The innervation of bone has been described for centuries, and our understanding of its function has rapidly evolved over the past several decades to encompass roles of subtype‐specific neurons in skeletal homeostasis. Current research has been largely focused on the distribution and function of specific neuronal populations within bone, as well as their cellular and molecular relationships with target cells in the bone microenvironment. This review provides a historical perspective of the field of skeletal neurobiology that highlights the diverse yet interconnected nature of nerves and skeletal health, particularly in the context of bone anabolism and pain. We explore what is known regarding the neuronal subtypes found in the skeleton, their distribution within bone compartments, and their central projection pathways. This neuroskeletal map then serves as a foundation for a comprehensive discussion of the neural control of skeletal development, homeostasis, repair, and bone pain. Active synthesis of this research recently led to the first biotherapeutic success story in the field. Specifically, the ongoing clinical trials of anti‐nerve growth factor therapeutics have been optimized to titrated doses that effectively alleviate pain while maintaining bone and joint health. Continued collaborations between neuroscientists and bone biologists are needed to build on this progress, leading to a more complete understanding of neural regulation of the skeleton and development of novel therapeutics. © 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.

Nerves in bone play well‐established roles in pain and vasoregulation and have been associated with progression of skeletal disorders, including osteoporosis, fracture, arthritis, and tumor metastasis. However, isolation of the region‐specific mechanisms underlying these relationships is limited by our lack of quantitative methods for neuroskeletal analysis and precise maps of skeletal innervation. To overcome these limitations, we developed an optimized workflow for imaging and quantitative analysis of axons in and around the bone, including validation of Baf53b‐Cre in concert with R26R‐tdTomato (Ai9) as a robust pan‐neuronal reporter system for use in musculoskeletal tissues. In addition, we created comprehensive maps of sympathetic adrenergic and sensory peptidergic axons within and around the full length of the femur and tibia in two strains of mice (B6 and C3H). In the periosteum, these maps were related to the surrounding musculature, including entheses and myotendinous attachments to bone. Three distinct patterns of periosteal innervation (termed type I, II, III) were defined at sites that are important for bone pain, bone repair, and skeletal homeostasis. For the first time, our results establish a gradient of bone marrow axon density that increases from proximal to distal along the length of the tibia and define key regions of interest for neuroskeletal studies. Lastly, this information was related to major nerve branches and local maps of specialized mechanoreceptors. This detailed mapping and contextualization of the axonal subtypes innervating the skeleton is intended to serve as a guide during the design, implementation, and interpretation of future neuroskeletal studies and was compiled as a resource for the field as part of the NIH SPARC consortium. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)..

Purpose of Review The goal of this review is to explore clinical associations between peripheral neuropathy and diabetic bone disease and to discuss how nerve dysfunction may contribute to dysregulation of bone metabolism, reduced bone quality, and fracture risk. Recent Findings Diabetic neuropathy can decrease peripheral sensation (sensory neuropathy), impair motor coordination (motor neuropathy), and increase postural hypotension (autonomic neuropathy). Together, this can impair overall balance and increase the risk for falls and fractures. In addition, the peripheral nervous system has the potential to regulate bone metabolism directly through the action of local neurotransmitters on bone cells and indirectly through neuroregulation of the skeletal vascular supply. Summary This review critically evaluates existing evidence for diabetic peripheral neuropathy as a risk factor or direct actor on bone disease. In addition, we address therapeutic and experimental considerations to guide patient care and future research evaluating the emerging relationship between diabetic neuropathy and bone health.

Acoustic features of speech include various spectral and temporal cues. It is known that temporal envelope plays a critical role for speech recognition by human listeners, while automated speech recognition (ASR) heavily relies on spectral analysis. This study compared sentence-recognition scores of humans and an ASR software, Dragon, when spectral and temporal-envelope cues were manipulated in background noise. Temporal fine structure of meaningful sentences was reduced by noise or tone vocoders. Three types of background noise were introduced: a white noise, a time-reversed multi-talker noise, and a fake-formant noise. Spectral information was manipulated by changing the number of frequency channels. With a 20-dB signal-to-noise ratio (SNR) and four vocoding channels, white noise had a stronger disruptive effect than the fake-formant noise. The same observation with 22 channels was made when SNR was lowered to 0 dB. In contrast, ASR was unable to function with four vocoding channels even with a 20-dB SNR. Its performance was least affected by white noise and most affected by the fake-formant noise. Increasing the number of channels, which improved the spectral resolution, generated nonmonotonic behaviors for the ASR with white noise but not with colored noise. The ASR also showed highly improved performance with tone vocoders. It is possible that fake-formant noise affected the software's performance by disrupting spectral cues, whereas white noise affected performance by compromising speech seg-mentation. Overall, these results suggest that human listeners and ASR utilize different listening strategies in noise.

Background/AimsBioelectric nerve stimulation (eStim) is an emerging clinical paradigm that can promote nerve regeneration after trauma, including within the context of diabetes. However, its ability to prevent the onset of diabetic peripheral neuropathy (DPN) has not yet been evaluated. Beyond the nerve itself, DPN has emerged as a potential contributor to sarcopenia and bone disease; thus, we hypothesized that eStim could serve as a strategy to simultaneously promote neural and musculoskeletal health in diabetes.MethodsTo address this question, an eStim paradigm pre-optimized to promote nerve regeneration was applied to the sciatic nerve, which directly innervates the tibia and lower limb, for 8 weeks in control and streptozotocin-induced type 1 diabetic (T1D) rats. Metabolic, gait, nerve and bone assessments were used to evaluate the progression of diabetes and the effect of sciatic nerve eStim on neuropathy and musculoskeletal disease, while also considering the effects of cuff placement and chronic eStim in otherwise healthy animals.ResultsRats with T1D exhibited increased mechanical allodynia in the hindpaw, reduced muscle mass, decreased cortical and cancellous bone volume fraction (BVF), reduced cortical bone tissue mineral density (TMD), and decreased bone marrow adiposity. Type 1 diabetes also had an independent effect on gait. Placement of the cuff electrode alone resulted in altered gait patterns and unilateral reductions in tibia length, cortical BVF, and bone marrow adiposity. Alterations in gait patterns were restored by eStim and tibial lengthening was favored unilaterally; however, eStim did not prevent T1D-induced changes in muscle, bone, marrow adiposity or mechanical sensitivity. Beyond this, chronic eStim resulted in an independent, bilateral reduction in cortical TMD.ConclusionOverall, these results provide new insight into the pathogenesis of diabetic neuroskeletal disease and its regulation by eStim. Though eStim did not prevent neural or musculoskeletal complications in T1D, our results demonstrate that clinical applications of peripheral neuromodulation ought to consider the impact of device placement and eStim on long-term skeletal health in both healthy individuals and those with metabolic disease. This includes monitoring for compounded bone loss to prevent unintended consequences including decreased bone mineral density and increased fracture risk.