigorous intracranial self-stimulation (ICSS). These studies complement existing targeting approaches by extending the generalizability of optogenetics to traditionally non-genetically-tractable but vital animal models.

Cortico-thalamo-cortical circuits mediate sensation and generate neural network oscillations associated with slow-wave sleep and various epilepsies. Cortical input to sensory thalamus is thought to mainly evoke feed-forward synaptic inhibition of thalamocortical (TC) cells via reticular thalamic nucleus (nRT) neurons, especially during oscillations. This relies on a stronger synaptic strength in the cortico-nRT pathway than in the cortico-TC pathway, allowing the feed-forward inhibition of TC cells to overcome direct cortico-TC excitation. We found a systemic and specific reduction in strength in GluA4-deficient (Gria4(-/-)) mice of one excitatory synapse of the rhythmogenic cortico-thalamo-cortical system, the cortico-nRT projection, and observed that the oscillations could still be initiated by cortical inputs via the cortico-TC-nRT-TC pathway. These results reveal a previously unknown mode of cortico-thalamo-cortical transmission, bypassing direct cortico-nRT excitation, and describe a mechanism for pathological oscillation generation. This mode could be active under other circumstances, representing a previously unknown channel of cortico-thalamo-cortical information processing.

Synchronized oscillations and inhibitory interneurons have important and interconnected roles within cortical microcircuits. In particular, interneurons defined by the fast-spiking phenotype and expression of the calcium-binding protein parvalbumin1,2 have been suggested to be involved in gamma (30–80 Hz) oscillations3–7, which are hypothesized to enhance information processing8,9. However, because parvalbumin interneurons cannot be selectively controlled, definitive tests of their functional significance in gamma oscillations, and quantitative assessment of the impact of parvalbumin interneurons and gamma oscillations on cortical circuits, have been lacking despite potentially enormous significance (for example, abnormalities in parvalbumin interneurons may underlie altered gamma-frequency synchronization and cognition in schizophrenia10 and autism11). Here we use a panel of optogenetic technologies12–14 in mice to selectively modulate multiple distinct circuit elements in neocortex, alone or in combination. We find that inhibiting parvalbumin interneurons suppresses gamma oscillations in vivo, whereas driving these interneurons (even by means of non-rhythmic principal cell activity) is sufficient to generate emergent gamma-frequency rhythmicity. Moreover, gamma-frequency modulation of excitatory input in turn was found to enhance signal transmission in neocortex by reducing circuit noise and amplifying circuit signals, including inputs to parvalbumin interneurons. As demonstrated here, optogenetics opens the door to a new kind of informational analysis of brain function, permitting quantitative delineation of the functional significance of individual elements in the emergent operation and function of intact neural circuitry.

Patients with a spinal cord injury (SCI) are susceptible to deep tissue injury (DTI), a necrosis in excessively deformed muscle tissue overlying bony prominences, which, in wheelchair users, typically occurs in the gluteus muscles under the ischial tuberosities. Recently, we developed a generic real-time, subject-specific finite element (FE) modeling method to provide monitoring of mechanical conditions in deep tissues deformed between bony prominences and external surfaces. We previously employed this method to study internal tissue loads in plantar tissues of the foot [Yarnitzky, G., Z. Yizhar, and A. Gefen. J. Biomech. 39:2673-2689, 2006] and in muscle flaps of residual limbs in patients who underwent transtibial amputation (Portnoy, S., G. Yarnitzky, Z. Yizhar, A. Kristal, U. Oppenheim, I. Siev-Ner, and A. Gefen. Ann. Biomed. Eng. 35:120-135, 2007). The goal of the present study was to adapt the method to study the time-dependent mechanical stresses in glutei of patients with SCI during wheelchair sitting, continuously in real-time, and to compare the trends of internal tissue load data with those of controls. Prior to human studies, the real-time FE model-adapted to study the buttocks during sitting-was validated by comparing its predictions to data from a physical phantom of a buttocks and to non-real-time, commercial FE software. Next, real-time, subject-specific, FE models were built for six participating subjects (3 patients with SCI, 3 controls) based on their individual anatomies from MRI scans. Subjects were asked to sit normally in a wheelchair, on a ROHO cushion, and to watch a 90 min movie. Continuous interface pressure measurements from a pressure mat were used as subject-specific boundary conditions for real-time FE analyses of deep muscle stresses. Highest peaks of compression, shear and von Mises stresses throughout the trial period, and averages of peaks of these stresses were recorded over the trial for each individual. These parameters generally had 3-times to 5-times greater values in patients with SCI compared with controls. Likewise, stress doses, defined as the integration of peak compression stress over time, were approximately 35-times and approximately 50-times greater in the subjects with SCI, the values referring to the highest of all peaks recorded throughout the trial, and to average of peaks over the trial, respectively. We believe that by allowing-for the first time-practical and continuous monitoring of internal tissue loads in patients with motosensory deficits, without any risk or interruption to their lifestyle, and either at the clinical setting or at home, the present method can make a substantial contribution to the prevention of severe pressure ulcers and DTI.

The clinical practice for minimizing the risk of pressure sores (PS) is to relief pressures under bony prominences of immobilized patients by changing their postures frequently. The US Department of Health advises to relief sitting pressures at least every 1 hour, and every 15 minutes for individuals who are body-abled. Surprisingly, there is paucity of information in the literature concerning motion of healthy subjects during prolonged sitting, which can be compared with these recommendations. Considering that healthy individuals are able to sit for hours without suffering injuries, such information seems particularly important. Accordingly, our objective was to measure frequency of postural changes and extent of motion during postural changes among healthy subjects who sit in a wheelchair (N=10), in order to provide information that is missing in the literature of PS biomechanics. Subjects were asked to sit comfortably for 90 minutes, during which their trunk's frontal and sagittal motions and sitting pressures were measured. We found that normals change their posture every 9 +/- 6 minutes in the sagittal plane, and independently, every 6 +/- 2 minutes in the frontal plane. Shoulders, thoracic-spine and lumbar-spine frontal plane motions were 8 +/- 4 degrees , 14 +/- 7 degrees and 15 +/- 7 degrees , respectively, and sagittal trunk-thigh movement was 10.3 +/- 7 degrees . The frequency of postural changes in normals, measured herein, was higher than frequencies reported in the literature for patients who suffered PS. This small study population therefore supports the hypothesis that prolonged immobilization contributes to PS onset.

The bed nucleus of the stria terminalis (BNST) is critical in mediating states of anxiety, and its dysfunction has been linked to stress-related mental disease. Although the anxiety-related role of distinct subregions of the anterior BNST was recently reported, little is known about the contribution of the posterior BNST (pBNST) to the behavioral and neuroendocrine responses to stress. Previously, we observed abnormal expression of corticotropin-releasing factor receptor type 2 (CRFR2) to be associated with post-traumatic stress disorder (PTSD)-like symptoms. Here, we found that CRFR2-expressing neurons within the pBNST send dense inhibitory projections to other stress-related brain regions (for example, the locus coeruleus, medial amygdala and paraventricular nucleus), implicating a prominent role of these neurons in orchestrating the neuroendocrine, autonomic and behavioral response to stressful situations. Local CRFR2 activation by urocortin 3 depolarized the cells, increased the neuronal input resistance and increased firing of action potentials, indicating an enhanced excitability. Furthermore, we showed that CRFR2-expressing neurons within the pBNST are critically involved in the modulation of the behavioral and neuroendocrine response to stress. Optogenetic activation of CRFR2 neurons in the pBNST decreased anxiety, attenuated the neuroendocrine stress response, ameliorated stress-induced anxiety and impaired the fear memory for the stressful event. Moreover, activation following trauma exposure reduced the susceptibility for PTSD-like symptoms. Optogenetic inhibition of pBNST CRFR2 neurons yielded opposite effects. These data indicate the relevance of pBNST activity for adaptive stress recovery.

Most morphometric studies on lumbar degenerative spondylolisthesis (DS) have focused solely on the L4–L5 slipped level, neglecting the shape of the entire lumbar segments. The purpose of this study was to present a morphometric analysis of the entire lumbar IVDs and VBs in DS. Out of 500 lumbar CTs, the first 100 CTs, 50 with DS at L4 and 50 age- and sex-matched control CTs, were randomly selected. All lumbar IVD and VB heights, widths, lengths and sagittal wedging as well as lumbar lordosis (LL) and sacral inclination (SI) were measured and relevant ratios calculated. The prevalence of lumbar vertebral osteophyte was also measured. A total of 6700 measurements were taken. Age, height, weight and BMI had no effect on all parameters. Compared with controls, in females with DS, the majority of IVDs were flatter, with increased kyphotic wedging at L1–L2 (Δ1.3°) and L2–L3 (Δ1.8°), turning to lordotic wedging at L3–L4 (Δ5.9°), and decreased lordotic wedging at L4–L5 (Δ2.7°) and L5–S1 (Δ5.3°). The posterior IVD/VB ratio of all lumbar levels, middle IVD/VB ratio of L3–S1 and anterior IVD/VB ratio of L4–S1 were smaller. In males with DS, the L2–L3 IVD manifested more kyphotic wedging (Δ3.8°), the L4 VB wedging was more lordotic (Δ2.4°) and all L4–L5 IVD/VB ratios and L3–L4 middle and posterior IVD/VB ratios were smaller. Individuals with DS have a more generalized degenerative disc disease on all lumbar vertebral levels, characterized by decreased disc space heights and kyphotic posture of the upper lumbar segments, occurring more predominantly in females than in males with DS.

Object. The authors retrospectively evaluated the safety and efficacy of a decompression and fixation technique in the treatment of patients with multilevel cervical spondylotic myelopathy (CSM). Methods. The authors describe the “hybrid decompression fixation” technique, a procedure involving a combination of corpectomies and discectomies to preserve a vertebra intact within the area of the decompression, thus augmenting mechanical stability. The authors retrospectively reviewed outcomes in 25 patients with multilevel CSM in whom the hybrid technique was performed between 1999 and 2003. Twelve patients underwent a single-level corpectomy and three-level discectomies. In 13 patients a two-level corpectomy and adjacent four-level discectomies were conducted, leaving a vertebral bridge the middle. All patients underwent fusion involving placement of disc and vertebral body cages filled with autogenous local bone and supplemental anterior dynamic plate fixation. The mean preoperative Nurick grade was 3 and improvement in status was reflected by a postoperative decrease to 2.6 (p < 0.05). In one patient neurological deterioration was demonstrated. At the end of the follow-up period (mean 29 months) radiography revealed evidence of osseous fusion in 24 patients; fusion status could not be determined in one patient. No evidence of late-onset instrumentation-related failure was observed in any of the 25 patients. Conclusions. The authors found the hybrid technique to be safe and efficient for anterior decompression in patients with multilevel CSM. The use of this technique obviates the need for staged circumferential procedures.

Neurotransmitter release is a multistep process that is coordinated by a large number of synaptic proteins and depends on proper protein–protein interactions. Using morphological, capacitance, and amperometric measurements, we investigated the effect of tomosyn, a Syntaxin-binding protein, on the different kinetic components of exocytosis in adrenal chromaffin cells. Overexpression of tomosyn decreased the release probability and led to a 50% reduction in the number of fusion-competent vesicles. The number of docked vesicles and the fusion kinetics of single vesicles were not altered suggesting that tomosyn inhibits the priming step. Interestingly, this inhibition is partially relieved at elevated calcium concentration. Calcium ramp experiments supported the latter finding and indicated that the reduction in secretion is caused by a shift in the calcium-dependence of release. These results indicate that secretion is not entirely blocked but occurs at higher calcium concentrations. We suggest that tomosyn inhibits the priming step and impairs the efficiency of vesicle pool refilling in a calcium-dependent manner.

SUMMARY An in vivo murine experiment was conducted to measure the capacities of viable intervertebral disc cells to recruit inflammatory cells. The objective was to determine whether compounds secreted from viable cells induce inflammation or whether inflammation in disc herniation simply requires exposure to structural cell or matrix components. Three tissue preparations were inserted into the right lower peritoneal cavity of male mice: tissue with viable annulus fibrosus and nucleus pulposus cells, tissue with viable annulus fibrosus cells, or devitalized annulus fibrosus and nucleus pulposus tissue. Controls included sham-operated and nonoperated groups. Mice were killed 1, 2, or 7 days after surgery. Macrophage recruitment occurred after exposure to viable disc tissue but not after exposure to devitalized disc components; recruitment increased over time. Viable disc cells play a role in the etiology of inflammation in disc herniation.

Study design A retrospective clinical study of patients with vertebral osteomyelitis of the lumbar spine necessitating surgical treatment. All patients underwent sequential (same-day) or simultaneous anterior decompression and posterior stabilization of the involved vertebrae. Objective To evaluate the efficacy and clinical out-come of sequential or simultaneous anterior and posterior surgical approaches in the management of vertebral osteomyelitis of the lumbar spine. Summary of background data Anterior approach alone and staged anterior decompression and posterior stabilization have been advocated as the surgical treatment methods of choice for patients with vertebral osteomyelitis of the lumbar spine. The drawbacks of the latter management plan are the necessity to use external support or the delayed patient mobilization and the need for additional anesthesia and surgical trauma. Sequential (same-day) anterior and posterior approaches are used regularly in the surgical management of scoliosis and other spinal deformities. It would appear advantageous to also use the same strategy (i.e., combined same-day double approaches) in the management of vertebral osteomyelitis of the lumbar spine. Methods Ten consecutive patients who had a diagnosis of vertebral osteomyelitis of the lumbar spine underwent combined (same-day) anterior and posterior approaches either in a sequential or simultaneous manner. Indications for surgery included neurologic deficit, abscess formation, instability with localized kyphosis formation, and failure of nonoperative treatment. Patients were evaluated clinically and radiographically after surgery. Results All 10 patients had uneventful surgery. Only one patient required a second surgical procedure because of expulsion of the anterior bone graft and pull-out of instrumentation. All patients were mobilized within the 2 days immediately after surgery. At the mean follow-up examination 30 months after surgery, all patients had regained their motor function and prior ambulatory status. Conclusions Patients with lumbar osteomyelitis necessitating surgery can undergo combined, same-day surgery either in a sequential or simultaneous manner. This is a safe and efficient way to control the infection and stabilize the affected segments, allowing for early mobilization of these sick elderly patients.

Tomosyn, a syntaxin-binding protein, is known to inhibit vesicle priming and synaptic transmission via interference with the formation of SNARE complexes. Using a lentiviral vector, we specifically overexpressed tomosyn1 in hippocampal dentate gyrus neurons in adult mice. Mice were then subjected to spatial learning and memory tasks and electrophysiological measurements from hippocampal slices. Tomosyn1-overexpression significantly impaired hippocampus-dependent spatial memory while tested in the Morris water maze. Further, tomosyn1-overexpressing mice utilize swimming strategies of lesser cognitive ability in the Morris water maze compared with control mice. Electrophysiological measurements at mossy fiber-CA3 synapses revealed impaired paired-pulse facilitation in the mossy fiber of tomosyn1-overexpressing mice. This study provides evidence for novel roles for tomosyn1 in hippocampus-dependent spatial learning and memory, potentially via decreased synaptic transmission in mossy fiber-CA3 synapses. Moreover, it provides new insight regarding the role of the hippocampal dentate gyrus and mossy fiber-CA3 synapses in swimming strategy preference, and in learning and memory.

We report four patients with unilateral postpartum sacroiliitis presenting with agonising unilateral pain, an elevated ESR, elevated alkaline phosphatase levels, leucocytosis and positive bone scans. The diagnosis of a non-infectious inflammatory cause was supported by the postpartum onset, the response to non-steroidal anti-inflammatory drugs, negative aspiration cultures in two cases and the lack of changes in the sacroiliac joints on long-term follow-up radiographs.

During the 10-year period 1981-1990, 59 patients suffering from spinal cord or cauda equina compression underwent anterior spinal decompression and in most cases spinal restabilization with methylmethacrylate cement and/or instrumentation. Follow-up in 55 patients showed that 75% were improved neurologically by the procedure, one-third of these showing complete recovery from the spinal cord compression. The results in younger female patients suffering from metastatic breast cancer were considerably better than those of older men with prostatic metastases. Other genitourinary system tumors also had a relatively poorer prognosis. There was a significantly better result for metastatic lesions of the thoracic or thoracolumbar spine than for lesions in the lumbar spine causing cauda equina paralysis.

Our aim was to evaluate the effect of adding inhibitory casting to the treatment of young children with cerebral palsy who received injections of botulinum neurotoxin A (BoNT-A) to gastrocnemius for equinus gait. Of the 20 patients in the series, 11 in group A had inhibitory casts applied on the day of the first set of BoNT-A injections and nine in group B did not have casting. Both groups received another BoNT-A injection four months later. The patients were followed for eight months and examined at five intervals. Both groups showed significant improvement in gait parameters and function (p < 0.0001) and selective motor control (p = 0.041, − 0.036) throughout the study. Group A had significantly better passive dorsiflexion of the ankle (p = 0.029), observational gait score (p = 0.006) and selective motor control (p = 0.036). We conclude that the addition of inhibitory casting enhances and prolongs the results of treatment and mainly influences the passive range of movement, while BoNT-A mostly influences the dynamic motion. The second injection further improved the results of most parameters. The gross motor function measure, the selective motor control test and the modified Tardieu scale correlated well with the results of treatment. We recommend the use of inhibitory casting whenever augmentation of the effect of treatment with BoNT-A is needed.

We present results from an ongoing electrophysiological study of cortical function in the awake, behaving monkey. Single and multiple neuron activity is recorded from the frontal cortex, while the monkey is engaged in a sensory-motor association task. Results show that neighboring neurons in the frontal cortex may be functionally related and share common features. However, even when neurons were reduced by the same microelectrode, they were not all activated in unison, nor did they all show the same functional properties. Correlation analysis reveals that interactions between neurons may strongly depend on stimulus context and/or behavioral state. Moreover, the interactions may be highly dynamic, with time constants of modulation as low as tens of milliseconds. These findings point at the need to distinguish between anatomical connectivity and functional coupling. The underlying mechanisms as well as the functional implications of such dynamic coupling in cortical networks are discussed.

Active transtibial amputation (TTA) patients are at risk for developing pressure ulcers (PU) and deep tissue injury (DTI) while using their prosthesis. It is therefore important to obtain knowledge of the mechanical state in the internal soft tissues of the residuum, as well as knowledge of the mechanical state upon its surface. Our aim was to apply patient-specific MRI-based non-linear finite element (FE) models to quantify internal strains in TTA prosthetic users (n=5) during load-bearing. By further employing a strain injury threshold for skeletal muscle, we identified patients susceptible to DTI. The geometrical characteristics of the residuum of the TTA participants varied substantially between patients, e.g. the residuum lengths were 7.6, 8.1, 9.2, 11.5 and 13.3cm. We generally found that internal strains were higher in the bone proximity than in the muscle flap periphery. The highest strains, which in some patients exceeded 50% (engineering strain) for compressive, tensile and shear strains, were found in the shortest residual limbs, i.e. the 7.6 and 8.1cm-long limbs. Correspondingly, the lowest strains were found in the 13.3cm-long residuum, which had the bulkiest muscle flap. Yet, even in the case of a long residuum, about a third of the soft tissue volume at the distal tibial proximity area was occupied by large (>5%) internal compressive, tensile and shear strains. For both patients with shorter residual limbs, the internal principal compressive strains above 5% occupied almost the entire distal tibial proximity area. For a patient whose distal tibial end was flat (non-beveled), internal strains were more uniformly distributed, compared to the strain distributions in the other models, where focal elevated strains accumulated in the bone proximity. We found no muscle strains above the immediate injury threshold, indicating that all patients were not at immediate risk for DTI. Two patients whose residuum fat padding was minimal to none, were the only ones identified as theoretically prone to DTI at long (>3h) continuous weight-bearing periods. We conclude that there is a wide variability in internal mechanical conditions between residual limbs across subjects, which necessitates patient-specific quantitative analyses of internal mechanical states in TTA patients, to assess the mechanical performance of the reconstructed limb and in particular, the individual risk for deep PU or DTI.

Although in situ posterolateral fusion is considered the gold standard for surgical treatment of low-grade adult spondylolisthesis, correction of the sagittal translation by instrumented slip reduction is more controversial in adults; nevertheless it may delay adjacent level disc degeneration.The present study was undertaken to evaluate the safety and clinical outcome of operative instrumented slip reduction in 12 adults with isthmic spondylolisthesis accompanied by advanced disc degeneration at that level.This study was a retrospective review of 12 consecutive lumbar or lumbosacral isthmic slip, which underwent operative slip reduction in our institute.All adult patients having operative instrumented slip reduction of isthmic spondylolisthesis from January 2000 to December 2005 were assessed.Outcome measures included the Oswestry Disability Index (ODI) for low back pain and the visual analog scale (VAS) of back and leg pain. Patient outcome was assessed by work status, participation in sports activities and intake of pain medications.Between January 2000 and December 2005, we performed slip reduction on 12 adults aged 28 to 62 years (average 47) with symptomatic lumbar or lumbosacral isthmic spondylolisthesis. The indications for surgery were long-standing low back and leg pain that had not responded to nonoperative management.The vertebral slip ranged between 15% and 90% (average 34%). Radiologic evidence of adult slip progression was available in 5 patients, one had a de novo slip formation and the others had increased sagittal translation on flexion-extension lateral x-rays. All 12 patients underwent posterior decompression, pedicle screw fixation, slip reduction, and posterior lumbar interbody fusion. The slip was anatomically reduced by 100% in 5 patients and between 90% and 95% in 7 (average 95% for the group). X-rays revealed no evidence of instrumentation failure at a mean follow-up of 38 months (range: 18 to 72). Minimal loss of correction (5%) was observed in 2 cases. No neurologic complications were encountered. The mean preoperative ODI of 49 dropped to 12 postoperatively (range: 0 to 20). The mean preoperative VAS for back pain of 7.3 dropped to 1.6 after surgery (range: 0 to 3). The mean preoperative VAS for leg pain of 8 dropped to 1 after surgery (range: 0 to 4). Five patients were followed for more than 3 years: none had evidence of adjacent level disc disease.Our results may support performing slip reduction in selected adults with isthmic spondylolisthesis.

Individuals with a spinal cord injury (SCI) are susceptible to deep tissue injury (DTI) which is a pressure-related-necrosis that onsets in the gluteus muscles under the ischial tuberosities (IT). The condition may exacerbate to widespread tissue necrosis and sepsis [1], but early detection is currently not feasible because the injury starts and progresses under intact skin. In SCI patients, local elevated mechanical strains and stresses are formed around the IT, and are not relieved through motion [2]. The excessive tissue strains and stresses, combined with ischemia and hindered diffusion, induce and promote muscle cell death [3]. Recently, we developed a real-time, patient-specific finite element (FE) modeling method and experimental system with a clinical orientation of providing early detection of sub-dermal mechanical conditions that potentially lead to DTI. We presented this system and initial data from healthy adults during the 2006 Summer Bioengineering Conference [4]. Herein, we provide, for the first time, data from trials in an individual with SCI monitored by the system, which indicates that mechanical conditions in gluteus muscles of SCI patients are substantially distinct from those of control subjects.Copyright © 2008 by ASME

Elevated stresses in deep plantar tissue of diabetic neuropathic patients were associated with an increased risk for foot ulceration, but only interfacial foot pressures are currently measured to evaluate susceptibility to ulcers. The goals of this study were to develop a real-time patient-specific plantar tissue stress monitor based on the Hertz contact theory. The biomechanical model for stress calculations considers the heel and metatarsal head pads, where most ulcers occur. For calculating stress concentrations around the bone-pad interface, plantar tissue is idealized as elastic and incompressible semi-infinite bulk (with properties measured by indentation), which is penetrated by a rigid sphere with the bone’s radius of curvature (from X-ray). Hertz’s theory is used to solve the bone-pad mechanical interactions, after introducing correction coefficients to consider large deformations. Foot-shoe forces are measured to solve and display the principal compressive, tensile, and von Mises plantar tissue stresses in real time. Our system can be miniaturized in a handheld computer, allowing plantar stress monitoring in the patient’s natural environment. Small groups of healthy subjects (N=6) and diabetic patients (N=3) participated in an evaluation study in which the differences between free walking and treadmill walking were examined. We also compared gait on a flat surface to gait on an ascending/descending slope of 3.5deg and when ascending/descending stairs. Peak internal compression stress was about threefold greater than the interface pressure at the calcaneus region. Subjects who were inexperience in treadmill walking displayed high gait-cycle variability in the internal stresses as well as poor foot loading. There was no statistical difference between gait on a flat surface and gait when ascending/descending a slope. Internal stresses under the calcaneus during gait on a flat surface, however, were significantly higher than when ascending/descending stairs. We conclude that the present stress monitor is a promising tool for real-time patient-specific evaluation of deep tissue stresses, providing valuable information in the effort to protect diabetic patients from foot ulceration. Clinical studies are now underway to identify which stress parameters can distinguish between diabetic and normal subjects; these parameters may be used for establishing injury threshold criteria.

A pressure-related deep tissue injury (DTI) is a severe pressure ulcer, which initiates in muscle tissue overlying a bony prominence (e.g. the ischial tuberosities, IT) and progresses outwards through fat and skin, unnoticed by the paralyzed patient. We recently showed that internal strains and stresses in muscle and fat of individuals at anatomical sites susceptible to DTI can be evaluated by integrating Open-MRI scans with subject-specific finite element (FE) analyzes (Linder-Ganz et al., Journal of Biomechanics, 2007); however, sub-dermal soft tissue strains/stresses from paraplegics are still missing in literature. We hypothesize that the pathoanatomy of the buttocks in paraplegia increases the internal soft tissue loads under the IT, making these patients inherently susceptible to DTI. We hence compared the strain and stress peaks in the gluteus muscle and fat tissues under the IT of six healthy and six paraplegic patients, using the coupled MRI-FE method. Peak principal compression, principal tension, von Mises and shear strains in the gluteus were 1.2-, 3.1-, 1.4- and 1.4-fold higher in paraplegics than in healthy, respectively (p

The cases of six adolescent males with a mild thoracic scoliosis of unknown etiology and a marked limitation of neck flexion are reported. All six complained of mild thoracic spine pain and were 13–17 years old at the onset of their symptoms. In addition to the thoracic scoliosis, all were found to have a marked limitation of neck flexion. They were unable to touch their chest wall with their chin. None had a positive family history of scoliosis. Radiological examination revealed a thoracic scoliosis of 10°–40°, no abnormalities were detected on cervical spine plain radiographs. Extensive investigations, including MRI of the entire spine, failed to disclose the cause of the spinal deformity or the mechanism causing the limitation of neck motion. Apart from the limited cervical flexion and mild pain, this condition was found to be benign and the spine deformity to be mild or moderate in nature and with limited progression. Review of the literature failed to identify similar cases.

Fitting of a prosthetic socket is a critical stage in the process of rehabilitation of a trans-tibial amputation (TTA) patient, since a misfit may cause pressure ulcers or a deep tissue injury (DTI: necrosis of the muscle flap under intact skin) in the residual limb. To date, prosthetic fitting typically depends on the subjective skills of the prosthetist, and is not supported by biomedical instrumentation that allows evaluation of the quality of fitting. Specifically, no technology is presently available to provide real-time continuous information on the internal distribution of mechanical stresses in the residual limb during fitting of the prosthesis, or while using it and this severely limits patient evaluations. In this study, a simplified yet clinically oriented patient-specific finite element (FE) model of the residual limb was developed for real-time stress analysis. For this purpose we employed a custom-made FE code that continuously calculates internal stresses in the residual limb, based on boundary conditions acquired in real-time from force sensors, located at the limb-prosthesis interface. Validation of the modeling system was accomplished by means of a synthetic phantom of the residual limb, which allowed simultaneous measurements of interface pressures and internal stresses. Human studies were conducted subsequently in five TTA patients. The dimensions of bones and soft tissues were obtained from X-rays of the residual limb of each patient. An indentation test was performed in order to obtain the effective elastic modulus of the soft tissues of the residual limb. Seven force sensors were placed between the residual limb and the prosthetic liner, and subjects walked on a treadmill during analysis. Generally, stresses under the shinbones were approximately threefold higher than stresses at the soft tissues behind the bones. Usage of a thigh corset decreased the stresses in the residual limb during gait by approximately 80%. Also, the stresses calculated during the trial of a subject who complained about pain and discomfort were the highest, confirming that his socket was not adequately fitted. We conclude that real-time patient-specific FE analysis of internal stresses in deep soft tissues of the residual limb in TTA patients is feasible. This method is promising for improving the fitting of prostheses in the clinical setting and for protecting the residual limb from pressure ulcers and DTI.

Hyperpronation may cause malalignment of the lower extremity, frequently leading to structural and functional deficits both in standing and walking. Our aim was to study the effect of induced foot hyperpronation on pelvic and lower limb alignment while standing. Thirty-five healthy subjects were requested to remain in a natural standing position for 20 s in four different modes: feet flat on the floor, and on wedges angled at 108 ,1 58 and 208, designed to induce hyperpronation. Sequencing was random, repeated three times and captured by eight computerizedcameras usingtheVICON 1 three-dimensional motionanalysis system.Wefoundthat standingonthewedgesatvariousangles, inducedhyperpronation,with 41%to90%of thechangesattributabletotheintervention.Inaddition, astatisticallysignificantincrease (paired t-test) in internal shank rotation (p < 0.0001), internal hip rotation (p < 0.0001) and anterior pelvic tilt (p < 0.0001) was identified. A strong correlation was found between segmental alignment in every two consecutive modes at all levels (r = 0.612‐0.985; p < 0.0001). These findings suggest that alignment of the lower extremity up to the pelvic girdle, can be altered, due to forces acting on the foot. Interaction between thefoot and pelvis occursin a kinematic chainreaction manner. Although this study waslimited tohealthy subjects, clinicians should be aware that when addressing pelvis and lower back dysfunction, foot alignment should be examined as a contributing factor. # 2006 Elsevier B.V. All rights reserved.

Lumbar or sacral nerve root compression is most commonly caused by intervertebral disc degeneration and/or herniation. Less frequently, other extradural causes may be implicated, such as infection, neoplasm, epidural hematoma, or ligamentum flavum pathology. We present the case of a patient with spontaneous ligamentum flavum hematoma compressing the L4 nerve root, without antecedent trauma. Although exceedingly rare, the diagnosis of ligamentum flavum pathology in general, and that of ligamentum flavum hematoma in particular, should be considered on those rare occasions when the etiology of lumbar or sacral nerve root compressions appears enigmatic on radiological studies. Usually surgical treatment produces excellent clinical outcome.

No technology is presently available to provide information on internal deformations and stresses in plantar soft tissues during evaluation of the gait pattern, in real-time. Because internal deformations and stresses in the plantar pad are critical factors in foot injuries, this severely limits evaluation of patients. To allow such analyses, we developed a hierarchical modeling system integrating structural and finite element (FE) foot models. The higher-order part is a two-dimensional model that provides analytical solution of the time-dependent plantar fascia tensile forces during the stance phase. These forces are transferred, together with measured ground reactions to the lower-order level of the modeling system, where they serve as boundary conditions for local FE analysis of deformations and stresses in the plantar pad. Boundary conditions from the higher-order model were validated with respect to previous, more detailed FE models that could not be utilized for real-time analysis. Subsequently, real-time deformations and stresses in the plantar pad were obtained during gait.

We describe a case of an L4 vertebra with communicating superior and inferior Schmorl’s nodes, creating a longitudinal tunnel through the vertebral body.