Evolving Refractory Major Depressive Disorder Diagnostic and Treatment Paradigms: Toward Closed-Loop Therapeutics

Current antidepressant therapies do not effectively control or cure depressive symptoms. Pharmaceutical therapies altogether fail to address an estimated 4 million Americans who suffer from a recurrent and severe treatment-resistant form of depression known as refractory major depressive disorder. Subjective diagnostic schemes, differing manifestations of the disorder, and antidepressant treatments with limited theoretical bases each contribute to the general lack of therapeutic efficacy and differing levels of treatment resistance in the refractory population. Stimulation-based therapies, such as vagus nerve stimulation, transcranial magnetic stimulation, and deep brain stimulation, are promising treatment alternatives for this treatment-resistant subset of patients, but are plagued with inconsistent reports of efficacy and variable side effects. Many of these problems stem from the unknown mechanisms of depressive disorder pathogenesis, which prevents the development of treatments that target the specific underlying causes of the disorder. Other problems likely arise due to the non-specific stimulation of various limbic and paralimbic structures in an open-loop configuration. This review critically assesses current literature on depressive disorder diagnostic methodologies, treatment schemes, and pathogenesis in order to emphasize the need for more stringent depressive disorder classifications, quantifiable biological markers that are suitable for objective diagnoses, and alternative closed-loop treatment options tailored to well-defined forms of the disorder. A closed-loop neurostimulation device design framework is proposed, utilizing symptom-linked biomarker abnormalities as control points for initiating and terminating a corrective electrical stimulus which is autonomously optimized for correcting the magnitude and direction of observed biomarker abnormality

Effects of a synthetic bioactive peptide on neurite growth and nerve growth factor release in chondroitin sulfate hydrogels.

Previous work has revealed robust dorsal root ganglia neurite growth in hydrogels of chondroitin sulfate. In the current work, it was determined whether addition of a synthetic bioactive peptide could augment neurite growth in these matrices via enhanced binding and sequestering of growth factors. Fluorescence recovery after photobleaching studies revealed that addition of peptide slowed nerve growth factor diffusivity in chondroitin sulfate gels, but not in control gels of hyaluronic acid. Furthermore, cultures of chick dorsal root ganglia in gels of hyaluronic acid or chondroitin sulfate revealed enhanced growth in chondroitin sulfate gels only upon addition of peptide. Taken together, these results suggest a synergistic nerve growth factor-binding activity between this peptide and chondroitin sulfate

A Chronically Implanted, Continuous pH Monitoring System for Rats

Many body systems operate within a strict pH range, and any deviation can cause harm. pH measurement systems are used in many biomedical research fields. Measurement systems have been able to continuously record pH for a short period of time wirelessly, or over a long period of time with wires, but no system is currently capable of long term, wireless, continuous pH recording. This paper proposes a new pH measurement system that is capable of such measurement. The system is composed of inexpensive, micro-scale, and easy to manufacture pH sensitive and reference electrodes and a data acquisition and transmission module that is wirelessly powered. The system is small enough to be chronically implanted in a rat. In vitro testing of the system showed a linear, stable pH response. The system provides a new tool to researchers who wish to study pH in vivo, chronically, and in micro scale applications

Wireless Myoelectric Sensor Minimization and Packaging

Many people suffer from amputation, which affects their lives severely by disabling them from doing chores in their daily life as well as chores related to work and leisure. For the last years, prosthetics’ development has been fast and the devices that are being used now are a miracle compared to what has been used before. But still, the battle is not over yet. Although scientists have techniques and devices to use nerve residues from the amputated limb to control the prosthetic, smaller devices that can detect the signals from those nerves better need to be developed. In this research project the main focus is to make a device that can detect those signals better than the devices that have already been made and minimize the size of it. To do that, constant development, diminishing, fabrication and testing (by implanting them in animals) of new devices needs to be performed. The findings of this research are that the device that is being worked on can be simultaneously wirelessly powered and it can receive live animal data from inside of the animal. Although that is a great achievement on its own, further research needs to be done to improve the device more. If development continues at this rate, the lives of people that have lost a limb will soon become so much better

Wirelessly Powered and Transmitting Current Sensing Device

As the rate of incidence of diabetes increases in the modern world, more accurate and reliable methods of glucose detection must be developed for patients with diabetes. Currently, 25.8 million people have diabetes in the United States alone and account for $174 billion in healthcare costs annually [1]. Devices that can be used without the need for as much patient interaction, regular replacement, or great patient expenses would be a large step forward in the ability of doctors and patients to effectively manage diabetes. To measure glucose concentrations in vivo, a biosensor is used to transduce glucose to an electrical current. Because of this, a device capable of converting an inputted current to a corresponding digital output, wirelessly transmitting the output to a computer, and operating completely on wireless powering was developed and tested. The device is able to take multiple measurements per second of an input current source within the range of 0 – 1mA at a resolution of about 4µA. This range can be reduced to smaller ranges with smaller resolutions within reason. For future work, the device will be tested with amperometric glucose sensors to create a fully, implantable wireless device

Pathway by which Vagus Nerve Stimulation of B Fibers Affects Heart Rate

Heart failure (HF) affects over 5 million adults in the United States. Many HF patients have a high resting heart rate, which is correlated with a high mortality rate. In recent years, vagus nerve stimulation (VNS) has become an increasingly researched therapy to reduce the resting heart rate of HF patients. However, current dosage given during VNS is increased incrementally at the doctor’s office until side effects present themselves in a patient. In addition, the means by which the therapy works is not completely understood. To better understand the therapy’s mechanisms, the right cervical vagus nerve of several Long Evans rats was exposed and cuffed. Autonomous Nerve Control (ANC) was utilized to activate various percentages of B Fibers, which have been found to be the most influential fiber on heart rate. After the first round of stimulation, a vagotomy was performed superior to the stimulation cuff on the nerve, and the stimulation was repeated. Initial experimentation was performed to confirm the electronics set-up and the surgical approach as well as ensure that a decrease in heart rate could be achieved with stimulation. Further experimentation is still needed to fully characterize the relationship between VNS and heart rate both before and after vagotomy. Knowing the pathway by which VNS affects heart rate can give further insight into how VNS treatment works. Additionally, further research needs to be performed to characterize the interaction between VNS therapy and drugs routinely prescribed to HF patients

Medical Applications of MRC

Consistent powering is a limiting reagent for many medical implants and sensors. Powering in-vivo devices in animal studies requires either transcutaneous wiring (limiting mobility and increasing the chance of infection) or an implanted battery (limited lifetime and limits size of device). Wireless power transfer (WPT) would be able to overcome these challenges and permit the use of more advanced implantable devices in a research setting. Magnetic resonance coupling (MRC), an advanced form of inductive charging, allows good transfer efficiencies over significant air gaps, but works best a specific location and frequency, limiting mobility in animal studies. Using band-pass filter theory, an MRC system was simulated and optimized, as well as a design for a continuous WPT animal cage system utilizing MRC with 896 cm2. Both the frequency response and the actual power transfer of the systems were tested; downstream rectification circuitry was also developed to demonstrate WPT. Results indicate using multiple coils in series in a circle orthogonal to the individual coils produced a homogenous magnetic field and frequency response, and using passive coils increased coupling and efficient power transfer. While MRC is traditionally not a robust system, our results show the application can be extended charging over a wide range of space, allowing animal mobility and current experiments to be aided with electronic implants

Towards a pan-European coastal flood awareness system: Skill of extreme sea-level forecasts from the Copernicus Marine Service

European coasts are regularly exposed to severe storms that trigger extreme water-level conditions, leading to coastal flooding and erosion. Early Warning Systems (EWS) are important tools for the increased preparedness and response against coastal flood events, hence greatly reducing associated risks. With this objective, a proof-of-concept for a European Coastal Flood Awareness System (ECFAS) was developed in the framework of the H2020 ECFAS project, which capitalizes on the Copernicus products. In this context, this manuscript evaluates for the first time the capability of the current Copernicus Marine operational ocean models to forecast extreme coastal water levels and hence to feed coastal flood awareness applications at European scale. A methodology is developed to focus the assessment on storm-driven extreme sea level events (EEs) from tide-gauge records. For the detected EEs, the event peak representation is validated, and the impact of forecast lead time is evaluated. Results show satisfactory performance but a general underprediction of peak magnitudes of 10% for water levels and 18% for surges across the detected EEs. In average, the models are capable of independently flagging 76% of the observed EEs. Forecasts show limited lead time impact up to a 4-day lead time, demonstrating the suitability of the systems for early warning applications. Finally, by separating the surge and tidal contributions to the extremes, the potential sources of the prediction misfits are discussed and consequent recommendations for the evolution of the Copernicus Marine Service forecasting models towards coastal flooding applications are provided