Accelerating neurotechnology development using an Agile methodology.

Novel bioelectronic medical devices that target neural control of visceral organs (e.g., liver, gut, spleen) or inflammatory reflex pathways are innovative class III medical devices like implantable cardiac pacemakers that are lifesaving and life-sustaining medical devices. Bringing innovative neurotechnologies early into the market and the hands of treatment providers would benefit a large population of patients inflicted with autonomic and chronic immune disorders. Medical device manufacturers and software developers widely use the Waterfall methodology to implement design controls through verification and validation. In the Waterfall methodology, after identifying user needs, a functional unit is fabricated following the verification loop (design, build, and verify) and then validated against user needs. Considerable time can lapse in building, verifying, and validating the product because this methodology has limitations for adjusting to unanticipated changes. The time lost in device development can cause significant delays in final production, increase costs, and may even result in the abandonment of the device development. Software developers have successfully implemented an Agile methodology that overcomes these limitations in developing medical software. However, Agile methodology is not routinely used to develop medical devices with implantable hardware because of the increased regulatory burden of the need to conduct animal and human studies. Here, we provide the pros and cons of the Waterfall methodology and make a case for adopting the Agile methodology in developing medical devices with physical components. We utilize a peripheral nerve interface as an example device to illustrate the use of the Agile approach to develop neurotechnologies.

Bionic intrafascicular interfaces for recording and stimulating peripheral nerve fibers.

The network of peripheral nerves presents extraordinary potential for modulating and/or monitoring the functioning of internal organs or the brain. The degree to which these pathways can be used to influence or observe neural activity patterns will depend greatly on the quality and specificity of the bionic interface. The anatomical organization, which consists of multiple nerve fibers clustered into fascicles within a nerve bundle, presents opportunities and challenges that may necessitate insertion of electrodes into individual fascicles to achieve the specificity that may be required for many clinical applications. This manuscript reviews the current state-of-the-art in bionic intrafascicular interfaces, presents specific concerns for stimulation and recording, describes key implementation considerations and discusses challenges for future designs of bionic intrafascicular interfaces.

Cortical and motor responses to acute forced exercise in Parkinson's disease.

INTRODUCTION: Studies in animal models of Parkinson's disease (PD) have suggested that the rate of exercise performance is important in treatment efficacy and neuroprotection. In humans with PD, lower-extremity forced-exercise (FE) produced global improvements in motor symptoms based on clinical ratings and biomechanical measures of upper extremity function. METHODS: fMRI was used to compare the underlying changes in brain activity in PD patients following the administration of anti-parkinsonian medication and following a session of FE. RESULTS: Nine individuals with PD completed fMRI scans under each condition: off anti-PD medication, on anti-PD medication, and off medication + FE. Unified Parkinson's Disease Rating Motor Scale scores improved by 50% in the FE condition compared to the off-medication condition. The pattern of fMRI activation after FE was similar to that seen with anti-PD medication. Direct comparison of the fMRI activation patterns showed high correlation between FE and anti-PD medication. CONCLUSION: These findings suggest that medication and FE likely utilize the same pathways to produce symptomatic relief in individuals with PD.

Quantification of the Balance Error Scoring System with Mobile Technology.

PURPOSE: The aim of this project was to develop a biomechanically based quantification of the Balance Error Scoring System (BESS) using data derived from the accelerometer and gyroscope of a mobile tablet device. METHODS: Thirty-two healthy young adults completed the BESS while an iPad was positioned at the sacrum. Data from the iPad were compared to position data gathered from a three-dimensional motion capture system. Peak-to-peak (P2P), normalized path length (NPL), and root mean squared (RMS) were calculated for each system and compared. Additionally, a 95% ellipsoid volume, iBESS volume, was calculated using center of mass (CoM) movements in the anteroposterior (AP), mediolateral (ML), and trunk rotation planes of movement to provide a comprehensive, 3D metric of postural stability. RESULTS: Across all kinematic outcomes, data from the iPad were significantly correlated with the same outcomes derived from the motion capture system (rho range, 0.37-0.94; P < 0.05). The iBESS volume metric was able to detect a difference in postural stability across stance and surface, showing a significant increase in volume in increasingly difficult conditions, whereas traditional error scoring was not as sensitive to these factors. CONCLUSIONS: The kinematic data provided by the iPad are of sufficient quality relative to motion capture data to accurately quantify postural stability in healthy young adults. The iBESS volume provides a more sensitive measure of postural stability than error scoring alone, particularly in conditions 1 and 4, which often suffer from floor effects, and condition 5, which can experience ceiling effects. The iBESS metric is ideally suited for clinical and in the field applications in which characterizing postural stability is of interest.

Using Accelerometer and Gyroscopic Measures to Quantify Postural Stability.

CONTEXT: Force platforms and 3-dimensional motion-capture systems provide an accurate method of quantifying postural stability. Substantial cost, space, time to administer, and need for trained personnel limit widespread use of biomechanical techniques in the assessment of postural stability in clinical or field environments. OBJECTIVE: To determine whether accelerometer and gyroscope data sampled from a consumer electronics device (iPad2) provide sufficient resolution of center-of-gravity (COG) movements to accurately quantify postural stability in healthy young people. DESIGN: Controlled laboratory study. SETTING: Research laboratory in an academic medical center. PATIENTS OR OTHER PARTICIPANTS: A total of 49 healthy individuals (age = 19.5 ± 3.1 years, height = 167.7 ± 13.2 cm, mass = 68.5 ± 17.5 kg). INTERVENTION(S): Participants completed the NeuroCom Sensory Organization Test (SOT) with an iPad2 affixed at the sacral level. MAIN OUTCOME MEASURE(S): Primary outcomes were equilibrium scores from both systems and the time series of the angular displacement of the anteroposterior COG sway during each trial. A Bland-Altman assessment for agreement was used to compare equilibrium scores produced by the NeuroCom and iPad2 devices. Limits of agreement was defined as the mean bias (NeuroCom - iPad) ± 2 standard deviations. Mean absolute percentage error and median difference between the NeuroCom and iPad2 measurements were used to evaluate how closely the real-time COG sway measured by the 2 systems tracked each other. RESULTS: The limits between the 2 devices ranged from -0.5° to 0.5° in SOT condition 1 to -2.9° to 1.3° in SOT condition 5. The largest absolute value of the measurement error within the 95% confidence intervals for all conditions was 2.9°. The mean absolute percentage error analysis indicated that the iPad2 tracked NeuroCom COG with an average error ranging from 5.87% to 10.42% of the NeuroCom measurement across SOT conditions. CONCLUSIONS: The iPad2 hardware provided data of sufficient precision and accuracy to quantify postural stability. Accuracy, portability, and affordability make using the iPad2 a reasonable approach for assessing postural stability in clinical and field environments.

A system and method to interface with multiple groups of axons in several fascicles of peripheral nerves.

BACKGROUND: Several neural interface technologies that stimulate and/or record from groups of axons have been developed. The longitudinal intrafascicular electrode (LIFE) is a fine wire that can provide access to a discrete population of axons within a peripheral nerve fascicle. Some applications require, or would benefit greatly from, technology that could provide access to multiple discrete sites in several fascicles. NEW METHOD: The distributed intrafascicular multi-electrode (DIME) lead was developed to deploy multiple LIFEs to several fascicles. It consists of several (e.g. six) LIFEs that are coiled and placed in a sheath for strength and durability, with a portion left uncoiled to allow insertion at distinct sites. We have also developed a multi-lead multi-electrode (MLME) management system that includes a set of sheaths and procedures for fabrication and deployment. RESULTS: A prototype with 3 DIME leads was fabricated and tested in a procedure in a cadaver arm. The leads were successfully routed through skin and connective tissue and the deployment procedures were utilized to insert the LIFEs into fascicles of two nerves. COMPARISON WITH EXISTING METHOD(S): Most multi-electrode systems use a single-lead, multi-electrode design. For some applications, this design may be limited by the bulk of the multi-contact array and/or by the spatial distribution of the electrodes. CONCLUSION: We have designed a system that can be used to access multiple sets of discrete groups of fibers that are spatially distributed in one or more fascicles of peripheral nerves. This system may be useful for neural-enabled prostheses or other applications.

The effect of forced-exercise therapy for Parkinson's disease on motor cortex functional connectivity.

Parkinson's disease (PD) is a progressive neurologic disorder primarily characterized by an altered motor function. Lower extremity forced exercise (FE) has been shown to reduce motor symptoms in patients with PD. Recent functional magnetic resonance imaging (fMRI) studies have shown that FE and medication produce similar changes in brain activation patterns. Functional connectivity MRI (fcMRI) affords the ability to look at how strongly nodes of the motor circuit communicate with each other and can provide insight into the complementary effects of various therapies. Past work has demonstrated an abnormal motor connectivity in patients with PD compared to controls and subsequent normalization after treatment. Here we compare the effects of FE and medication using both resting and continuous visuomotor task fcMRI. Ten patients with mild to moderate PD completed three fMRI and fcMRI scanning sessions randomized under the following conditions: on PD medication, off PD medication, and FE+off medication. Blinded clinical ratings of motor function (a Unified Parkinson's Disease Rating Motor Scale-III exam) indicated that FE and medication resulted in 51% and 33% improvement in clinical ratings, respectively. In most nodes of the motor circuit, the observed changes in the functional connectivity produced by FE and medication were strongly positively correlated. These findings suggest that medication and FE likely use the same pathways to produce symptomatic relief in patients with PD. However, the connectivity changes, while consistent across therapy, were inconsistent in polarity for each patient. This finding may explain some past inconsistencies in connectivity changes after medication therapy.

Effects of combined robotic therapy and repetitive-task practice on upper-extremity function in a patient with chronic stroke.

OBJECTIVE: This article describes the effect of a robotic device combined with repetitive-task practice (RTP) on upper-extremity function in a patient with chronic stroke. METHOD: The client was a 32-year-old woman, 11 months after stroke, with minimal wrist and finger movement. She received approximately 48 hr of intervention split evenly between a robotic device (Hand Mentor) and RTP during 3 weeks. RESULTS: Favorable scores in the Wolf Motor Function Test were observed from pre- to postevaluation. Active range of motion, from pre- to postintervention, increased by 35 degrees in the shoulder, 65 degrees in the wrist, and 70 degrees in the thumb. Kinetic analysis of a bimanual dexterity task indicated improved specification of grasping forces for both limbs. CONCLUSION: Improvements in upper-extremity motor functioning and functional performance in daily tasks followed this client's engagement in distal initiation of movement during an RTP exercise regimen that was robotically reinforced.

Neuromechanical control of locomotion in the rat.

Rodent models are being extensively used to investigate the effects of traumatic injury and develop and assess the mechanisms of repair and regeneration. We present quantitative assessment of two-dimensional (2D) kinematics of overground walking and for the first time three-dimensional (3D) joint angle kinematics of all four limbs during treadmill walking in intact adult female Long-Evans rats. Gait cycle with subphases and intralimb and interlimb cyclograms are presented. Phase relationships between joint angles on a cycle-by-cycle basis and interlimb footfalls are assessed using a simple technique. Electromyogram (EMG) data from major flexor and extensor muscles for each of the hindlimb joints and elbow extensor muscles of the forelimbs synchronized to the 3D kinematics are also obtained. Overground walking kinematics, provides information on base of support, stride length, and hindfoot rotation. Treadmill walking kinematics indicate primarily monophasic angle trajectories for the hip and shoulder joints, weak double peak patterns for the knee and elbow joints, and a prominent double peak pattern for the ankle joints. Maximum flexion of the knee during swing precedes that of the ankle, which precedes that of the hip. A mild exercise regimen over 8 weeks does not alter the kinematics. EMG activity indicates specific relationships of the neural activity to joint angle kinematics. We find that the ankle flexors as well as the hip and elbow extensors maintain constant burst duration with changing cycle duration. Data and techniques described here are likely to be useful for quantitative assessment of altered gait and neural control mechanisms after neurotrauma.