Electrocorticography (ECoG), the use of nonpenetrating electrodes to record brain potentials directly from the surface of the cerebral cortex, has emerged as a promising tool for obtaining recordings of high spatial and temporal resolution. Numerous studies have described the patterns of ECoG
Vagal fibers travel inside fascicles and form branches to innervate organs and regulate organ functions. Existing vagus nerve stimulation (VNS) therapies activate vagal fibers non-selectively, often resulting in reduced efficacy and side effects from non-targeted organs. The transverse and longitudinal arrangement of fibers inside the vagal trunk with respect to the functions they mediate and organs they innervate is unknown, however it is crucial for selective VNS. Using micro-computed tomography tracking, we found that, in swine, fascicles are arranged in 2 overlapping axes, with sensory and motor fascicles separated cephalad and merging caudad, and larynx-, heart- and lung-specific fascicles separated caudad and progressively merging cephalad. Using quantified immunohistochemistry, we found that the distribution of single fibers is highly nonuniform: myelinated afferents and efferents occupy separate fascicles, unmyelinated efferents co-localize with myelinated afferents, and small unmyelinated afferents are widely distributed. We developed a multi-contact cuff electrode that accommodates the fascicular organization of the vagal trunk and used it to deliver fascicle-selective cervical VNS in anesthetized and awake swine. Compound action potentials, from distinct fiber types, and physiological responses from different organs, including laryngeal muscle, cough, breathing, heart rate and blood pressure responses are elicited in a radially asymmetric manner, with consistent angular separations that agree with the documented fascicular organization. These results indicate that fibers in the trunk of the vagus nerve are anatomically organized according to functions they mediate and organs they innervate and can be asymmetrically activated by fascicular cervical VNS.
Afferent and efferent fibers in the vagus nerve travel inside fascicles and form branches to innervate organs and regulate organ functions. The spatial organization of fibers and fascicles, with respect to the functions they mediate and the organs they innervate, is unknown. Accordingly, it is unknown whether such organization can be leveraged by bioelectronic devices for function- and organ-specific neurostimulation. To characterize the functional microscopic anatomy of the vagus nerve, we developed a pipeline consisting of micro-computed tomography and 3D reconstruction of fascicles, and immunohistochemistry, annotation and classification of single fibers. In swine, fascicles are organized along two overlapping functional axes: one axis specific to sensory vs. motor somatic and visceral functions, with fascicle clusters increasingly separating in the cephalad direction, and a second axis specific to innervated organs, including larynx, lungs and heart, with increasing separation in the caudad direction. In the cervical vagus, myelinated afferent and efferent fibers occupy separate fascicle clusters, parasympathetic and sympathetic fibers occupy largely non-overlapping fascicles, and small unmyelinated afferents are found in most fascicles. To test whether fibers can be selectively modulated, we used multi-contact cuff electrodes to stimulate separate nerve sections. Spatially selective stimuli evoke compound action potentials from fibers of distinct functional types and elicit differential organ responses, including laryngeal muscle contraction, cough reflex, and changes in breathing, heart rate and blood pressure. Our results indicate that vagus fibers are anatomically organized according to functions they mediate and organs they innervate and can be differentially modulated by spatially selective nerve stimulation.
Abstract Objective. Vagus nerve stimulation (VNS) is typically delivered at increasing stimulus intensity until a neurological or physiological response is observed (‘threshold’) for dose calibration, preclinically and therapeutically. Factors affecting VNS thresholds have not been studied systematically. In a rodent model of VNS we measured neural and physiological responses to increasing VNS intensity, determined neurological and physiological thresholds and examined the effect of implant- and anesthesia-related factors on thresholds. Approach. In acute and chronic vagus implants (45 and 20 rats, respectively) VNS was delivered under isoflurane, ketamine-xylazine, or awake conditions. Evoked compound action potentials (CAPs) were recorded and activation of different fiber types was extracted. Elicited physiological responses were registered, including changes in heart rate (HR), breathing rate (BR), and blood pressure (BP). CAP and physiological thresholds were determined. Main results . The threshold for evoking discernable CAPs (>10 µ V) (CAP threshold) is significantly lower than what elicits 5%–10% drop in heart rate (heart rate threshold, HRT) (25 µ A ± 1.8 vs. 80 µ A ± 5.1, respectively; mean ± SEM). Changes in BP and small changes in BR (bradypnea) occur at lowest intensities (70 µ A ± 8.3), followed by HR changes (80 µ A ± 5.1) and finally significant changes in BR (apnea) (310 μ A ± 32.5). HRT and electrode impedance are correlated in chronic (Pearson correlation r = 0.47; p < 0.001) but not in acute implants ( r = −0.34; p NS); HRT and impedance both increase with implant age ( r = 0.44; p < 0.001 and r = 0.64; p < 0.001, respectively). HRT is lowest when animals are awake (200 µ A ± 35.5), followed by ketamine-xylazine (640 µ A ± 151.5), and isoflurane (1000 µ A ± 139.5). The sequence of physiological responses with increasing VNS intensity is the same in anesthetized and awake animals. Pulsing frequency affects physiological responses but not CAPs. Significance . Implant age, electrode impedance, and type of anesthesia affect VNS thresholds and should be accounted for when calibrating stimulation dose.
The relationship among iron status, ferritin, and folate levels, and the possible contribution of folate measurement in the prediction of iron response in hemodialysis patients, have not been assessed. In addition to serum ferritin and transferrin saturation (TSAT), serum and red blood cell (RBC) folate levels were evaluated as indices for intravenous iron therapy responsiveness in 60 hemodialysis patients. Patients were classified as iron responders or nonresponders depending on whether they exhibited a rise in hemoglobin above 1 g/dl after administration of 1 g of iron sucrose. An inverse relation between serum ferritin concentration and RBC folate levels was found in iron responders (n=26, r=-0.62, p<0.001) but not in nonresponders (n=34, r=0.07, p=nonsignificant). Only serum and RBC folate levels could predict iron response in patients with ferritin levels above 150 microg/l (n=25), with a sensitivity of 83.3% and a specificity of 94.7%. Our findings suggest that RBC folate concentration is inversely related with ferritin levels in iron-responsive but not in non-responsive hemodialysis patients. Serum and RBC folate concentration seems to predict response to iron administration better than serum ferritin or TSAT in patients with ferritin levels above 150 microg/l; therefore, in these patients, it might be used to guide iron management.
The vagus nerve is involved in the autonomic regulation of physiological homeostasis, through vast innervation of cervical, thoracic and abdominal visceral organs. Stimulation of the vagus with bioelectronic devices represents a therapeutic opportunity for several disorders implicating the autonomic nervous system and affecting different organs. During clinical translation, vagus stimulation therapies may benefit from a precision medicine approach, in which stimulation accommodates individual variability due to nerve anatomy, nerve-electrode interface or disease state and aims at eliciting therapeutic effects in targeted organs, while minimally affecting non-targeted organs. In this review, we discuss the anatomical and physiological basis for precision neuromodulation of the vagus at the level of nerve fibers, fascicles, branches and innervated organs. We then discuss different strategies for precision vagus neuromodulation, including fascicle- or fiber-selective cervical vagus nerve stimulation, stimulation of vagal branches near the end-organs, and ultrasound stimulation of vagus terminals at the end-organs themselves. Finally, we summarize targets for vagus neuromodulation in neurological, cardiovascular and gastrointestinal disorders and suggest potential precision neuromodulation strategies that could form the basis for effective and safe therapies.
Slow wave sleep (SWS) has been identified as the sleep stage involved in consolidating newly acquired information. A growing body of evidence has shown that delta (1-4 Hz) oscillatory activity, the characteristic electroencephalographic signature of SWS, is involved in coordinating interaction between the hippocampus and the neocortex and is thought to take a role in stabilizing memory traces related to a novel task. This case report describes a new protocol that uses neuroprosthetics training of a non-human primate to evaluate the effects of surface cortical electrical stimulation triggered from SWS cycles. The results suggest that stimulation phase-locked to SWS oscillatory activity promoted learning of the neuroprosthetic task. This protocol could be used to elucidate mechanisms of synaptic plasticity underlying off-line learning during sleep and offers new insights into the role of brain oscillations in information processing and memory consolidation.
