Introduction: Vagus nerve stimulation (VNS) is an FDA-approved neuromodulatory treatment used in the clinic today for epilepsy, depression, and cluster headaches. Moreover, evidence in the literature has led to a growing list of possible clinical indications, with several small clinical trials applying VNS to treat conditions ranging from neurodegenerative diseases to arthritis, anxiety disorders, and obesity. Despite the growing list of therapeutic applications, the fundamental mechanisms by which VNS achieves its beneficial effects are poorly understood. In parallel, the glymphatic and meningeal lymphatic systems have recently been described as methods by which the brain maintains a healthy homeostasis and removes waste without a traditionally defined lymphatic system. In particular, the glymphatic system relates to the interchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF) whose net effect is to wash through the brain parenchyma removing metabolic waste products and misfolded proteins. Objective/Hypothesis: As VNS has well-documented effects on many of the pathways recently linked to the clearance systems of the brain, we hypothesized that VNS could increase CSF penetrance in the brain. Methods: We injected a low molecular weight lysine-fixable fluorescent tracer (TxRed-3kD) into the CSF system of mice with a cervical vagus nerve cuff implant and measured the amount of CSF penetrance following an application of a clinically-derived VNS paradigm (30 Hz, 10% duty cycle). Results: We found that the clinical VNS group showed a significant increase in CSF tracer penetrance as compared to the naïve control and sham groups. Conclusion: (s):This study demonstrates that VNS therapeutic strategies already being applied in the clinic today may induce intended effects and/or unwanted side effects by altering CSF/ISF exchange in the brain. This may have broad ranging implications in the treatment of various CNS pathologies.
The proposed approach opens new lines of research with potential applications in understanding the role of different cell types in the cerebrovascular regulatory mechanisms and the study of the adaptive process of angiogenesis in the cerebral cortex. The observation of incoherent responses of vessel diameter, blood flow-rate, and velocity suggests that such detailed information is necessary to obtain an accurate interpretation of the data acquired via hemodynamic based functional imaging techniques.
Background:Clinical outcomes after nerve injury and repair remain suboptimal. Patients may be plagued by poor functional recovery and painful neuroma at the repair site, characterized by disorganized collagen and sprouting axons. Collagen deposition during wound healing can be intrinsically imaged using second harmonic generation (SHG) microscopy. The purpose of this study was to develop a protocol for SHG imaging of nerves and to assess whether collagen alignment can be quantified after nerve repair.Methods:Sciatic nerve transection and epineural repair was performed in male rats. The contralateral nerves were used as intra-animal controls. Ten-millimeter nerve segments were harvested and fixed onto slides. SHG images were collected using a 20× objective on a multiphoton microscope. Collagen fiber alignment was calculated using CurveAlign software. Alignment was calculated on a scale from 0 to 1, where 1 represents perfect alignment. Statistical analysis was performed using a linear mixed-effects model.Results:Eight male rats underwent right sciatic nerve repair using 9-0 Nylon suture. There were gross variations in collagen fiber organization in the repaired nerves compared with the controls. Quantitatively, collagen fibers were more aligned in the control nerves (mean alignment 0.754, SE 0.055) than in the repairs (mean alignment 0.413, SE 0.047; P < 0.001).Conclusions:SHG microscopy can be used to quantitate collagen after nerve repair via fiber alignment. Given that the development of neuroma likely reflects aberrant wound healing, ex vivo and/or in vivo SHG imaging may be useful for further investigation of the variables predisposing to neuroma.
Authors contributed equally to this work One Sentence Summary: Cervical vagus nerve stimulation using clinically derived parameters enhances movement of cerebrospinal fluid into the brain parenchyma presenting a previously unreported effect of vagus nerve stimulation with potential clinical utility.Abstract: Vagal nerve stimulation (VNS) is an FDA approved treatment method for intractable epilepsy, treatment resistant depression, cluster headaches and migraine with over 100,000 patients having received vagal nerve implants to date. Moreover, evidence in the literature has led to a growing list of possible clinical indications, with several small clinical trials applying VNS to treat conditions ranging from neurodegenerative diseases to arthritis, anxiety disorders, and obesity. Despite the growing list of therapeutic applications, the fundamental mechanisms by which VNS achieves its beneficial effects are poorly understood and an area of active research. In parallel, the glymphatic and meningeal lymphatic systems have recently been proposed and experimentally validated to explain how the brain maintains a healthy homeostasis without a traditionally defined lymphatic system. In particular, the glymphatic system relates to the interchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF) whose net effect is to wash through the brain parenchyma removing metabolic waste products and misfolded proteins from the interstitium. Of note, clearance is sensitive to adrenergic signaling, and a primary driver of CSF influx into the parenchyma appears to be cerebral arterial pulsations and respiration. As VNS has well-documented effects on cardiovascular and respiratory physiology as well as brain adrenergic signaling, we hypothesized that VNS delivered at clinically derived parameters would increase CSF influx in the brain. To test this hypothesis, we injected a low molecular weight (3 kD) lysine-fixable fluorescent tracer (TxRed) into the CSF system of mice with a cervical vagus nerve cuff implant and measured the amount of CSF penetrance following VNS. We found that the clinical VNS group showed a significant increase in CSF dye penetrance as compared to the naïve control and sham groups. This study demonstrates that VNS therapeutic strategies already being applied in the clinic today may induce intended effects and/or unwanted side effects by altering CSF/ISF exchange in the brain. This may have broad ranging implications in the treatment of various CNS pathologies.
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