Development of a Smart Wireless Multisensor Platform for an Optogenetic Brain Implant.

Implantable cell replacement therapies promise to completely restore the function of neural structures, possibly changing how we currently perceive the onset of neurodegenerative diseases. One of the major clinical hurdles for the routine implementation of stem cell therapies is poor cell retention and survival, demanding the need to better understand these mechanisms while providing precise and scalable approaches to monitor these cell-based therapies in both pre-clinical and clinical scenarios. This poses significant multidisciplinary challenges regarding planning, defining the methodology and requirements, prototyping and different stages of testing. Aiming toward an optogenetic neural stem cell implant controlled by a smart wireless electronic frontend, we show how an iterative development methodology coupled with a modular design philosophy can mitigate some of these challenges. In this study, we present a miniaturized, wireless-controlled, modular multisensor platform with fully interfaced electronics featuring three different modules: an impedance analyzer, a potentiostat and an optical stimulator. We show the application of the platform for electrical impedance spectroscopy-based cell monitoring, optical stimulation to induce dopamine release from optogenetically modified neurons and a potentiostat for cyclic voltammetry and amperometric detection of dopamine release. The multisensor platform is designed to be used as an opto-electric headstage for future in vivo animal experiments.

Diabetic Foot Assessment using Skin Impedance in a Custom Made Sensor-sock.

Diabetic peripheral neuropathy (DPN) may lead to several changes in the skin, and some of these may influence the skin impedance spectrum. In the present study we have developed a prototype solution for skin impedance spectroscopy at selected skin sites (big toe pulp, heel and toe ball) that was tested in a pilot study on five patients with DPN and five healthy controls. At the big toe, most of the controls had markedly lower impedance than the DPN group, especially in the range of 1-100 kHz. The separation between the groups seems to be weaker at the heel and weakest at the toeball. The results may indicate that monitoring of the skin impedance spectrum may be a method for detection of skin changes associated with DPN, encouraging further studies with the big toe sensor in particular.

A multiparameter model for non-invasive detection of hypoglycemia.

OBJECTIVE: Severe hypoglycemia is the most serious acute complication for people with type 1 diabetes (T1D). Approximately 25% of people with T1D have impaired ability to recognize impending hypoglycemia, and nocturnal episodes are feared. APPROACH: We have investigated the use of non-invasive sensors for detection of hypoglycemia based on a mathematical model which combines several sensor measurements to identify physiological responses to hypoglycemia. Data from randomized single-blinded euglycemic and hypoglycemic glucose clamps in 20 participants with T1D and impaired awareness of hypoglycemia was used in the analyses. MAIN RESULTS: Using a sensor combination of sudomotor activity at three skin sites, ECG-derived heart rate and heart rate corrected QT interval, near-infrared and bioimpedance spectroscopy; physiological responses associated with hypoglycemia could be identified with an F1 score accuracy up to 88%. SIGNIFICANCE: We present a novel model for identification of non-invasively measurable physiological responses related to hypoglycemia, showing potential for detection of moderate hypoglycemia using a wearable sensor system.

An Investigation on Bilateral Asymmetry in Electrodermal Activity.

The Multiple Arousal Theory (Picard et al., 2016) was proposed to explain retrospective observations of bilateral differences in electrodermal activities occurring in threat-related high-stake situations. The theory proposes different cortical and subcortical structures to be involved in the processing of various facets of emotional states. Systematic investigations of this effect are still scarce. This study tested the prediction of bilateral electrodermal effects in a controlled laboratory environment where electrodermal activity (EDA) was recorded bilaterally during normal activity and two stress-tasks in 25 healthy volunteers. A visual search stress task with a performance-related staircase algorithm was used, ensuring intersubjectively comparable stress levels across individuals. After completion of the task, a sense of ownership of an attractive price was created and loss aversion introduced to create a high-stake situation. Confirmation of the theory should satisfy the hypothesis of a bilateral difference in EDA between the dominant and non-dominant hand, which is larger during high-stake stressors than during low-stake stressors. The bilateral difference was quantified and compared statistically between the two stress-tasks, revealing no significant difference between them nor any significant difference between the stress tasks and the period of normal activity. Subgroup analysis of only the participants with maximum self-rating of their desire to win the price (n = 7) revealed neither any significant difference between the two tasks nor between the stress-tasks and the period of normal activity. Although the theory was not confirmed by this study, eight cases suggestive of bilateral difference within the recordings were identified and are presented. Because the study is limited in using one of several possible operationalizations of the phenomenon, it is not possible to draw a general conclusion on the theory. Nevertheless, the study might contribute to a better understanding and encourage systematic review and hypothesis development regarding this new theory. Possible explanations and suggestions for future pathways to systematically investigate the Multiple Arousal Theory are discussed.

Author Correction: Evaluation of Hypoglycaemia with Non-Invasive Sensors in People with Type 1 Diabetes and Impaired Awareness of Hypoglycaemia.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Electrosurgery and Temperature Increase in Tissue With a Passive Metal Implant.

Importance: During monopolar electrosurgery in patients, current paths can be influenced by metal implants, which can cause unintentional tissue heating in proximity to implants. Guidelines concerning electrosurgery and active implants such as pacemakers or implantable cardioverter defibrillators have been published, but most describe interference between electrosurgery and the active implant rather than the risk of unintended tissue heating. Tissue heating in proximity to implants during electrosurgery may cause an increased risk of patient injury. Objective: To determine the temperature of tissue close to metal implants during electrosurgery in an in-vitro model. Design, Setting, and Participants: Thirty tissue samples (15 with a metal implant placed in center, 15 controls without implant) were placed in an in vitro measurement chamber. Electrosurgery was applied at 5-60 W with the active electrode at three defined distances from the implant while temperatures at four defined distances from the implant were measured using fiber-optic sensors. Main Outcomes and Measures: Tissue temperature increase at the four tissue sites was determined for all power levels and each of the electrode-to-implant distances. Based on a linear mixed effects model analysis, the primary outcomes were the difference in temperature increase between implant and control tissue, and the estimated temperature increase per watt per minute. Results: Tissues with an implant had higher temperature increases than controls at all power levels after 1 min of applied electrosurgery (mean difference of 0.16°C at 5 W, 0.50°C at 15 W, 1.11°C at 30 W, and 2.22°C at 60 W, all with p < 0.001). Temperature increase close to the implant was estimated to be 0.088°C/W/min (95% CI: 0.078-0.099°C/W/min; p < 0.001). Temperature could increase to above 43°C after 1 min of 60 W. Active electrode position had no significant effect on temperature increases for tissues with implant (p = 0.6). Conclusions and Relevance: The temperature of tissue close to a metal implant increases with passing electrosurgery current. There is a significant risk of high tissue temperature when long activation times or high power levels are used.

Measuring Blood Pulse Wave Velocity with Bioimpedance in Different Age Groups.

In this project, we have studied the use of electrical impedance cardiography as a possible method for measuring blood pulse wave velocity, and hence be an aid in the assessment of the degree of arteriosclerosis. Using two different four-electrode setups, we measured the timing of the systolic pulse at two locations, the upper arm and the thorax, and found that the pulse wave velocity was in general higher in older volunteers and furthermore that it was also more heart rate dependent for older subjects. We attribute this to the fact that the degree of arteriosclerosis typically increases with age and that stiffening of the arterial wall will make the arteries less able to comply with increased heart rate (and corresponding blood pressure), without leading to increased pulse wave velocity. In view of these findings, we conclude that impedance cardiography seems to be well suited and practical for pulse wave velocity measurements and possibly for the assessment of the degree of arteriosclerosis. However, further studies are needed for comparison between this approach and reference methods for pulse wave velocity and assessment of arteriosclerosis before any firm conclusions can be drawn.

Non-invasive prediction of blood glucose trends during hypoglycemia.

Over the last four decades, there has been a pursuit for a non-invasive solution for glucose measurement, but there is not yet any viable product released. Of the many sensor modalities tried, the combination of electrical and optical measurement is among the most promising for continuous measurements. Although non-invasive prediction of exact glucose levels may seem futile, prediction of their trends may be useful for certain applications. Hypoglycemia is the most serious of the acute complications in type-1 diabetes highlighting the need for a reliable alarm, but little is known about the performance of this technology in predicting hypoglycemic glucose levels and associated trends. We aimed to assess such performance on the way to develop a multisensor system for detection of hypoglycemia, based on near-infrared (NIR), bioimpedance and skin temperature measurements taken during hypoglycemic and euglycemic glucose clamps in 20 subjects with type-1 diabetes. Performance of blood glucose prediction was assessed by global partial least squares and neural network regression models using repeated double cross-validation. Best trend prediction was obtained by including all measurements in a neural network model. Prediction of glucose level was inaccurate for threshold-based detection of hypoglycemia, but the trend predictions may provide useful information in a multisensor system. Comparing NIR and bioimpedance measurements, NIR seems to be the main predictor of blood glucose while bioimpedance may act as correction for individual confounding properties.

Electrical Impedance to Assess Facial Nerve Proximity During Robotic Cochlear Implantation.

Reported studies pertaining to needle guidance suggest that tissue impedance available from neuromonitoring systems can be used to discriminate nerve tissue proximity. In this pilot study, the existence of a relationship between intraoperative electrical impedance and tissue density, estimated from computer tomography (CT) images, is evaluated in the mastoid bone of in vivo sheep. In five subjects, nine trajectories were drilled using an image-guided surgical robot. Per trajectory, five measurement points near the facial nerve were accessed and electrical impedance was measured (≤1 KHz) using a multipolar electrode probe. Micro-CT was used postoperatively to measure the distances from the drilled trajectories to the facial nerve. Tissue density was determined from coregistered preoperative CT images and, following sensitivity field modeling of the measuring tip, tissue resistivity was calculated. The relationship between impedance and density was determined for 29 trajectories passing or intersecting the facial nerve. A monotonic decrease in impedance magnitude was observed in all trajectories with a drill axis intersecting the facial nerve. Mean tissue densities intersecting with the facial nerve (971-1161 HU) were different (p <0.01) from those along safe trajectories passing the nerve (1194-1449 HU). However, mean resistivity values of trajectories intersecting the facial nerve (14-24 Ωm) were similar to those of safe passing trajectories (17-23 Ωm). The determined relationship between tissue density and electrical impedance during neuromonitoring of the facial nerve suggests that impedance spectroscopy may be used to increase the accuracy of tissue discrimination, and ultimately improve nerve safety distance assessment in the future.

A Circuit for Simultaneous Measurements of Skin Electrical Conductance, Susceptance, and Potential.

A circuit is presented that enables measurement of skin electrical conductance, susceptance, and potential simultaneously beneath the same monopolar electrode. Example measurements are shown to confirm the function of the circuit. The measurements are also in accordance with earlier findings that changes in skin conductance and potential do not always correspond and hence contain unique information.

Age-related Differences in the Morphology of the Impedance Cardiography Signal.

Impedance cardiography (ICG) is a non-invasive method of hemodynamic measurement, mostly known for estimation of stroke volume and cardiac output based on characteristic features of the signal. Compared with electrocardiography, the knowledge on the morphology of the ICG signal is scarce, especially with respect to age-dependent changes in ICG waveforms. Based on recordings from ten younger (20-29 years) and ten older (60-79) healthy human subjects after three different levels of physical activity, the typical interbeat ICG waveforms were derived based on ensemble averages. Comparison of these waveforms between the age groups indicates the following differences: a later initial upward deflection for the younger group, an additional hump in the waveform from many older subjects not presented in the younger group, and a more pronounced second wave in the younger group. The explanation for these differences is not clear, but may be related to arterial stiffness. Further studies are suggested to determine whether these morphological differences have clinical value.

Evaluation of Hypoglycaemia with Non-Invasive Sensors in People with Type 1 Diabetes and Impaired Awareness of Hypoglycaemia.

People with type 1 diabetes and impaired awareness of hypoglycaemia (IAH) are prone to severe hypoglycaemia. Previous attempts to develop non-invasive hypoglycaemia alarm systems have shown promising results, but it is not known if such alarms can detect severe hypoglycaemia in people with IAH. We aimed to explore whether a combination of non-invasive sensors could reliably evaluate hypoglycaemia (plasma glucose (PG) minimum 2.5 mmol/L) in people with IAH. Twenty participants with type 1 diabetes and IAH underwent randomly ordered, single blinded hyperinsulinemic euglycaemic and hyperinsulinemic hypoglycaemic clamps. Sweating, skin temperature, ECG, counterregulatory hormones and symptoms of hypoglycaemia were assessed. Overall, we were not able to detect clamp-induced hypoglycaemia with sufficient sensitivity and specificity for further clinical use. As a post-hoc analysis, we stratified participants according to their ability to identify hypoglycaemic symptoms during hypoglycaemic clamps. Five out of 20 participants could identify such symptoms. These participants had a significantly higher adrenaline response to hypoglycaemia (p < 0.001) and were reliably identified by sensors. Based on our observations, a non-invasive alarm system based on measurement of sweating responses and ECG changes during hypoglycaemia might provide an alert at a plasma glucose concentration around 2.5 mmol/L if an adequate sympatho-adrenal reaction is elicited.

Influence of Relative Humidity on Electrodermal Levels and Responses.

BACKGROUND/AIM: Electrodermal activity (EDA) is a widely used measure in psychophysiological research, and its use in wearable devices has grown in recent times. It is recommended to have proper conditions for EDA measurement, and skin hydration is one factor that has a significant influence. It is, however, not known to what extent the ambient humidity influences the recording. This study explored the influence of relative humidity (RH) on EDA levels, and also the responses using a new technique for simultaneous recording of all measures of EDA: skin conductance (SC), skin susceptance (SS), and skin potential (SP) at the same skin site. METHODS: A total of 10 healthy subjects were exposed to environments of low and high RH while EDA measures were recorded, including cognitive, visual and breathing stimuli for evoking electrodermal responses of different origin. EDA levels and responses were compared between the two humidity levels for all stimuli and all EDA measures. RESULTS: It was found that EDA levels, in particular for SC and SS, were significantly increased during high humidity exposure, but that the change in EDA responses (SC, SS, and SP) was not statistically significant (p > 0.05, paired t test). CONCLUSION: This suggests that ambient humidity influences the recording of EDA levels and is important to consider when these parameters are used, but is not important in the recording or analysis of EDA responses.

Small intestinal ischemia and reperfusion-bioimpedance measurements.

OBJECTIVE: Trans-intestinal bioimpedance measurements have previously been used to investigate changes in electrical parameters during 6 h of ischemia in the small intestine. Knowledge is lacking regarding the time course of trans-intestinal bioimpedance parameters during reperfusion. As reperfusion is an important part in the clinical treatment of intestinal ischemia, we need to know how it affects the bioimpedance measurements. APPROACH: We performed bioimpedance measurements, using a two-electrode setup on selected segments of the jejunum in 15 pigs. A controlled voltage signal was applied while measuring the resulting current. In each pig, five or six 30 cm segments of the jejunum were made ischemic by clamping the mesenteric arteries and veins creating segments with ischemia from 1-16 h duration. Reperfusion was initiated at selected time intervals of ischemia, and measured for 5-15 h afterwards. MAIN RESULTS: The tan δ parameter (loss tangent) was different (p < 0.016) comparing ischemic and control tissue for the duration of the experiment (16 h). Comparing the control tissue 30 cm from the ischemic area with the control tissue 60 cm from the ischemic tissue, we found that the mean tan δ amplitude in the frequency range (3900-6300 Hz) was significantly higher (p < 0.036) in the proximal control after 10 h of experiment duration. After reperfusion, the time development of tanδm (loss tangent maximum over a frequency range) amplitude and frequency overlapped and periodically increased above the tanδm in the ischemic intestine. Dependent on the ischemic duration pre-reperfusion, the initial increase in tan δ stabilizes or increases drastically over time, compared to the tan δ amplitude of the ischemic tissue. SIGNIFICANCE: As during ischemia, the electrical parameters during reperfusion also follow a characteristic time-course, depending on the ischemic exposure before pre-reperfusion. The temporal changes in electrical parameters during small intestinal ischemia followed by reperfusion provides important information for assessment of tissue injury.

Electrodermal Activity Responses for Quantitative Assessment of Felt Pain.

Accurate assessment of experienced pain is a well-known problem in the clinical practices. Therefore, a proper method for pain detection is highly desirable. Electrodermal activity (EDA) is known as a measure of the sympathetic nervous system activity, which changes during various mental stresses. As pain causes mental stress, EDA measures may reflect the felt pain. This study aims to evaluate changes in skin conductance responses (SCRs), skin potential responses (SPRs), and skin susceptance responses (SSRs) simultaneously as a result of sequences of electrical (painful) stimuli with different intensities. EDA responses as results of painful stimuli were recorded from 40 healthy volunteers. The stimuli with three different intensities were produced by using an electrical stimulator. EDA responses significantly changed (increased) with respect to the intensity of the stimuli. Both SCRs and SSRs showed linear relationship with the painful stimuli. It was found that the EDA responses, particularly SCRs (p < 0.001) and SSRs (p = 0.001) were linearly affected by the intensity of the painful stimuli. EDA responses, in particular SCRs, may be used as a useful indicator for assessment of experienced pain in clinical settings.

Detection of needle to nerve contact based on electric bioimpedance and machine learning methods.

In an ongoing project for electrical impedance-based needle guidance we have previously showed in an animal model that intraneural needle positions can be detected with bioimpedance measurement. To enhance the power of this method we in this study have investigated whether an early detection of the needle only touching the nerve also is feasible. Measurement of complex impedance during needle to nerve contact was compared with needle positions in surrounding tissues in a volunteer study on 32 subjects. Classification analysis using Support-Vector Machines demonstrated that discrimination is possible, but that the sensitivity and specificity for the nerve touch algorithm not is at the same level of performance as for intra-neuralintraneural detection.

Detection of sympathoadrenal discharge by parameterisation of skin conductance and ECG measurement.

Detection of sympathoadrenal discharge is valuable for stress monitoring, but measuring the circulating adrenaline level directly is inconvenient, making non-invasive physiological sensors an attractive alternative. Little is known however, about their performance in detecting different adrenaline levels. In this study, adrenaline measurements over time from 20 subjects × 2 trials were compared with skin conductance (SC) from different skin sites and ECG recordings from which the heart rate and QT interval were derived. The frequency of sudomotor responses (FSR) was derived from the SC recording, and a new composite parameter for amplification of synchronous changes in multiple sensor signals was calculated for different combinations of FSR from different skin sites, heart rate and QT interval. The single and composite parameters were evaluated for detection performance of adrenaline levels above 1000, 1500 and 2000 pmol/L. The best prediction performance was indicated for the composite parameter using the FSR from the abdomen, FSR from the forehead and the heart rate, with a ROC area under the curve of 0.93 for the 2000 pmol/L threshold. In conclusion, detection of strong sympathoadrenal discharges is feasible with good accuracy during resting conditions in comfortable room temperature.

Ischemic small intestine-in vivo versus ex vivo bioimpedance measurements.

OBJECTIVE: Bioimpedance has been used to investigate changes in electrical parameters during ischemia in various tissues. The small intestine is a multi-layered structure, with several distinct tissue types, and ischemia related changes occur at different times in the different intestinal layers. When investigating how the electrical properties in the small intestine is affected by ischemia, some researchers have used ex vivo models while others have used in vivo models. In this study, we compare ischemic time development of electrical parameters in ischemic in vivo versus ex vivo small intestine. APPROACH: Measurements were performed using a two-electrode setup, with a Solartron 1260/1294 impedance gain-phase analyser. Electrodes were placed on the surface of ischemic pig jejunum, applying a voltage and measuring the resulting electrical admittance. In each pig, 4 segments of the jejunum were made ischemic by clamping the mesenteric arteries and veins, resulting in a 30 cm central zone of warm ischemia and edema. The in vivo part of the experiment lasted 10 h, after which 3 pieces of perfused small intestine were resected, stored in Ringer-acetat at 38 °C, and measured during a 10 h ex vivo experiment. Main results and significance: We found significant differences (p < 0.0001) between the values of electric parameters when comparing the in vivo and ex vivo measurements as a function of ischemic time development. We also observed some similarities in the trends. In vivo, we measured an overall decrease in impedance during the duration of the experiment, probably as a result from the formation of edema. Ex vivo, the low frequency impedance increased initially for approximately 3 h before starting to decrease.

Detection of intraneural needle-placement with multiple frequency bioimpedance monitoring: a novel method.

Electrical impedance measurements have been used to detect intraneural needle placement, but there is still a lack of precision with this method. The purpose of the study was to develop a method for the discrimination of nerve tissue from other tissue types based on multiple frequency impedance measurements. Impedance measurements with 25 different frequencies between 1.26 and 398 kHz were obtained in eight pigs while placing the tip of a stimulation needle within the sciatic nerve and in other tissues. Various impedance variables and measurement frequencies were tested for tissue discrimination. Best tissue discrimination was obtained by using three different impedance parameters with optimal measurement frequencies: Modulus (126 kHz), Phase angle (40 kHz) and the Delta of the phase angle (between 126 and 158 kHz). These variables were combined in a Compound variable C. The area under the curve in a receiver operating characteristic was consecutively increased for the Modulus (78 %), Phase angle (86 %), Delta of the phase angle (94 %), and the Compound variable C (97 %), indicating highest specificity and sensitivity for C. An algorithm based on C was implemented in a real-time feasibility test and used in an additional test animal to demonstrate our new method. Discrimination between nerve tissue and other tissue types was improved by combining several impedance variables at multiple measurement frequencies.

Waveform difference between skin conductance and skin potential responses in relation to electrical and evaporative properties of skin.

The shapes of skin conductance (SC) and skin potential (SP) responses are often similar, but can also be very different due to an unexplained cause. Using a new method to measure SC and SP simultaneously at the same electrode, this difference was investigated in a new way by comparing their temporal peak differences. SC, SP, skin susceptance (SS), and transepidermal water loss (TEWL) were recorded from 40 participants during relaxation and stress. The SP response could peak anywhere between the onset of an SC response to some time after the peak of an SC response. This peak time difference was associated with the magnitude of the SCR, the hydration of the skin, and the filling of the sweat ducts. Interpretation of the results in light of existing biophysical theories suggests that this peak difference may indicate the hydraulic capacity state of the sweat ducts at the time of a response.