Noninvasive Neuroprosthesis Promotes Cardiovascular Recovery After Spinal Cord Injury.

Spinal cord injury (SCI) leads to severe impairment in cardiovascular control, commonly manifested as a rapid, uncontrolled rise in blood pressure triggered by peripheral stimuli-a condition called autonomic dysreflexia. The objective was to demonstrate the translational potential of noninvasive transcutaneous stimulation (TCS) in mitigating autonomic dysreflexia following SCI, using pre-clinical evidence and a clinical case report. In rats with SCI, we show that TCS not only prevents the instigation of autonomic dysreflexia, but also mitigates its severity when delivered during an already-triggered episode. Furthermore, when TCS was delivered as a multisession therapy for 6 weeks post-SCI, the severity of autonomic dysreflexia was significantly reduced when tested in the absence of concurrent TCS. This treatment effect persisted for at least 1 week after the end of therapy. More importantly, we demonstrate the clinical applicability of TCS in treatment of autonomic dysreflexia in an individual with cervical, motor-complete, chronic SCI. We anticipate that TCS will offer significant therapeutic advantages, such as obviating the need for surgery resulting in reduced risk and medical expenses. Furthermore, this study provides a framework for testing the potential of TCS in improving recovery of other autonomic functions such lower urinary tract, bowel, and sexual dysfunction following SCI.

EEG: Characteristics of drug-induced seizures in rats, dogs and non-human primates.

Seizures are amongst the most frequent neurological issues encountered in pre-clinical safety testing. The objective was to characterize EEG morphologies and premonitory signs in drug-induced seizures in preclinical species. A comparative (inter-species) retrospective analysis for drug-induced seizures recorded by video-telemetry was conducted in rats (n = 53), dogs (n = 195), and non-human primates (n = 234). The most frequent premonitory signs were, in rats, myoclonus (100%), tremors (93%), salivation (75%), partial ptosis (58%) and chewing/bruxism (58%); in dogs, tremors (77%), ataxia/uncoordination (60%), myoclonus (45%), salivation (43%), excessive licking (38%), high vocalization (38%) and decreased activity (34%); in non-human primates, tremors (79%), decreased activity (70%), myoclonus (57%), retching/emesis (37%), hunched posture (30%) and ataxia/uncoordination (27%). Seizure duration ranged from 3 s to 14 min with an average of 46 ±â€¯21 s, comparable across species. At seizure onset, spike frequency averaged 9.4 Hz for the three species compared to 4.3 Hz at seizure end. Peak average amplitudes were attained at mid-seizure and amplitudes at seizure end decreased from peak but remained higher than onset amplitudes. Spike duration was inversely correlated with frequency and presented a crescendo pattern. Morphological characteristics can serve to refine automated EEG analysis. From a regulatory perspective, the most common paradigm is to use the most sensitive species in seizure liability studies but translational potential and clinical relevance may be under represented in the decision making process in some cases. EEG morphologies during drug-induced seizures presented remarkable similarities between species and tremors were identified as a predominant premonitory clinical sign in all species.

Comparison of a Traditional and Novel Evoked Compound Action Potentials Recording Approach and Evoked Auditory Brainstem Responses in Pediatric Cochlear Implants Users.

OBJECTIVES: Electrically evoked compound action potentials (eCAP) recordings are widely used in functional evaluation and fitting of cochlear implants (CI) in clinics. We compared the results from two eCAP recording approaches (StandardART and FineGrain, MED-EL, Austria). The FineGrain method is more advanced than the Auditory Nerve Response Telemetry (StandardART) method in terms of the stimulation and algorithm for the eCAP threshold detection. To understand the benefits of these alterations, we compared the two methods on a larger scale in pediatric CI users alongside evoked auditory brainstem responses (eABR). MATERIALS AND METHODS: We collected the eCAP recordings obtained with both methods from a population of pediatric subjects with CI, either intra- or post-operatively. The eABR recordings were only collected post-operatively. For comparability reasons, we used the same stimulation rate and similar amplitude levels for all three approaches. RESULTS: Our results demonstrate that, although the success rates are similar, the FineGrain method outperforms traditional StandardART in terms of robustness and measurement duration. The eCAP recordings in general outperform the eABR in terms of speed. CONCLUSION: We conclude that the eCAP recordings are the method of choice for measuring the auditory neural activity, and FineGrain outperforms StandardART. From the three investigated approaches, we conclude that FineGrain performed best and should be the first-choice method in pediatric patients.

A comprehensive analysis of auditory event-related potentials and network oscillations in an NMDA receptor antagonist mouse model using a novel wireless recording technology.

There is growing evidence that impaired sensory processing significantly contributes to cognitive deficits found in schizophrenia. Electroencephalography (EEG) has become an important preclinical and clinical technique to investigate the underlying mechanisms of neurophysiological dysfunctions in psychiatric disorders. Patients with schizophrenia show marked deficits in auditory event-related potentials (ERP), the detection of deviant auditory stimuli (mismatch negativity, MMN), the generation and synchronization of 40 Hz gamma oscillations in response to steady-state auditory stimulation (ASSR) and reduced auditory-evoked oscillation in the gamma range. Due to a novel data-logging technology (Neurologger, TSE Systems), it is now possible to record wireless EEG data in awake, free-moving small rodents without any restrictions due to size of the device or attached cables. Recently, a new version of the Neurologger was released with improved performance to record time-locked event-related EEG signals. In this study, we were able to show in mice that pharmacological intervention with the NMDA receptor antagonists Ketamine and MK-801 can impair a comprehensive selection of EEG/ERP readouts (ERP N1 amplitude, 40 Hz ASSR, basal and evoked gamma oscillation, MMN) and therefore mimic the EEG deficits observed in patients with schizophrenia. Our data support the translational value of NMDA receptor antagonists as a model for preclinical evaluation of sensory processing deficits relevant to schizophrenia. Further, the new Neurologger system is a suitable device for wireless recording of clinically relevant EEG biomarkers in freely moving mice and a robust translational tool to investigate novel therapeutic approaches regarding sensory processing deficits related to psychiatric disorders such as schizophrenia.

A predictive index of biomarkers for ictogenesis from tier I safety pharmacology testing that may warrant tier II EEG studies.

Three significant contributions to the field of safety pharmacology were recently published detailing the use of electroencephalography (EEG) by telemetry in a critical role in the successful evaluation of a compound during drug development (1] Authier, Delatte, Kallman, Stevens & Markgraf; JPTM 2016; 81:274-285; 2] Accardi, Pugsley, Forster, Troncy, Huang & Authier; JPTM; 81: 47-59; 3] Bassett, Troncy, Pouliot, Paquette, Ascaha, & Authier; JPTM 2016; 70: 230-240). These authors present a convincing case for monitoring neocortical biopotential waveforms (EEG, ECoG, etc) during preclinical toxicology studies as an opportunity for early identification of a central nervous system (CNS) risk during Investigational New Drug (IND) Enabling Studies. This review is about "ictogenesis" not "epileptogenesis". It is intended to characterize overt behavioral and physiological changes suggestive of drug-induced neurotoxicity/ictogenesis in experimental animals during Tier 1 safety pharmacology testing, prior to first dose administration in man. It is the presence of these predictive or comorbid biomarkers expressed during the requisite conduct of daily clinical or cage side observations, and in early ICH S7A Tier I CNS, pulmonary and cardiovascular safety study designs that should initiate an early conversation regarding Tier II inclusion of EEG monitoring. We conclude that there is no single definitive clinical marker for seizure liability but plasma exposures might add to set proper safety margins when clinical convulsions are observed. Even the observation of a study-related full tonic-clonic convulsion does not establish solid ground to require the financial and temporal investment of a full EEG study under the current regulatory standards. PREFATORY NOTE: For purposes of this review, we have adopted the FDA term "sponsor" as it refers to any person who takes the responsibility for and initiates a nonclinical investigations of new molecular entities; FDA uses the term "sponsor" primarily in relation to investigational new drug application submissions.

Development and Feasibility of a Home Pulmonary Rehabilitation Program With Health Coaching.

BACKGROUND: Pulmonary rehabilitation (PR) is an effective intervention for COPD. However, traditional center-based PR programs suffer from low uptake. Home-based PR is a viable solution, but few studies have shown the effectiveness of remote PR, as there is a scarcity of systems that can be easily adopted in clinical practice. The aim of this report is to communicate the development and feasibility of a home PR program that includes commercially available technology that allows the PR health coach to follow the patient through his or her PR process and to present the design of a prospective clinical trial. METHODS: We developed a home PR system that includes a computer tablet, an activity monitor, and an oximeter connected to a cloud server. The home PR consists of 12 min of walking and 6 full-body exercises, to be completed 6 d/week, plus weekly telephone calls with the PR health coach. Two pilot studies were conducted in subjects with moderate-to-severe COPD. The first aimed to fine-tune the system development (N = 3), and the second tested the program feasibility of the 8-week program (N = 12). RESULTS: In pilot study 1, PR monitoring data from the subjects' home PR sessions were transmitted to the health coach application successfully. On a 10-point scale, participants rated the system as helpful (median = 8, interquartile range 8-9) and simple to use (median = 10, interquartile range 9-10). In pilot study 2, adherence ± SD for prescribed use was 87 ± 0.24%. Overall, participants gave the home PR system a rating of 6.2 ± 0.94 on a 7-point scale. CONCLUSIONS: A home PR program was developed that integrated health coaching and a home PR system that facilitated remote monitoring. Pilot testing indicated that the program is well-developed and feasible in a population of individuals with COPD. (ClinicalTrials.gov registration NCT02999685.).

New pulmonary hypertension model in conscious dogs to investigate pulmonary-selectivity of acute pharmacological interventions.

PURPOSE: Testing of investigational drugs in animal models is a critical step in drug development. Current models of pulmonary hypertension (PH) have limitations. The most relevant outcome parameters such as pulmonary artery pressure (PAP) are measured invasively which requires anesthesia of the animal. We developed a new canine PH model in which pulmonary vasodilators can be characterized in conscious dogs and lung selectivity can be assessed non-invasively. METHODS: Telemetry devices were implanted to measure relevant hemodynamic parameters in conscious dogs. A hypoxic chamber was constructed in which the animals were placed in a conscious state. By reducing the inspired oxygen fraction (FiO2) to 10%, a hypoxic pulmonary vasoconstriction was induced leading to PH. The PDE-5 inhibitor sildenafil, the current standard of care was compared to atrial natriuretic peptide (ANP). RESULTS: The new hypoxic chamber provided a stable hypoxic atmosphere during all experiments. The mean PAP under normoxic conditions was 15.8 ± 1.8 mmHg. Hypoxia caused a reliable increase in mean PAP (+ 12.2 ± 3.2 mmHg, p < 0.0001). Both, sildenafil (- 6.8 ± 4.4 mmHg) and ANP (- 6.4 ± 3.8 mmHg) significantly (p < 0.05) decreased PAP. Furthermore sildenafil and ANP showed similar effects on systemic hemodynamics. In subsequent studies, the in vitro effects and gene expression pattern of the two pathways were exemplified. CONCLUSIONS: By combining the hypoxic environment with the telemetric approach, we could successfully establish a new acute PH model. Sildenafil and ANP demonstrated equal effects regarding pulmonary selectivity. This non-invasive model could help to rapidly screen pulmonary vasodilators with decreased animal burden.

GLIMPSE: Google Glass interface for sensory feedback in myoelectric hand prostheses.

OBJECTIVE: Providing sensory feedback to the user of the prosthesis is an important challenge. The common approach is to use tactile stimulation, which is easy to implement but requires training and has limited information bandwidth. In this study, we propose an alternative approach based on augmented reality. APPROACH: We have developed the GLIMPSE, a Google Glass application which connects to the prosthesis via a Bluetooth interface and renders the prosthesis states (EMG signals, aperture, force and contact) using augmented reality (see-through display) and sound (bone conduction transducer). The interface was tested in healthy subjects that used the prosthesis with (FB group) and without (NFB group) feedback during a modified clothespins test that allowed us to vary the difficulty of the task. The outcome measures were the number of unsuccessful trials, the time to accomplish the task, and the subjective ratings of the relevance of the feedback. MAIN RESULTS: There was no difference in performance between FB and NFB groups in the case of a simple task (basic, same-color clothespins test), but the feedback significantly improved the performance in a more complex task (pins of different resistances). Importantly, the GLIMPSE feedback did not increase the time to accomplish the task. Therefore, the supplemental feedback might be useful in the tasks which are more demanding, and thereby less likely to benefit from learning and feedforward control. The subjects integrated the supplemental feedback with the intrinsic sources (vision and muscle proprioception), developing their own idiosyncratic strategies to accomplish the task. SIGNIFICANCE: The present study demonstrates a novel self-contained, ready-to-deploy, wearable feedback interface. The interface was successfully tested and was proven to be feasible and functionally beneficial. The GLIMPSE can be used as a practical solution but also as a general and flexible instrument to investigate closed-loop prosthesis control.

Impact of Age and Polytherapy on Fingolimod Induced Bradycardia: a Preclinical Study.

Fingolimod is a an oral disease modifying drug for relapsing remitting multiple sclerosis (MS) preventing egress of B and T cells from lymph nodes. Relevant first dose adverse events include bradycardia and atrioventricular conduction slowing. Cardiac side effects of fingolimod and combinational pharmacotherapy including duloxetine and tolterodine were monitored in mice of different age using implantable ECG telemetric systems. Cardiac tissue was assessed for S1P-receptor subtype (1 and 3), and for GIRK1 expression. Fingolimod led to a significant heart rate reduction within 60 min, which returned to baseline values within 24 h. In older mice bradycardia was more pronounced compared to younger mice. Atrioventricular conduction was not affected. Older mice showed a higher S1PR3 expression in a naïve state and receptor expression was reduced after fingolimod administration. Combination with duloxetine or tolterodine alleviated fingolimod induced heart rate decrease. Our data provide preclinical evidence that negative chronotropic effects of fingolimod might be age dependent, possibly due to an altered expression and internalization of cardiac S1PR3 in older animals. This data could be relevant for future clinical monitoring and patient selection in the aging MS population. Combinational therapies of fingolimod and duloxetine or tolterodine are well tolerated and safe without an increased risk for pronounced bradycardia or arrhythmia.

Mapping-guided characterization of mechanical and electrical activation patterns in patients with normal systolic function using a sensor-based tracking technology.

AIMS: In times of evolving cardiac resynchronization therapy, intra-procedural characterization of left ventricular (LV) mechanical activation patterns is desired but technically challenging with currently available technologies. In patients with normal systolic function, we evaluated the feasibility of characterizing LV wall motion using a novel sensor-based, real-time tracking technology. METHODS AND RESULTS: Ten patients underwent simultaneous motion and electrical mapping of the LV endocardium during sinus rhythm using electroanatomical mapping and navigational systems (EnSite™ NavX™ and MediGuide™, SJM). Epicardial motion data were also collected simultaneously at corresponding locations from accessible coronary sinus branches. Displacements at each mapping point and times of electrical and mechanical activation were combined over each of the six standard LV wall segments. Mechanical activation timing was compared with that from electrical activation and preoperative 2D speckle tracking echocardiography (echo). MediGuide-based displacement data were further analysed to estimate LV chamber volumes that were compared with echo and magnetic resonance imaging (MRI). The lateral and septal walls exhibited the largest (12.5 [11.6-15.0] mm) and smallest (10.2 [9.0-11.3] mm) displacement, respectively. Radial displacement was significantly larger endocardially than epicardially (endo: 6.7 [5.0-9.1] mm; epi: 3.8 [2.4-5.6] mm), while longitudinal displacement was significantly larger epicardially (endo: 8.0 [5.0-10.6] mm; epi: 10.3 [7.4-13.8] mm). Most often, the anteroseptal/anterior and lateral walls showed the earliest and latest mechanical activations, respectively. 9/10 patients had concordant or adjacent wall segments of latest mechanical and electrical activation, and 6/10 patients had concordant or adjacent wall segments of latest mechanical activation as measured by MediGuide and echo. MediGuide's LV chamber volumes were significantly correlated with MRI (R2= 0.73, P < 0.01) and echo (R2= 0.75, P < 0.001). CONCLUSION: The feasibility of mapping-guided intra-procedural characterization of LV wall motion was established. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov; Unique identifier: CT01629160.

MD-Logic overnight type 1 diabetes control in home settings: A multicentre, multinational, single blind randomized trial.

AIMS: To evaluate the safety, efficacy and need for remote monitoring of the MD-Logic closed-loop system during short-term overnight use at home. METHODS: Seventy-five patients (38 male; aged 10-54 years; average A1c, 7.8% ± 0.7%, 61.8 ± 7.2 mmol/mol) were enrolled from 3 clinical sites. Patients were randomly assigned to participate in 2 overnight crossover periods, each including 4 consecutive nights, 1 under closed-loop control and 1 under sensor-augmented pump (SAP) therapy in the patient's home. Both study arms were supervised using a remote-monitoring system in a blinded manner. Primary endpoints were time spent with glucose levels below 70 mg/dL and percentage of nights in which mean overnight glucose levels were within 90 to 140 mg/dL. RESULTS: The median [interquartile range] percentage of time spent in hypoglycaemia was significantly lower on nights when MD-Logic was used, compared to SAP therapy (2.07 [0, 4.78] and 2.6 [0, 10.34], respectively; P = .004) and the percentage of individual nights with a mean overnight glucose level in target was significantly greater (75 [42, 75] and 50 [25,75], respectively; P = .008). The time spent in target range was increased by a median of 28% (P = .001), with the same amount of insulin (10.69 [7.28, 13.94] and 10.41[6.9, 14.07], respectively; P = .087). The remote monitoring triggered calls for hypoglycaemia at twice the rate during SAP therapy compared to closed-loop control (62 and 29, respectively; P = .002). CONCLUSIONS: The MD-Logic system demonstrated a safe and efficient profile during overnight use by children, adolescents and adults with type 1 diabetes and, therefore, provides an effective means of mitigating the risk of nocturnal hypoglycaemia.

Conventional and novel body temperature measurement during rest and exercise induced hyperthermia.

Despite technological advances in thermal sensory equipment, few core temperature (TCORE) measurement techniques have met the established validity criteria in exercise science. Additionally, there is debate as to what method serves as the most practically viable, yet upholds the proposed measurement accuracy. This study assessed the accuracy of current and novel TCORE measurement techniques in comparison to rectal temperature (TREC) as a reference standard. Fifteen well-trained subjects (11 male, 4 female) completed 60min of exercise at an intensity equating to the lactate threshold; measured via a discontinuous exercise test. TREC was significantly elevated from resting values (37.2±0.3°C) at the end of moderate intensity exercise (39.6±0.04°C; P=0.001). Intestinal telemetric pill (TPILL) temperature and temporal artery temperature (TTEM) did not differ significantly from TREC at rest or during exercise (P>0.05). However, aural canal temperature (TAUR) and thermal imaging temperature (TIMA) were both significantly lower than TREC (P<0.05). Bland Altman analysis revealed only TPILL was within acceptable limits of agreement (mean bias; 0.04°C), while TTEM, TAUR and TIMA demonstrated mean bias values outside of the acceptable range (>0.27°C). Against TREC, these results support the use of TPILL over all other techniques as a valid measure of TCORE at rest and during exercise induced hyperthermia. Novel findings illustrate that TIMA (when measured at the inner eye canthus) shows poor agreement to TREC during rest and exercise, which is similar to other 'surface' measures.

Asynchronous Detection of Trials Onset from Raw EEG Signals.

Clinical processing of event-related potentials (ERPs) requires a precise synchrony between the stimulation and the acquisition units that are guaranteed by means of a physical link between them. This precise synchrony is needed since temporal misalignments during trial averaging can lead to high deviations of peak times, thus causing error in diagnosis or inefficiency in classification in brain-computer interfaces (BCIs). Out of the laboratory, mobile EEG systems and BCI headsets are not provided with the physical link, thus being inadequate for acquisition of ERPs. In this study, we propose a method for the asynchronous detection of trials onset from raw EEG without physical links. We validate it with a BCI application based on the dichotic listening task. The user goal was to attend the cued auditory message and to report three keywords contained in it while ignoring the other message. The BCI goal was to detect the attended message from the analysis of auditory ERPs. The rate of successful onset detection in both synchronous (using the real onset) and asynchronous (blind detection of trial onset from raw EEG) was 73% with a synchronization error of less than 1[Formula: see text]ms. The level of synchronization provided by this proposal would allow home-based acquisition of ERPs with low cost BCI headsets and any media player unit without physical links between them.

Digital monitoring and care: Virtual medicine.

Remote digital health monitoring technologies can be synergistically organized to create a virtual medical system providing more continuous care centered on the patient rather than the bricks and mortar medical complex. Utilization of the digitalized patient health monitoring can facilitate diagnosis, treatment plans, physician-patient interaction, and accelerate the progress of medical research, education, and training. The field of cardiac electrophysiology has been an early adopter of this shift in care and serves as a paradigm applicable to all areas of medicine. The overall impact of this remote virtual care model on the quality of medical care and patient experience requires greater study, as well as vigilance as to the differences between technology and care in order to preserve the intangible and immeasurable factors that bring humanity to the art and science of medicine.

Characterization of an investigative safety pharmacology model to assess comprehensive cardiac function and structure in chronically instrumented conscious beagle dogs.

INTRODUCTION: There has been an increasing need to conduct investigative safety pharmacology studies to complement regulatory-required studies, particularly as it applies to a comprehensive assessment of cardiovascular (CV) risk. METHODS: We describe refined methodology using a combination of telemetry and direct signal acquisition to record concomitant peripheral hemodynamics, ECG, and left ventricular (LV) structure (LV chamber size and LV wall thickness) and function, including LV pressure-volume (PV) loops to determine load independent measures of contractility (end systolic elastance, Ees, and preload recruitable stroke work, PRSW) in conscious beagle dogs. Following baseline characterization, 28days of chronic rapid ventricular pacing (RVP) was performed and cardiac function monitored: both as a way to compare measures during development of dysfunction and to characterize feasibility of a model to assess CV safety in animals with underlying cardiac dysfunction. RESULTS: While ±dP/dT decreased within a few days of RVP and remained stable, more comprehensive cardiac function measurements, including Ees and PRSW, provided a more sensitive assessment confirming the value of such endpoints for a more clear functional assessment. After 28days of RVP, the inodilator pimobendan was administered to further demonstrate the ability to detect changes in cardiac function. Expectedly pimobendan caused a leftward shift in the PV loop, improved ejection fraction (EF) and significantly improved Ees and PRSW. DISCUSSION: In summary, the data show the feasibility and importance in measuring enhanced cardiac functional parameters in conscious normal beagle dogs and further describe a relatively stable cardiac dysfunction model that could be used as an investigative safety pharmacology risk assessment tool.

Health and training monitoring system based on wearable sensors.

ITEA2 project CareWare approach efficiently perform wearable sensor data processing and data fusion in order to visualize the holistic view of user's health and training status personalized, intuitively and trustworthy way and give feedback for user about individualized intensity and time of exercising control.

ECG telemetry in conscious guinea pigs.

INTRODUCTION: During preclinical drug development, monitoring of the electrocardiogram (ECG) is an important part of cardiac safety assessment. To detect potential pro-arrhythmic liabilities of a drug candidate and for internal decision-making during early stage drug development an in vivo model in small animals with translatability to human cardiac function is required. METHODS: Over the last years, modifications/improvements regarding animal housing, ECG electrode placement, and data evaluation have been introduced into an established model for ECG recordings using telemetry in conscious, freely moving guinea pigs. Pharmacological validation using selected reference compounds affecting different mechanisms relevant for cardiac electrophysiology (quinidine, flecainide, atenolol, dl-sotalol, dofetilide, nifedipine, moxifloxacin) was conducted and findings were compared with results obtained in telemetered Beagle dogs. RESULTS AND CONCLUSION: Under standardized conditions, reliable ECG data with low variability allowing largely automated evaluation were obtained from the telemetered guinea pig model. The model is sensitive to compounds blocking cardiac sodium channels, hERG K(+) channels and calcium channels, and appears to be even more sensitive to ß-blockers as observed in dogs at rest. QT interval correction according to Bazett and Sarma appears to be appropriate methods in conscious guinea pigs. Overall, the telemetered guinea pig is a suitable model for the conduct of early stage preclinical ECG assessment.