Brain-computer interface devices for patients with paralysis and amputation: a meeting report.

OBJECTIVE: The Food and Drug Administration's (FDA) Center for Devices and Radiological Health (CDRH) believes it is important to help stakeholders (e.g., manufacturers, health-care professionals, patients, patient advocates, academia, and other government agencies) navigate the regulatory landscape for medical devices. For innovative devices involving brain-computer interfaces, this is particularly important. APPROACH: Towards this goal, on 21 November, 2014, CDRH held an open public workshop on its White Oak, MD campus with the aim of fostering an open discussion on the scientific and clinical considerations associated with the development of brain-computer interface (BCI) devices, defined for the purposes of this workshop as neuroprostheses that interface with the central or peripheral nervous system to restore lost motor or sensory capabilities. MAIN RESULTS: This paper summarizes the presentations and discussions from that workshop. SIGNIFICANCE: CDRH plans to use this information to develop regulatory considerations that will promote innovation while maintaining appropriate patient protections. FDA plans to build on advances in regulatory science and input provided in this workshop to develop guidance that provides recommendations for premarket submissions for BCI devices. These proceedings will be a resource for the BCI community during the development of medical devices for consumers.

Medical service redesign shares the load saving 6000 bed days and improving morale.

BACKGROUND AND AIMS: In 2010, demand on the Auckland City Hospital general medical service exceeded capacity. A review by the Royal Australasian College of Physicians was critical of training offered to registered medical officers, and low morale was a problem across the service. Management offered support for an improved model that would solve these problems. METHODS: A project to redesign the general medical service was undertaken. Baseline analysis found uneven workload and insufficient capacity at peak times for patient presentations. Workshops involving the entire service led to a new model that splits workload and teams into patients likely to have a short stay from those requiring longer, ward-based care. Admissions are now distributed over 12 teams on weekdays and 4 on the weekends. There was an increase of approximately 2.5 in consultant full time equivalents but no change in registrar or house officer staffing. RESULTS: Since the introduction of the new model, the average length of stay has fallen from 3.7 to 3.2 days (14%) and the median length of stay by 28%, resulting in a saving of 6000 bed days per year. Readmission, inpatient and 30-day mortality rates are unchanged. These results have been sustained over 18 months with signs of continuing improvement. CONCLUSION: This project owes its success to the following factors - management support; iterative engagement of a range of staff; provision of timely data analysis; increases in senior medical officer staffing and reorganisation leading to more predictable and fair work practices. One challenge is discontinuity, whether between doctors and patients or within the medical team.

Development and validation of a portable platform for deploying decision-support algorithms in prehospital settings.

BACKGROUND: Advanced decision-support capabilities for prehospital trauma care may prove effective at improving patient care. Such functionality would be possible if an analysis platform were connected to a transport vital-signs monitor. In practice, there are technical challenges to implementing such a system. Not only must each individual component be reliable, but, in addition, the connectivity between components must be reliable. OBJECTIVE: We describe the development, validation, and deployment of the Automated Processing of Physiologic Registry for Assessment of Injury Severity (APPRAISE) platform, intended to serve as a test bed to help evaluate the performance of decision-support algorithms in a prehospital environment. METHODS: We describe the hardware selected and the software implemented, and the procedures used for laboratory and field testing. RESULTS: The APPRAISE platform met performance goals in both laboratory testing (using a vital-sign data simulator) and initial field testing. After its field testing, the platform has been in use on Boston MedFlight air ambulances since February of 2010. CONCLUSION: These experiences may prove informative to other technology developers and to healthcare stakeholders seeking to invest in connected electronic systems for prehospital as well as in-hospital use. Our experiences illustrate two sets of important questions: are the individual components reliable (e.g., physical integrity, power, core functionality, and end-user interaction) and is the connectivity between components reliable (e.g., communication protocols and the metadata necessary for data interpretation)? While all potential operational issues cannot be fully anticipated and eliminated during development, thoughtful design and phased testing steps can reduce, if not eliminate, technical surprises.

A chronic generalized bi-directional brain-machine interface.

A bi-directional neural interface (NI) system was designed and prototyped by incorporating a novel neural recording and processing subsystem into a commercial neural stimulator architecture. The NI system prototype leverages the system infrastructure from an existing neurostimulator to ensure reliable operation in a chronic implantation environment. In addition to providing predicate therapy capabilities, the device adds key elements to facilitate chronic research, such as four channels of electrocortigram/local field potential amplification and spectral analysis, a three-axis accelerometer, algorithm processing, event-based data logging, and wireless telemetry for data uploads and algorithm/configuration updates. The custom-integrated micropower sensor and interface circuits facilitate extended operation in a power-limited device. The prototype underwent significant verification testing to ensure reliability, and meets the requirements for a class CF instrument per IEC-60601 protocols. The ability of the device system to process and aid in classifying brain states was preclinically validated using an in vivo non-human primate model for brain control of a computer cursor (i.e. brain-machine interface or BMI). The primate BMI model was chosen for its ability to quantitatively measure signal decoding performance from brain activity that is similar in both amplitude and spectral content to other biomarkers used to detect disease states (e.g. Parkinson's disease). A key goal of this research prototype is to help broaden the clinical scope and acceptance of NI techniques, particularly real-time brain state detection. These techniques have the potential to be generalized beyond motor prosthesis, and are being explored for unmet needs in other neurological conditions such as movement disorders, stroke and epilepsy.

24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3] controls growth plate development by inhibiting apoptosis in the reserve zone and stimulating response to 1alpha,25(OH)2D3 in hypertrophic cells.

Previously we showed that costochondral growth plate resting zone (RC) chondrocytes response primarily to 24R,25(OH)2D3 whereas prehypertrophic and hypertrophic (GC) cells respond to 1alpha,25(OH)2D3. 24R,25(OH)2D3 increases RC cell proliferation and inhibits activity of matrix processing enzymes, suggesting it stabilizes cells in the reserve zone, possibly by inhibiting the matrix degradation characteristic of apoptotic hypertrophic GC cells. To test this, apoptosis was induced in rat RC cells by treatment with exogenous inorganic phosphate (Pi). 24R,25(OH)2D3 blocked apoptotic effects in a dose-dependent manner. Similarly, apoptosis was induced in ATDC5 cell cultures and 24R,25(OH)2D3 blocked this effect. Further studies indicated that 24R,25(OH)2D3 acts via at least two independent pathways. 24R,25(OH)2D3 increases LPA receptor-1 (LPA R1) expression and production of lysophosphatidic acid (LPA), and subsequent LPA R1/3-dependent signaling, thereby decreasing p53 abundance. LPA also increases the Bcl-2/Bax ratio. In addition, 24R,25(OH)2D3 acts by increasing PKC activity. 24R,25(OH)2D3 stimulates 1-hydroxylase activity, resulting in increased levels of 1,25(OH)2D3, and it increases levels of phospholipase A2 activating protein, which is required for rapid 1alpha,25(OH)2D3-dependent activation of PKC in GC cells. These results suggest that 24R,25(OH)2D3 modulates growth plate development by controlling the rate and extent of RC chondrocyte transition to a GC chondrocyte phenotype.

Osteoblast response to fluid induced shear depends on substrate microarchitecture and varies with time.

Osteoblasts are exposed to fluid shear in vivo but the effects are not well understood, particularly how substrate properties or length of exposure modify the response. Short exposure (1 h) to shear reduces the stimulatory effect of micron-scale surface structure on osteoblast differentiation, but the effects of longer term exposures are not known. To test the hypothesis that substrate-dependent responses of osteoblasts to shear depend on the length of exposure to fluid flow, MG63 osteoblasts were grown on tissue culture glass, which has an average roughness (Ra) < 0.2 microm; machined Ti disks (PT, Ra < 0.6 microm); Ti disks with a complex microarchitecture [sand blasted acid etched (SLA), Ra = 4-5 microm); and Ti plasma-sprayed surfaces [Ti via plasma spray (TPS), Ra = 7 microm]. Confluent cultures were exposed to pulsatile flow at shear forces of 0, 1, and 14 dynes/cm(2) for 0, 6, 12, and 24 h. Shear reduced cell number on all surfaces, with greatest effects on TPS. Shear had no effect on alkaline phosphatase on smooth surfaces but increased enzyme activity on SLA and TPS in a time-dependent manner. Its effects on osteocalcin, TGF-beta1, and PGE(2) in the conditioned media were greatest on these surfaces as well. Responses to fluid-induced shear were blocked by the general Cox inhibitor indomethacin and the Cox-2 inhibitor meloxicam, indicating that response to shear is mediated by prostaglandin produced via a Cox-2 dependent mechanism. These results show that the effects of fluid induced shear change with time and are substrate dependent, suggesting that substrate microarchitecture regulates the osteoblast phenotype and effects of shear are determined by the maturation state of the responding population.

The effect of longer-term creatine supplementation on elite swimming performance after an acute creatine loading.

We investigated the effect of an acute creatine loading (25 g per day for 4 days) and longer-term creatine supplementation (5 g of creatine or 5 g of placebo per day for 2 months) on the performance of 22 elite swimmers during maximal interval sessions. After the acute creatine loading, the mean of the average interval swim times for all swimmers (n = 22) improved (44.3+/-16.5 s before vs. 43.7+/-16.3 s after supplementation; P<0.01). Three of the 22 swimmers did not respond positively to supplementation. After 2 months of longer-term creatine supplementation or placebo, neither group showed a significant change in swimming performance (38.7+/-13.5 s before vs. 38.7+/-14.1 s after for the creatine group; 48.7+/-18.0 s before vs. 48.7+/-18.1 s after for the placebo group). We conclude that, in elite swimmers, 4 days of acute creatine loading improves swimming performance significantly when assessed by maximal interval sessions. However, longer-term supplementation for 2 months (5 g of creatine per day) did not benefit significantly the creatine group compared with the placebo group.

Simulation of B1 field distribution and intrinsic signal-to-noise in cardiac MRI as a function of static magnetic field.

Two issues that pertain to the optimal static magnetic field for cardiac MRI were addressed: intrinsic signal-to-noise ratio (ISNR) and radiofrequency power deposition. From 1.5 to 9.5 T, proton Larmor frequencies of 63 to 400 MHz, numerical simulations were performed of the RF fields from a surface coil and a body coil loaded by a heterogeneous, three-dimensional, symmetric model of the human chest. The RF field distribution, the power required to produce the RF field, and the ISNR at the center of the heart were computed. The model was validated by comparison with experimental data up to 4 T. The RF field distortion was quantified and found to increase linearly up to 6 T due mostly to dielectric resonance modes. Body coil simulations beyond 6 T showed the onset of higher-order modes at the center of the heart. A range of expected RF power requirements was constructed as a function of field up to 9.5 T for surface coils and up to 6.8 T for body coils. Over this range of static field, ISNR for a constant coil geometry was bracketed by an upper limit that was slightly greater than linear with field and a lower limit that was slightly less than linear with field. The RF power and ISNR showed a strong dependence on chest thickness at 1.5 and 4.0 T. Additionally, independent of chest thickness, the model predicts a lower limit of a factor of 5 increase in RF power as the static field is increased from 1.5 to 4 T. Implications for imaging with other nuclei are discussed. Methods for checking the self-consistency of electrodynamic simulations are presented.

The intrinsic signal-to-noise ratio in human cardiac imaging at 1.5, 3, and 4 T.

Cardiac imaging is inherently demanding on the signal-to-noise performance of the MR scanner and may benefit from high field strengths. However, the complex behavior of the radiofrequency field in the human body at high frequencies makes model-based analyses difficult. This study aims to obtain reliable comparisons of the signal-to-noise profile in the human chest in vivo at 1.5, 3, and 4 T. By using an RF-field-mapping method, it is shown that the intrinsic signal-to-noise increases with the field strength up to 4 T with a less than linear relation. The RF field profile is markedly distorted at 4 T, and the onset of this distortion is dependent on the body size. The high power deposition and the consequences of the RF field distortion are discussed.

The evaluation of dielectric resonators containing H2O or D2O as RF coils for high-field MR imaging and spectroscopy.

Electromagnetic resonators consisting of low-loss dielectric material and/or metallic boundaries are widely used in microwave technologies. These dielectric resonators usually have high Q factors and well-defined field distributions. Magnetic resonance imaging was shown as a way of visualizing the magnetic field distribution of the resonant modes of these resonators, if the dielectric body contains NMR sensitive nuclei. Dielectric resonators have also been proposed as RF coils for magnetic resonance experiments. The feasibility of this idea in high-field MR is discussed here. Specifically, the dielectric resonances of cylindrical water columns were characterized at 170.7 MHz (4 T 1H Larmor frequency), and evaluated as NMR transmit and receive coils. The dielectric resonance of a cylindrical volume of D2O was used to image a hand at 170.7 MHz. This study demonstrated that MRI is an effective way of visualizing the magnetic field in dielectric structures such as a water cylinder, and can potentially be generalized to solid-state dielectric devices. The possible applications of dielectric resonators other than simple cylindrical volumes in MRI and MR solution spectroscopy at high field strengths are also discussed.

Multi-electrode array for measuring evoked potentials from surface of ferret primary auditory cortex.

Using silicon-integrated circuit technology, we have fabricated a flexible multi-electrode array and used it for measuring evoked potentials at the surface of the ferret primary auditory cortex (AI). Traditionally, maps of cortical activity are recorded from numerous sequential penetrations with a single electrode. A common problem with this approach is that the state of the cortex (defined in part by level of anesthesia and number of active cells) changes during the time required to generate these maps. The multi-electrode array reduces this problem by allowing the recording of 24 locations simultaneously. The specific array described in this report is designed to record cortical activity over a 1 mm2 area. It is comprised of 24 gold electrodes (40 x 40 microns2) each spaced 210 microns apart. These electrodes are connected to contact pads via gold leads (5 cm in length). The electrodes, leads, and contact pads are sandwiched between two layers of polyimide. The polyimide passivates the device and makes the device flexible enough to conform to the shape of the cortex. The fabrication procedures described here allow various other layouts and areas to be readily implemented. Measurements of the electrical properties of the electrodes, together with details of the multichannel amplification, acquisition, and display of the data are also discussed. Finally, results of AI mapping experiments with these arrays are illustrated.

Stability of maxillary surgery in openbite versus nonopenbite malocclusions.

Lateral cephalometric radiographs were evaluated to determine the posttreatment stability of 66 patients treated with LeFort I osteotomies to reposition their maxillae superiorly. The sample was divided into three groups based on the degree of pretreatment overbite: openbite subsample--no incisal overlap; overlap subsample--incisal overlap and no incisal contact; contact subsample--incisal overlap with incisal contact. The cephalograms were superimposed and linear measurements were made at each interval (pretreatment, posttreatment, and at least one year posttreatment). The results clearly show that the three subsamples reacted differently during the posttreatment interval. 42.9 percent of the subsample with pretreatment openbite showed a significant increase in facial height, significant eruption of maxillary molars, and a significant decrease in overbite. 28.6 percent of the openbite subsample and 16.7 percent of the overlap subsample showed a significant increase in facial height, significant eruption of maxillary incisors, and no change in overbite. The contact subsample had no significant posttreatment changes. Possible reasons for the posttreatment instability in the openbite subsample are proposed.

Aspirin allergy.

This paper represents a 17-year prospective study of the clinical characteristics of patients with a history of having had allergic reactions to aspirin. The following points are especially important. (1) The most common manifestation is urticarica/angioedema; the second most common, asthma. (2) Women of child-bearing age are especially prone to develop aspirin sensitivity, otherwise the age of onset is approximately equal in the two sexes, varying from one year to 60 years. (3) Although an immunologic basis of aspirin sensitivity has not been demonstrated, 90% of its victims are also sensitive to inhalants (76%), foods (74%) or drugs (43%). (4) The authors could not confirm the widely held view that aspirin cross-reacts with tartrazine. (5) They were also unable to confirm another widely held view that asthmatic patients who are sensitive to aspirin have a strong tendency to develop nasal polyps. (6) The prognosis of asthma in patients sensitive to aspirin does not differ from that of patients who are not. These findings underline the importance of giving every aspirin-sensitive patient the benefit of a complete allergic work-up.