Neuromechanobiology: An Expanding Field Driven by the Force of Greater Focus.

The brain processes information by transmitting signals through highly connected and dynamic networks of neurons. Neurons use specific cellular structures, including axons, dendrites and synapses, and specific molecules, including cell adhesion molecules, ion channels and chemical receptors to form, maintain and communicate among cells in the networks. These cellular and molecular processes take place in environments rich of mechanical cues, thus offering ample opportunities for mechanical regulation of neural development and function. Recent studies have suggested the importance of mechanical cues and their potential regulatory roles in the development and maintenance of these neuronal structures. Also suggested are the importance of mechanical cues and their potential regulatory roles in the interaction and function of molecules mediating the interneuronal communications. In this review, the current understanding is integrated and promising future directions of neuromechanobiology are suggested at the cellular and molecular levels. Several neuronal processes where mechanics likely plays a role are examined and how forces affect ligand binding, conformational change, and signal induction of molecules key to these neuronal processes are indicated, especially at the synapse. The disease relevance of neuromechanobiology as well as therapies and engineering solutions to neurological disorders stemmed from this emergent field of study are also discussed.

Toward Functional Restoration of the Central Nervous System: A Review of Translational Neuroscience Principles.

Injury to the central nervous system (CNS) can leave patients with devastating neurological deficits that may permanently impair independence and diminish quality of life. Recent insights into how the CNS responds to injury and reacts to critically timed interventions are being translated into clinical applications that have the capacity to drastically improve outcomes for patients suffering from permanent neurological deficits due to spinal cord injury, stroke, or other CNS disorders. The translation of such knowledge into practical and impactful treatments involves the strategic collaboration between neurosurgeons, clinicians, therapists, scientists, and industry. Therefore, a common understanding of key neuroscientific principles is crucial. Conceptually, current approaches to CNS revitalization can be divided by scale into macroscopic (systems-circuitry) and microscopic (cellular-molecular). Here we review both emerging and well-established tenets that are being utilized to enhance CNS recovery on both levels, and we explore the role of neurosurgeons in developing therapies moving forward. Key principles include plasticity-driven functional recovery, cellular signaling mechanisms in axonal sprouting, critical timing for recovery after injury, and mechanisms of action underlying cellular replacement strategies. We then discuss integrative approaches aimed at synergizing interventions across scales, and we make recommendations for the basis of future clinical trial design. Ultimately, we argue that strategic modulation of microscopic cellular behavior within a macroscopic framework of functional circuitry re-establishment should provide the foundation for most neural restoration strategies, and the early involvement of neurosurgeons in the process will be crucial to successful clinical translation.

Engineering Controlled Peritumoral Inflammation to Constrain Brain Tumor Growth.

Brain tumors remain a great clinical challenge, in part due to their capacity to invade into eloquent, inoperable regions of the brain. In contrast, inflammation in the central nervous system (CNS) due to injuries activates microglia and astrocytes culminating in an astroglial scar that typically "walls-off" the injury site. Here, the hypothesis is tested that targeting peritumoral cells surrounding tumors to activate them via an inflammatory stimulus that recapitulates the sequelae of a traumatic CNS injury, could generate an environment that would wall-off and contain invasive tumors in the brain. Gold nanoparticles coated with inflammatory polypeptides to target stromal cells in close vicinity to glioblastoma (GBM) tumors, in order to activate these cells and stimulate stromal CNS inflammation, are engineered. It is reported that this approach significantly contains tumors in rodent models of GBM relative to control treatments (reduction in tumor volume by over 300% in comparison to controls), by the activation of the innate and adaptive immune response, and by triggering pathways related to cell clustering. Overall, this report outlines an approach to contain invasive tumors that can complement adjuvant interventions for invasive GBM such as radiation and chemotherapy.

Pathophysiology of essential hypertension: an update.

INTRODUCTION: Hypertension is caused by increased cardiac output and/or increased peripheral resistance. Areas covered: The various mechanisms affecting cardiac output/peripheral resistance involved in the development of essential hypertension are covered. These include genetics; sympathetic nervous system overactivity; renal mechanisms: excess sodium intake and pressure natriuresis; vascular mechanisms: endothelial cell dysfunction and the nitric oxide pathway; hormonal mechanisms: the renin-angiotensin-aldosterone system (RAAS); obesity, obstructive sleep apnea (OSA); insulin resistance and metabolic syndrome; uric acid; vitamin D; gender differences; racial, ethnic, and environmental factors; increased left ventricular ejection force and hypertension and its association with increased basal sympathetic activity - cortical connections. Expert commentary: Maximum association of hypertension is found with sympathetic overactivity which is directly or indirectly involved in different mechanisms of hypertension including RAAS, OSA, obesity, etc.. It is not overt sympathetic activity but disturbed basal sympathetic tone. Basal sympathetic tone arises from hypothalamus; possibly affected by cortical influences. Therefore, hypertension is not merely a disease of circulatory system alone. Its pathogenesis involves alteration in ANS (autonomic nervous system) and likely in cortical-hypothalamic connections. Assessment of ANS and cortical-hypothalamic connections may be required for better understanding of hypertension.

Correlation of mRNA Expression and Signal Variability in Chronic Intracortical Electrodes.

OBJECTIVE: The goal for this research was to identify molecular mechanisms that explain animal-to-animal variability in chronic intracortical recordings. APPROACH: Microwire electrodes were implanted into Sprague Dawley rats at an acute (1 week) and a chronic (14 weeks) time point. Weekly recordings were conducted, and action potentials were evoked in the barrel cortex by deflecting the rat's whiskers. At 1 and 14 weeks, tissue was collected, and mRNA was extracted. mRNA expression was compared between 1 and 14 weeks using a high throughput multiplexed qRT-PCR. Pearson correlation coefficients were calculated between mRNA expression and signal-to-noise ratios at 14 weeks. MAIN RESULTS: At 14 weeks, a positive correlation between signal-to-noise ratio (SNR) and NeuN and GFAP mRNA expression was observed, indicating a relationship between recording strength and neuronal population, as well as reactive astrocyte activity. The inflammatory state around the electrode interface was evaluated using M1-like and M2-like markers. Expression for both M1-like and M2-like mRNA markers remained steady from 1 to 14 weeks. Anti-inflammatory markers, CD206 and CD163, however, demonstrated a significant positive correlation with SNR quality at 14 weeks. VE-cadherin, a marker for adherens junctions, and PDGFR-ß, a marker for pericytes, both partial representatives of blood-brain barrier health, had a positive correlation with SNR at 14 weeks. Endothelial adhesion markers revealed a significant increase in expression at 14 weeks, while CD45, a pan-leukocyte marker, significantly decreased at 14 weeks. No significant correlation was found for either the endothelial adhesion or pan-leukocyte markers. SIGNIFICANCE: A positive correlation between anti-inflammatory and blood-brain barrier health mRNA markers with electrophysiological efficacy of implanted intracortical electrodes has been demonstrated. These data reveal potential mechanisms for further evaluation to determine potential target mechanisms to improve consistency of intracortical electrodes recordings and reduce animal-to-animal/implant-to-implant variability.

Enrichment of endogenous fractalkine and anti-inflammatory cells via aptamer-functionalized hydrogels.

Early recruitment of non-classical monocytes and their macrophage derivatives is associated with augmented tissue repair and improved integration of biomaterial constructs. A promising therapeutic approach to recruit these subpopulations is by elevating local concentrations of chemoattractants such as fractalkine (FKN, CX3CL1). However, delivering recombinant or purified proteins is not ideal due to their short half-lives, suboptimal efficacy, immunogenic potential, batch variabilities, and cost. Here we report an approach to enrich endogenous FKN, obviating the need for delivery of exogenous proteins. In this study, modified FKN-binding-aptamers are integrated with poly(ethylene glycol) diacrylate to form aptamer-functionalized hydrogels ("aptagels") that localize, dramatically enrich and passively release FKN in vitro for at least one week. Implantation in a mouse model of excisional skin injury demonstrates that aptagels enrich endogenous FKN and stimulate significant local increases in Ly6CloCX3CR1hi non-classical monocytes and CD206+ M2-like macrophages. The results demonstrate that orchestrators of inflammation can be manipulated without delivery of foreign proteins or cells and FKN-aptamer functionalized biomaterials may be a promising approach to recruit anti-inflammatory subpopulations to sites of injury. Aptagels are readily synthesized, highly customizable and could combine different aptamers to treat complex diseases in which regulation or enrichment of multiple proteins may be therapeutic.

Engineering challenges for brain tumor immunotherapy.

Malignant brain tumors represent one of the most devastating forms of cancer with abject survival rates that have not changed in the past 60years. This is partly because the brain is a critical organ, and poses unique anatomical, physiological, and immunological barriers. The unique interplay of these barriers also provides an opportunity for creative engineering solutions. Cancer immunotherapy, a means of harnessing the host immune system for anti-tumor efficacy, is becoming a standard approach for treating many cancers. However, its use in brain tumors is not widespread. This review discusses the current approaches, and hurdles to these approaches in treating brain tumors, with a focus on immunotherapies. We identify critical barriers to immunoengineering brain tumor therapies and discuss possible solutions to these challenges.

Corrigendum: Kilohertz frequency nerve block enhances anti-inflammatory effects of vagus nerve stimulation.

This corrects the article DOI: 10.1038/srep39810.

Kilohertz frequency nerve block enhances anti-inflammatory effects of vagus nerve stimulation.

Efferent activation of the cervical vagus nerve (cVN) dampens systemic inflammatory processes, potentially modulating a wide-range of inflammatory pathological conditions. In contrast, afferent cVN activation amplifies systemic inflammatory processes, leading to activation of the hypothalamic-pituitary-adrenal (HPA) axis, the sympathetic nervous system through the greater splanchnic nerve (GSN), and elevation of pro-inflammatory cytokines. Ideally, to clinically implement anti-inflammatory therapy via cervical vagus nerve stimulation (cVNS) one should selectively activate the efferent pathway. Unfortunately, current implementations, in animal and clinical investigations, activate both afferent and efferent pathways. We paired cVNS with kilohertz electrical stimulation (KES) nerve block to preferentially activate efferent pathways while blocking afferent pathways. Selective efferent cVNS enhanced the anti-inflammatory effects of cVNS. Our results demonstrate that: (i) afferent, but not efferent, cVNS synchronously activates the GSN in a dose-dependent manner; (ii) efferent cVNS enabled by complete afferent KES nerve block enhances the anti-inflammatory benefits of cVNS; and (iii) incomplete afferent KES nerve block exacerbates systemic inflammation. Overall, these data demonstrate the utility of paired efferent cVNS and afferent KES nerve block for achieving selective efferent cVNS, specifically as it relates to neuromodulation of systemic inflammation.

Assessment of left ventricular ejection force and sympathetic skin response in normotensive and hypertensive subjects: A double-blind observational comparative case-control study.

BACKGROUND: Pathophysiology of essential hypertension remains obscure. Correlation among ventricular ejection force, sympathetic activity, and hypertension is less clearly narrated in hypertensive subjects. AIMS AND OBJECTIVES: To assess correlation among ventricular ejection force, sympathetic activity, and hypertension in hypertensive subjects, and to be compared with normotensive subjects. METHODS: This is a case-control study to assess left ventricular ejection force (LVEF) and sympathetic skin response, in normotensive (group 1; control), and hypertensive subjects (group 2; cases). 100 cases were selected. Subjects having stages 1 and 2 hypertension were categorized in groups 2A and 2B, respectively. LVEF was calculated by using echocardiography observing aortic acceleration time (AT) and peak systolic velocity. Comparison among groups was done by using one-way ANOVA. RESULTS: Both groups were comparable. In group 2, 60 cases had stage 1 hypertension and 40 had stage 2 hypertension. Significantly short AT and significantly high LVEF were found in hypertension (groups 2A and 2B) (p<0.0001). Sympathetic activity was high in group 2A (p<0.0001). Stroke volume (SV) was high in group 2B (p<0.0001). CONCLUSION: Stage 1 hypertension is a stage of increased sympathetic activity, leading to increased LVEF and hypertension (resetting of baroreceptors); stage 2 hypertension is a stage of normal sympathetic activity, increased LVEF, increased SV, and hypertension (possibly a stage of shift of renal equilibrium curve/renal output curve and blood pressure to a newer level).

Chondroitin Sulfate Glycosaminoglycan Hydrogels Create Endogenous Niches for Neural Stem Cells.

Neural stem cells (NSCs) possess great potential for neural tissue repair after traumatic injuries to the central nervous system (CNS). However, poor survival and self-renewal of NSCs after injury severely limits its therapeutic potential. Sulfated chondroitin sulfate glycosaminoglycans (CS-GAGs) linked to CS proteoglycans (CSPGs) in the brain extracellular matrix (ECM) have the ability to bind and potentiate trophic factor efficacy, and promote NSC self-renewal in vivo. In this study, we investigated the potential of CS-GAG hydrogels composed of monosulfated CS-4 (CS-A), CS-6 (CS-C), and disulfated CS-4,6 (CS-E) CS-GAGs as NSC carriers, and their ability to create endogenous niches by enriching specific trophic factors to support NSC self-renewal. We demonstrate that CS-GAG hydrogel scaffolds showed minimal swelling and degradation over a period of 15 days in vitro, absorbing only 6.5 ± 0.019% of their initial weight, and showing no significant loss of mass during this period. Trophic factors FGF-2, BDNF, and IL10 bound with high affinity to CS-GAGs, and were significantly (p < 0.05) enriched in CS-GAG hydrogels when compared to unsulfated hyaluronic acid (HA) hydrogels. Dissociated rat subventricular zone (SVZ) NSCs when encapsulated in CS-GAG hydrogels demonstrated ∼88.5 ± 6.1% cell viability in vitro. Finally, rat neurospheres in CS-GAG hydrogels conditioned with the mitogen FGF-2 demonstrated significantly (p < 0.05) higher self-renewal when compared to neurospheres cultured in unconditioned hydrogels. Taken together, these findings demonstrate the ability of CS-GAG based hydrogels to regulate NSC self-renewal, and facilitate growth factor enrichment locally.

Tailoring between network rigidity and nanosecond transient absorption in a-Ge(x)As(35-x)Se65 thin films.

In this Letter, we report the first observation of dramatic decrease in nanosecond (ns) pulsed laser-induced transient absorption (TA) in a-Ge(x)As(35-x)Se65 thin films by tuning the amorphous network from floppy to rigid. Our results provide the direct experimental evidence of a self-trapped exciton mechanism, where trapping of the excitons occurs through bond rearrangements. Taken together, a rigid amorphous network with more constraints than degrees of freedom are unable to undergo any such bond rearrangements and results in weaker TA. However, we also demonstrate that excitation fluence can be effectively utilized as a simple tool to lift up enough constraints to introduce large TA even in rigid networks. Apart from this, we also show that TA is tunable with network rigidity as it blueshifts when the mean coordination is increased from 2.35 to 2.6.

Intracortical recording interfaces: current challenges to chronic recording function.

Brain Computer Interfaces (BCIs) offer significant hope to tetraplegic and paraplegic individuals. This technology relies on extracting and translating motor intent to facilitate control of a computer cursor or to enable fine control of an external assistive device such as a prosthetic limb. Intracortical recording interfaces (IRIs) are critical components of BCIs and consist of arrays of penetrating electrodes that are implanted into the motor cortex of the brain. These multielectrode arrays (MEAs) are responsible for recording and conducting neural signals from local ensembles of neurons in the motor cortex with the high speed and spatiotemporal resolution that is required for exercising control of external assistive prostheses. Recent design and technological innovations in the field have led to significant improvements in BCI function. However, long-term (chronic) BCI function is severely compromised by short-term (acute) IRI recording failure. In this review, we will discuss the design and function of current IRIs. We will also review a host of recent advances that contribute significantly to our overall understanding of the cellular and molecular events that lead to acute recording failure of these invasive implants. We will also present recent improvements to IRI design and provide insights into the futuristic design of more chronically functional IRIs.

Nanocarrier-mediated inhibition of macrophage migration inhibitory factor attenuates secondary injury after spinal cord injury.

Spinal cord injury (SCI) can lead to permanent motor and sensory deficits. Following the initial traumatic insult, secondary injury mechanisms characterized by persistent heightened inflammation are initiated and lead to continued and pervasive cell death and tissue damage. Anti-inflammatory drugs such as methylprednisolone (MP) used clinically have ambiguous benefits with debilitating side effects. Typically, these drugs are administered systemically at high doses, resulting in toxicity and paradoxically increased inflammation. Furthermore, these drugs have a small time window postinjury (few hours) during which they need to be infused to be effective. As an alternative to MP, we investigated the effect of a small molecule inhibitor (Chicago sky blue, CSB) of macrophage migration inhibitory factor (MIF) for treating SCI. The pleiotropic cytokine MIF is known to contribute to upregulation of several pro-inflammatory cytokines in various disease and injury states. In vitro, CSB administration alleviated endotoxin-mediated inflammation in primary microglia and macrophages. Nanocarriers such as liposomes can potentially alleviate systemic side effects of high-dose therapy by enabling site-specific drug delivery to the spinal cord. However, the therapeutic window of 100 nm scale nanoparticle localization to the spinal cord after contusion injury is not fully known. Thus, we first investigated the ability of nanocarriers of different sizes to localize to the injured spinal cord up to 2 weeks postinjury. Results from the study showed that nanocarriers as large as 200 nm in diameter could extravasate into the injured spinal cord up to 96 h postinjury. We then formulated nanocarriers (liposomes) encapsulating CSB and administered them intravenously 48 h postinjury, within the previously determined 96 h therapeutic window. In vivo, in this clinically relevant contusion injury model in rats, CSB administration led to preservation of vascular and white matter integrity, improved wound healing, and an increase in levels of arginase and other transcripts indicative of a resolution phase of wound healing. This study demonstrates the potential of MIF inhibition in SCI and the utility of nanocarrier-mediated drug delivery selectively to the injured cord.

Extracellular matrix-based intracortical microelectrodes: Toward a microfabricated neural interface based on natural materials.

Extracellular matrix (ECM)-based implantable neural electrodes (NEs) were achieved using a microfabrication strategy on natural-substrate-based organic materials. The ECM-based design minimized the introduction of non-natural products into the brain. Further, it rendered the implants sufficiently rigid for penetration into the target brain region and allowed them subsequently to soften to match the elastic modulus of brain tissue upon exposure to physiological conditions, thereby reducing inflammatory strain fields in the tissue. Preliminary studies suggested that ECM-NEs produce a reduced inflammatory response compared with inorganic rigid and flexible approaches. In vivo intracortical recordings from the rat motor cortex illustrate one mode of use for these ECM-NEs.

Nanosecond light induced, thermally tunable transient dual absorption bands in a-Ge5As30Se65 thin film.

In this article, we report the first observation of nanosecond laser induced transient dual absorption bands, one in the bandgap (TA1) and another in the sub-bandgap (TA2) regions of a-Ge5As30Se65 thin films. Strikingly, these bands are thermally tunable and exhibit a unique contrasting characteristic: the magnitude of TA1 decreases while that of TA2 increases with increasing temperature. Further, the decay kinetics of these bands is strongly influenced by the temperature, which signifies a strong temperature dependent exciton recombination mechanism. The induced absorption shows quadratic and the decay time constant shows linear dependence on the laser beam fluence.

Chondroitin sulfate glycosaminoglycans for CNS homeostasis-implications for material design.

Chondroitin sulfate proteoglycans (CSPGs) are complex biomolecules that are known to facilitate patterning of axonal direction and cell migration during the early growth and development phase of the mammalian central nervous system (CNS). In adults, they continue to control neuronal plasticity as major constituents of the "peri-neuronal nets" (PNNs) that surround adult CNS neurons. CSPGs are also barrier-forming molecules that are selectively upregulated by invading reactive astroglia after injury to the CNS, and are responsible for the active repulsion of regenerating neurons post-injury. Recent evidence however suggests that the diverse sulfated glycosaminoglycan (GAG) side chains attached to CSPGs are key components that play paradoxical roles in influencing nerve regeneration post-injury to the CNS. Sulfated GAG repeats attached to the CSPG core protein help mediate cell migration, neuritogenesis, axonal pathfinding, and axonal repulsion by directly trapping and presenting a whole host of growth factors to cells locally, or by binding to specific membrane bound proteins on the cell surface to influence cellular function. In this review, we will present the current gamut of interventional strategies used to bridge CNS deficits, and discuss the potential advantages of using sulfated GAG based biomaterials to facilitate the repair and regeneration of the injured CNS.

Aetiopathogenesis of type-2 diabetes mellitus: could chronic stress play an important role?

OBJECTIVES: Pathogenesis of type-2 diabetes remains elusive. Various factors including diet, physical exercise, obesity, genetic factors and stress, have been discussed. Among these factors role of stress is still poorly understood in diabetes. Therefore the study was planned to assess effect of stress in diabetic and non-diabetic population in a comparative descriptive manner. METHODS: 1000 diabetic cases (group A) and equal number of healthy individuals were selected as a comparison group (group B). Both groups were examined at 0, 12, 24 months. To assess stress 17 points were examined (factors mainly related to emotions, hurriedness, relaxed status etc.), total 68 points for stress were given; > 30/68 was considered as severe stress. Mental health life style factors like duration of sleep and working mental hours were also examined. EEG and SSR were done at 24 months to assess stress and sympathetic response. RESULTS: There was presence of chronic stress, (> 90% had > 30/68 scoring) more mental work and less sleep duration in group A. EEG showed synchronised v/s desynchronised basal rhythm in group B v/s group A. SSR suggestive of increased sympathetic activity in group A. CONCLUSION: It is concluded that chronic stress leads to increased basal sympathetic activity, resulting from disturbed cortical hypothalamic axis, leading to central insulin resistance and diabetes.

Relationship between intracortical electrode design and chronic recording function.

Intracortical electrodes record neural signals directly from local populations of neurons in the brain, and conduct them to external electronics that control prosthetics. However, the relationship between electrode design, defined by shape, size and tethering; and long-term (chronic) stability of the neuron-electrode interface is poorly understood. Here, we studied the effects of various commercially available intracortical electrode designs that vary in shape (cylindrical, planar), size (15 µm, 50 µm and 75 µm), and tethering [electrode connections to connector with (tethered) and without tethering cable (untethered)] using histological, transcriptomic, and electrophysiological analyses over acute (3 day) and chronic (12 week) timepoints. Quantitative analysis of histological sections indicated that Michigan 50 µm (M50) and Michigan tethered (MT) electrodes induced significantly (p < 0.01) higher glial scarring, and lesser survival of neurons in regions of blood-brain barrier (BBB) breach when compared to microwire (MW) and Michigan 15 µm (M15) electrodes acutely and chronically. Gene expression analysis of the neurotoxic cytokines interleukin (Il)1 (Il1α, Il1ß), Il6, Il17 (Il17a, Il17b, Il17f), and tumor necrosis factor alpha (Tnf) indicated that MW electrodes induced significantly (p < 0.05) reduced expression of these transcripts when compared to M15, M50 and FMAA electrodes chronically. Finally, electrophysiological assessment of electrode function indicated that MW electrodes performed significantly (p < 0.05) better than all other electrodes over a period of 12 weeks. These studies reveal that intracortical electrodes with smaller size, cylindrical shape, and without tethering cables produce significantly diminished inflammatory responses when compared to large, planar and tethered electrodes. These studies provide a platform for the rational design and assessment of chronically functional intracortical electrode implants in the future.