Rib detection using pitch-catch ultrasound and classification algorithms for a novel ultrasound therapy device.

BACKGROUND: Noninvasive ultrasound (US) has been used therapeutically for decades, with applications in tissue ablation, lithotripsy, and physical therapy. There is increasing evidence that low intensity US stimulation of organs can alter physiological and clinical outcomes for treatment of health disorders including rheumatoid arthritis and diabetes. One major translational challenge is designing portable and reliable US devices that can be used by patients in their homes, with automated features to detect rib location and aid in efficient transmission of energy to organs of interest. This feasibility study aimed to assess efficacy in rib bone detection without conventional imaging, using a single channel US pitch-catch technique integrated into an US therapy device to detect pulsed US reflections from ribs. METHODS: In 20 healthy volunteers, the location of the ribs and spleen were identified using a diagnostic US imaging system. Reflected ultrasound signals were recorded at five positions over the spleen and adjacent ribs using the therapy device. Signals were classified as between ribs (intercostal), partially over a rib, or fully over a rib using four models: threshold-based time domain classification, threshold-based frequency domain classification, logistic regression, and support vector machine (SVM). RESULTS: SVM performed best overall on the All Participants cohort with accuracy up to 96.25%. All models' accuracies were improved by separating participants into two cohorts based on Body Mass Index (BMI) and re-fitting each model. After separation into Low BMI and High BMI cohorts, a simple time-thresholding approach achieved accuracies up to 100% and 93.75%, respectively. CONCLUSION: These results demonstrate that US reflection signal classification can accurately provide low complexity, real-time automated onboard rib detection and user feedback to advance at-home therapeutic US delivery.

Quantifying Rheumatoid Arthritis Disease Activity Using a Multimodal Sensing Knee Brace.

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory syndrome that features painful and destructive joint disease. Aggressive disease-modifying treatment can result in reduced symptoms and protection from irreversible joint damage; however, assessment of treatment efficacy is currently based largely on subjective measures of patient and physician impressions. In this work, we address this compelling need to provide an accurate and quantitative capability for monitoring joint health in patients with RA. METHODS: Joint acoustic emissions (JAEs), electrical bioimpedance (EBI), and kinematics were measured noninvasively from 11 patients with RA over the course of three weeks using a custom multimodal sensing brace, resulting in 49 visits with JAE recordings and 43 with EBI recordings. Features derived from all sensing modalities were fed into a linear discriminant analysis (LDA) model to predict disease activity according to the validated disease activity index (the DAS28-ESR). Erythrocyte sedimentation rate (ESR) was predicted using ridge regression and classified into a high or low class using LDA. RESULTS: DAS28-ESR level was predicted with an area under the receiver operating characteristic curve (AUC) of 0.82. With JAEs alone, we were able to track intrasubject differences in the disease activity score as well as classify ESR level with an AUC of 0.93. The majority of patients reported both an interest and ability to use the brace at home for longitudinal monitoring. CONCLUSION: This work demonstrates the ability to detect RA disease activity using noninvasive sensing. SIGNIFICANCE: This system has the potential to improve RA disease activity monitoring by giving treating clinicians objective data that can be acquired independent of a face-to-face clinic visit.

Ultrasound does not activate but can inhibit in vivo mammalian nerves across a wide range of parameters.

Ultrasound (US) has been shown to stimulate brain circuits, however, the ability to excite peripheral nerves with US remains controversial. To the best of our knowledge, there is still no in vivo neural recording study that has applied US stimulation to a nerve isolated from surrounding tissue to confirm direct activation effects. Here, we show that US cannot excite an isolated mammalian sciatic nerve in an in vivo preparation, even at high pressures (relative to levels recommended in the FDA guidance for diagnostic ultrasound) and for a wide range of parameters, including different pulse patterns and center frequencies. US can, however, reliably inhibit nerve activity whereby greater suppression is correlated with increases in nerve temperature. By prohibiting the nerve temperature from increasing during US application, we did not observe suppressive effects. Overall, these findings demonstrate that US can reliably inhibit nerve activity through a thermal mechanism that has potential for various health disorders, though future studies are needed to evaluate the long-term safety of therapeutic ultrasound applications.

Single-step label-free nanowell immunoassay accurately quantifies serum stress hormones within minutes.

A non-faradaic label-free cortisol sensing platform is presented using a nanowell array design, in which the two probe electrodes are integrated within the nanowell structure. Rapid and low volume (≤5 µl) sensing was realized through functionalizing nanoscale volume wells with antibodies and monitoring the real-time binding events. A 28-well plate biochip was built on a glass substrate by sequential deposition, patterning, and etching steps to create a stack nanowell array sensor with an electrode gap of 40 nm. Sensor response for cortisol concentrations between 1 and 15 µg/dl in buffer solution was recorded, and a limit of detection of 0.5 µg/dl was achieved. Last, 65 human serum samples were collected to compare the response from human serum samples with results from the standard enzyme-linked immunosorbent assay (ELISA). These results confirm that nanowell array sensors could be a promising platform for point-of-care testing, where real-time, laboratory-quality diagnostic results are essential.

Peripheral Focused Ultrasound Stimulation (pFUS): New Competitor in Pharmaceutical Markets?

A new study published in Nature Communications outlines our group's results using focused ultrasound stimulation within peripheral organs to precisely activate autonomic nerve circuits. The concept is demonstrated by modulating two different (and potentially therapeutic) targets in animal models, a neuroimmune connection in the spleen (that modulates blood cytokine concentrations) and a nutrient sensory pathway within the liver (that modulates metabolism). Connected to this work is a companion Nature Communications publication that utilizes an ultrasound stimulus focused on the spleen to reduce disease severity in a serum-transferred rodent model of inflammatory arthritis. These reports highlight the growing evidence that ultrasound energy (previously shown to enable activation or modulation of central nervous system pathways) may be used to perform peripheral neuromodulation. In this commentary, we highlight the main findings and discuss their implications for new forms of ultrasound-based therapy. Though challenges remain, a new noninvasive method for precision neuromodulation could solve many of the challenges facing the nascent field of bioelectronic medicine. That is, the use of ultrasound to directly modulate neurophysiological systems therapeutically may provide alternatives to traditional pharmaceuticals. However, to alter the current pharmaceutical paradigm, the field will need to develop a new understanding of how traditional drug concepts (such as dose and pharmacokinetics-pharmacodynamics) relate to the parameters, protocols, and outcomes of this new stimulation technology.

Noninvasive ultrasound stimulation of the spleen to treat inflammatory arthritis.

Targeted noninvasive control of the nervous system and end-organs may enable safer and more effective treatment of multiple diseases compared to invasive devices or systemic medications. One target is the cholinergic anti-inflammatory pathway that consists of the vagus nerve to spleen circuit, which has been stimulated with implantable devices to improve autoimmune conditions such as rheumatoid arthritis. Here we report that daily noninvasive ultrasound (US) stimulation targeting the spleen significantly reduces disease severity in a mouse model of inflammatory arthritis. Improvements are observed only with specific parameters, in which US can provide both protective and therapeutic effects. Single cell RNA sequencing of splenocytes and experiments in genetically-immunodeficient mice reveal the importance of both T and B cell populations in the anti-inflammatory pathway. These findings demonstrate the potential for US stimulation of the spleen to treat inflammatory diseases.

Optogenetic activation of cholinergic neurons in the PPT or LDT induces REM sleep.

Rapid eye movement (REM) sleep is an important component of the natural sleep/wake cycle, yet the mechanisms that regulate REM sleep remain incompletely understood. Cholinergic neurons in the mesopontine tegmentum have been implicated in REM sleep regulation, but lesions of this area have had varying effects on REM sleep. Therefore, this study aimed to clarify the role of cholinergic neurons in the pedunculopontine tegmentum (PPT) and laterodorsal tegmentum (LDT) in REM sleep generation. Selective optogenetic activation of cholinergic neurons in the PPT or LDT during non-REM (NREM) sleep increased the number of REM sleep episodes and did not change REM sleep episode duration. Activation of cholinergic neurons in the PPT or LDT during NREM sleep was sufficient to induce REM sleep.