Temporal and spatial dynamics of spinal sensorimotor processing in an intersegmental cutaneous nociceptive reflex.

The cutaneus trunci muscle (CTM) reflex produces a skin "shrug" in response to pinch on a rat's back through a three-part neural circuit: 1) A-fiber and C-fiber afferents in segmental dorsal cutaneous nerves (DCNs) from lumbar to cervical levels, 2) ascending propriospinal interneurons, and 3) the CTM motoneuron pool located at the cervicothoracic junction. We recorded neurograms from a CTM nerve branch in response to electrical stimulation. The pulse trains were delivered at multiple DCNs (T6-L1), on both sides of the midline, at two stimulus strengths (0.5 or 5 mA, to activate Aδ fibers or Aδ and C fibers, respectively) and four stimulation frequencies (1, 2, 5, or 10 Hz) for 20 s. We quantified both the temporal dynamics (i.e., latency, sensitization, habituation, and frequency dependence) and the spatial dynamics (spinal level) of the reflex. The evoked responses were time-windowed into Early, Mid, Late, and Ongoing phases, of which the Mid phase, between the Early (Aδ fiber mediated) and Late (C fiber mediated) phases, has not been previously identified. All phases of the response varied with stimulus strength, frequency, history, and DCN level/side stimulated. In addition, we observed nociceptive characteristics like C fiber-mediated sensitization (wind-up) and habituation. Finally, the range of latencies in the ipsilateral responses were not very large rostrocaudally, suggesting a myelinated neural path within the ipsilateral spinal cord for at least the A fiber-mediated Early-phase response. Overall, these results demonstrate that the CTM reflex shares the temporal dynamics in other nociceptive reflexes and exhibits spatial (segmental and lateral) dynamics not seen in those reflexes.NEW & NOTEWORTHY We have physiologically studied an intersegmental reflex exploring detailed temporal, stimulus strength-based, stimulation history-dependent, lateral and segmental quantification of the reflex responses to cutaneous nociceptive stimulations. We found several physiological features in this reflex pathway, e.g., wind-up, latency changes, and somatotopic differences. These physiological observations allow us to understand how the anatomy of this reflex may be organized. We have also identified a new phase of this reflex, termed the "mid" response.

Cutaneous sensory feedback from paw pads affects lateral balance control during split-belt locomotion in the cat.

Cutaneous sensory feedback from the paw pads plays an important role in regulating body balance, especially in challenging environments like ladder or slope walking. Here, we investigated the contribution of cutaneous sensory feedback from the paw pads to balance control in cats stepping on a split-belt treadmill. Forepaws and hindpaws were anesthetized unilaterally using lidocaine injections. We evaluated body balance in intact and compromised cutaneous feedback conditions during split-belt locomotion with belt-speed ratios of 0.5, 1.0, 1.5 and 2.0. Measures of body balance included step width, relative duration of limb support phases, lateral bias of center of mass (CoM) and margins of static and dynamic stability. In the intact condition, static and dynamic balance declined with increasing belt-speed ratio as a result of a lateral shift of the CoM toward the borders of support on the slower moving belt. Anesthesia of the ipsilateral paws improved locomotor balance with increasing belt-speed ratios by reversing the CoM shift, decreasing the relative duration of the two-limb support phase, increasing the duration of four- or three-limb support phases, and increasing the hindlimb step width and static stability. We observed no changes in most balance measures in anesthetized conditions during tied-belt locomotion at 0.4 m s-1 CoM lateral displacements closely resembled those of the inverted pendulum and of human walking. We propose that unilaterally compromised cutaneous feedback from the paw pads is compensated for by improving lateral balance and by shifting the body toward the anesthetized paws to increase tactile sensation during the stance phase.

Electrical Stimulation of Distal Tibial Nerve During Stance Phase of Walking May Reverse Effects of Unilateral Paw Pad Anesthesia in the Cat.

Cutaneous feedback from feet is involved in regulation of muscle activity during locomotion, and the lack of this feedback results in motor deficits. We tested the hypothesis that locomotor changes caused by local unilateral anesthesia of paw pads in the cat could be reduced/reversed by electrical stimulation of cutaneous and proprioceptive afferents in the distal tibial nerve during stance. Several split-belt conditions were investigated in four adult female cats. In addition, we investigated the effects of similar distal tibial nerve stimulation on overground walking of one male cat that had a transtibial, bone-anchored prosthesis for 29 months and, thus, had no cutaneous/proprioceptive feedback from the foot. In all treadmill conditions, cats walked with intact cutaneous feedback (control), with right fore- and hindpaw pads anesthetized by lidocaine injections, and with a combination of anesthesia and electrical stimulation of the ipsilateral distal tibial nerve during the stance phase at 1.2× threshold of afferent activation. Electrical stimulation of the distal tibial nerve during the stance phase of walking with anesthetized ipsilateral paw pads reversed or significantly reduced the effects of paw pad anesthesia on several kinematic variables, including lateral center of mass shift, cycle and swing durations, and duty factor. We also found that stimulation of the residual distal tibial nerve in the prosthetic hindlimb often had different effects on kinematics compared with stimulation of the intact hindlimb with paw anesthetized. We suggest that stimulation of cutaneous and proprioceptive afferents in the distal tibial nerve provides functionally meaningful motion-dependent sensory feedback, and stimulation responses depend on limb conditions.

Fitts' Law Based Performance Metrics to Quantify Tremor in Individuals With Essential Tremor.

Current methods of evaluating essential tremor (ET) either rely on subjective ratings or use limited tremor metrics (i.e., severity/amplitude and frequency). In this study, we explored performance metrics from Fitts' law tasks that replicate and expand existing tremor metrics, to enable low-cost, home-based tremor quantification and analyze the cursor movements of individuals using a 3D mouse while performing a collection of drawing tasks. We analyzed the 3D mouse cursor movements of 11 patients with ET and three controls, on three computer-based tasks-a spiral navigation (SPN) task, a rectangular track navigation (RTN) task, and multi-directional tapping/clicking (MDT)-with several performance metrics (i.e., outside area (OA), throughput (TP in Fitts' law), path efficiency (PE), and completion time (CT). Using an accelerometer and scores from the Essential Tremor Rating Assessment Scale (TETRAS), we correlated the proposed performance metrics with the baseline tremor metrics and found that the OA of the SPN and RTN tasks were strongly correlated with baseline tremor severity (R2 = 0.57, and R2 = 0.83). We also found that the TP in the MDT tasks were strongly correlated with tremor frequency (R2 = 0.70). In addition, as the OA of the SPN and RTN tasks was correlated with tremor severity and frequency, it may represent an independent metric that increases the dimensionality of the characterization of an individual's tremor. Thus, this pilot study of the analysis of those with ET-associated tremor performing Fitts' law tasks demonstrates the feasibility of introducing a new tremor metric that can be expanded for repeatable multi-dimensional data analyses.

Analyzing the Effects of Parameters for Tremor Modulation via Phase-Locked Electrical Stimulation on a Peripheral Nerve.

(1) Background: Non-invasive neuromodulation is a promising alternative to medication or deep-brain stimulation treatment for Parkinson's Disease or essential tremor. In previous work, we developed and tested a wearable system that modulates tremor via the non-invasive, electrical stimulation of peripheral nerves. In this article, we examine the proper range and the effects of various stimulation parameters for phase-locked stimulation. (2) Methods: We recruited nine participants with essential tremor. The subjects performed a bean-transfer task that mimics an eating activity to elicit kinetic tremor while using the wearable stimulation system. We examined the effects of stimulation with a fixed duty cycle, at different stimulation amplitudes and frequencies. The epochs of stimulation were locked to one of four phase positions of ongoing tremor, as measured with an accelerometer. We analyzed stimulation-evoked changes of the frequency and amplitude of tremor. (3) Results: We found that the higher tremor amplitude group experienced a higher rate of tremor power reduction (up to 65%) with a higher amplitude of stimulation when the stimulation was applied at the ±peak of tremor phase. (4) Conclusions: The stimulation parameter can be adjusted to optimize tremor reduction, and this study lays the foundation for future large-scale parameter optimization experiments for personalized peripheral nerve stimulation.

A Wearable System for Attenuating Essential Tremor Based on Peripheral Nerve Stimulation.

OBJECTIVE: Currently available treatments for kinetic tremor can cause intolerable side effects or be highly invasive and expensive. Even though several studies have shown the positive effects of external feedback (i.e., electrical stimulation) for suppressing tremor, such approaches have not been fully integrated into wearable real-time feedback systems. METHOD: We have developed a wireless wearable stimulation system that analyzes upper limb tremor using a three-axis accelerometer and that modulates/attenuates tremor using peripheral-nerve electrical stimulation with adjustable stimulation parameters and a real-time tremor detection algorithm. We outfitted nine subjects with tremor with a wearable system and a set of surface electrodes placed on the skin overlying the radial nerve and tested the effects of stimulation with nine combinations of parameters for open- and closed-loop stimulation on tremor. To quantify the effects of the stimulation, we measured tremor movements, and analyzed the dominant tremor frequency and tremor power. RESULTS: Baseline tremor power gradually decreased over the course of 18 stimulation trials. During the last trial, compared with the control trial, the reduction rate of tremor power was 42.17 ± 3.09%. The dominant tremor frequency could be modulated more efficiently by phase-locked closed-loop stimulation. The tremor power was equally reduced by open- and closed-loop stimulation. CONCLUSION: Peripheral nerve stimulation significantly affects tremor, and stimulation parameters need to be optimized to modulate tremor metrics. Clinical Impact: This preliminary study lays the foundation for future studies that will evaluate the efficacy of the proposed closed-loop peripheral nerve stimulation method in a larger group of patients with kinetic tremor.

A retrofitted neural recording system with a novel stimulation IC to monitor early neural responses from a stimulating electrode.

Extracellular electrical stimulation is increasingly used for in vitro neural experimentation, including brain slices and cultured cells. Although it is desirable to record directly from the stimulating electrode, relatively high stimulation levels make it extremely difficult to record immediately after the stimulation. We have shown that this is feasible by a stimulation system (analog IC) that includes the feature of active electrode discharge. Here, we piggybacked the new IC onto an existing recording amplifier system, making it possible to record neural responses directly from the stimulating channel as early as 3 ms after the stimulation. We used the retrofitted recording system to stimulate and record from dissociated hippocampal neurons in culture. This new strategy of retrofitting an existing system is a simple but attractive approach for instrumentation designers interested in adding a new feature for extracellular recording without replacing already existing recording systems.

Neuromechanical tuning of nonlinear postural control dynamics.

Postural control may be an ideal physiological motor task for elucidating general questions about the organization, diversity, flexibility, and variability of biological motor behaviors using nonlinear dynamical analysis techniques. Rather than presenting "problems" to the nervous system, the redundancy of biological systems and variability in their behaviors may actually be exploited to allow for the flexible achievement of multiple and concurrent task-level goals associated with movement. Such variability may reflect the constant "tuning" of neuromechanical elements and their interactions for movement control. The problem faced by researchers is that there is no one-to-one mapping between the task goal and the coordination of the underlying elements. We review recent and ongoing research in postural control with the goal of identifying common mechanisms underlying variability in postural control, coordination of multiple postural strategies, and transitions between them. We present a delayed-feedback model used to characterize the variability observed in muscle coordination patterns during postural responses to perturbation. We emphasize the significance of delays in physiological postural systems, requiring the modulation and coordination of both the instantaneous, "passive" response to perturbations as well as the delayed, "active" responses to perturbations. The challenge for future research lies in understanding the mechanisms and principles underlying neuromechanical tuning of and transitions between the diversity of postural behaviors. Here we describe some of our recent and ongoing studies aimed at understanding variability in postural control using physical robotic systems, human experiments, dimensional analysis, and computational models that could be enhanced from a nonlinear dynamics approach.

Differential cardiovascular responses to cutaneous afferent subtypes in a nociceptive intersegmental spinal reflex.

Electrical stimulation to segmental dorsal cutaneous nerves (DCNs) activates a nociceptive sensorimotor reflex and the same afferent stimulation also evokes blood pressure (BP) and heart rate (HR) responses in rats. To investigate the relationship between those cardiovascular responses and the activation of nociceptive afferents, we analyzed BP and HR responses to electrical stimulations at each DCN from T6 to L1 at 0.5 mA to activate A-fiber alone or 5 mA to activate both A- and C-fibers at different frequencies. Evoked cardiovascular responses showed a decrease and then an increase in BP and an increase and then a plateau in HR. Segmentally, both cardiovascular responses tended to be larger when evoked from the more rostral DCNs. Stimulation frequency had a larger effect on cardiovascular responses than the rostrocaudal level of the DCN input. Stimulation strength showed a large effect on BP changes dependent on C-fibers whereas HR changes were dependent on A-fibers. Additional A-fiber activation by stimulating up to 4 adjacent DCNs concurrently, but only at 0.5 mA, affected HR but not BP. These data support that cutaneous nociceptive afferent subtypes preferentially contribute to different cardiovascular responses, A-fibers to HR and C-fibers to BP, with temporal (stimulation frequency) and spatial (rostrocaudal level) dynamics.

A Prototype of a Neural, Powered, Transtibial Prosthesis for the Cat: Benchtop Characterization.

We developed a prototype of a neural, powered, transtibial prosthesis for the use in a feline model of prosthetic gait. The prosthesis was designed for attachment to a percutaneous porous titanium implant integrated with bone, skin, and residual nerves and muscles. In the benchtop testing, the prosthesis was fixed in a testing rig and subjected to rhythmic vertical displacements and interactions with the ground at a cadence corresponding to cat walking. Several prosthesis functions were evaluated. They included sensing ground contact, control of transitions between the finite states of prosthesis loading, and a closed-loop modulation of the linear actuator gain in each loading cycle. The prosthetic design parameters (prosthesis length = 55 mm, mass = 63 g, peak extension moment = 1 Nm) corresponded closely to those of the cat foot-ankle with distal shank and the peak ankle extension moment during level walking. The linear actuator operated the prosthetic ankle joint using inputs emulating myoelectric activity of residual muscles. The linear actuator gain was modulated in each cycle to minimize the difference between the peak of ground reaction forces (GRF) recorded by a ground force sensor and a target force value. The benchtop test results demonstrated a close agreement between the GRF peaks and patterns produced by the prosthesis and by cats during level walking.

Sensory feedback in a half-center oscillator model.

We hypothesize that one role of sensorimotor feedback for rhythmic movements in biological organisms is to synchronize the frequency of movements to the mechanical resonance of the body. Our hypothesis is based on recent studies that have shown the advantage of moving at mechanical resonance and how such synchronization may be possible in biology. We test our hypothesis by developing a physical system that consists of a silicon-neuron central pattern generator (CPG), which controls the motion of a beam, and position sensors that provide feedback information to the CPG. The silicon neurons that we use are integrated circuits that generate neural signals based on the Hodgkin-Huxley dynamics. We use this physical system to develop a model of the interaction between the sensory feedback and the complex dynamics of the neurons to create the closed-loop system behavior. This model is then used to describe the conditions under which our hypothesis is valid and the general effects of sensorimotor feedback on the rhythmic movements of this system.

Resonance tuning of a neuromechanical system with two negative sensory feedback configurations.

Resonance tuning in a model of rhythmic movement is compared when the central pattern generator (CPG) consists of two endogenously bursting or two tonically spiking neurons that are connected with reciprocally inhibitory synapses. The CPG receives inhibitory and/or excitatory position feedback from a linear, one-degree-of-freedom mechanical subsystem. As with previously published results [5, 15], resonance tuning is limited to frequencies that are greater than the intrinsic CPG frequency with endogenously bursting neurons. In contrast, with tonically spiking neurons, the resonance tuning range is expanded to frequencies that are below the intrinsic CPG frequency.

Optimization of Stimulation Parameters for Targeted Activation of Multiple Neurons Using Closed-Loop Search Methods.

Differential activation of neuronal populations can improve the efficacy of clinical devices such as sensory or cortical prostheses. Improving stimulus specificity will facilitate targeted neuronal activation to convey biologically realistic percepts. In order to deliver more complex stimuli to a neuronal population, stimulus optimization techniques must be developed that will enable a single electrode to activate subpopulations of neurons. However, determining the stimulus needed to evoke targeted neuronal activity is challenging. To find the most selective waveform for a particular population, we apply an optimization-based search routine, Powell's conjugate direction method, to systematically search the stimulus waveform space. This routine utilizes a 1-D sigmoid activation model and a 2-D strength-duration curve to measure neuronal activation throughout the stimulus waveform space. We implement our search routine in both an experimental study and a simulation study to characterize potential stimulus-evoked populations and the associated selective stimulus waveform spaces. We found that for a population of five neurons, seven distinct sub-populations could be activated. The stimulus waveform space and evoked neuronal activation curves vary with each new combination of neuronal culture and electrode array, resulting in a unique selectivity space. The method presented here can be used to efficiently uncover the selectivity space, focusing experiments in regions with the desired activation pattern.

A Stretchable Microneedle Electrode Array for Stimulating and Measuring Intramuscular Electromyographic Activity.

We have developed a stretchablemicroneedle electrode array (sMEA) to stimulate andmeasure the electrical activity of muscle across multiple sites. The technology provides the signal fidelity and spatial resolution of intramuscular electrodesacross a large area of tissue. Our sMEA is composed of a polydimethylsiloxane (PDMS) substrate, conductive-PDMS traces, and stainless-steel penetrating electrodes. The traces and microneedles maintain a resistance of less than 10 [Formula: see text] when stretched up to a ~63% tensile strain, which allows for the full range of physiological motion of felinemuscle. The device and its constituent materials are cytocompatible for at least 28 days in vivo. When implanted in vivo, the device measures electromyographic (EMG) activity with clear compound motor unit action potentials. The sMEA also maintains a stable connection with moving muscle while electrically stimulating the tissue. This technology has direct application to wearable sensors, neuroprostheses, and electrophysiological studies of animals and humans.

Two-dimensional variation of bursting properties in a silicon-neuron half-center oscillator.

We are developing hardware models of central pattern generators (CPGs) to enhance neural prostheses, create biologically based controllers for autonomous machines, and to better understand how biology creates stable and robust movements. Previously, we designed and implemented an analog integrated circuit model of a neuron with Hodgkin-Huxley like dynamics, the silicon neuron. In this work, we use silicon neurons to implement a half-center oscillator and show that the underlying dynamics of this CPG produce bursting behaviors that are well matched to the biological counterpart on which our model is based. In addition, we demonstrate the robustness of the bursting behavior by systematically varying two parameters in each silicon neuron and mapping the corresponding effects on the bursting.

Quantitative assessment of arm tremor in people with neurological disorders.

Abnormal oscillatory movement (i.e. tremor) is usually evaluated with qualitative assessment by clinicians, and quantified with subjective scoring methods. These methods are often inaccurate. We utilized a quantitative and standardized task based on the Fitts' law to assess the performance of arm movement with tremor by controlling a gyration mouse on a computer. The experiment included the center-out tapping (COT) and rectangular track navigation (RTN) tasks. We report the results of a pilot study in which we collected the performance for healthy participants in whom tremor was simulated by imposing oscillatory movements to the arm with a vibration motor. We compared their movement speed and accuracy with and without the artificial "tremor." We found that the artificial tremor significantly affected the path efficiency for both tasks (COT: 56.8 vs. 46.2%, p <; 0.05; RTN: 94.2 vs. 67.4%, p <; 0.05), and we were able to distinguish the presence of tremor. From this result, we expect to quantify severity of tremor and the effectiveness therapy for tremor patients.

Longitudinal wearable tremor measurement system with activity recognition algorithms for upper limb tremor.

Assessments of tremor characteristics by movement disorder physicians are usually done at single time points in clinic settings, so that the description of the tremor does not take into account the dependence of the tremor on specific behavioral situations. Moreover, treatment-induced changes in tremor or behavior cannot be quantitatively tracked for extended periods of time. We developed a wearable tremor measurement system with tremor and activity recognition algorithms for long-term upper limb behavior tracking, to characterize tremor characteristics and treatment effects in their daily lives. In this pilot study, we collected sensor data of arm movement from three healthy participants using a wrist device that included a 3-axis accelerometer and a 3-axis gyroscope, and classified tremor and activities within scenario tasks which resembled real life situations. Our results show that the system was able to classify the tremor and activities with 89.71% and 74.48% accuracies during the scenario tasks. From this results, we expect to expand our tremor and activity measurement in longer time period.

Mechanical trauma induces immediate changes in neuronal network activity.

During a traumatic insult to the brain, tissue is subjected to large stresses at high rates which often surpass cellular thresholds leading to cell dysfunction or death. The acute response of neurons to a mechanical trauma, however, is poorly understood. Plasma membrane disruption may be the earliest cellular outcome from a mechanical trauma. The increase in membrane permeability due to such disruptions may therefore play an important role in the initiation of deleterious cascades following brain injury. The immediate consequences of an increase in plasma membrane permeability on the electrophysiological behavior of a neuronal network exposed to the trauma have not been elucidated. We have developed an in vitro model of traumatic brain injury (TBI) that utilizes a novel device capable of applying stress at high rates to neuronal cells cultured on a microelectrode array. The mechanical insult produced by the device caused a transient increase in neuronal plasma membrane permeability, which subsided after 10 min. We were able to monitor acute spontaneous electrophysiological activity of injured cultures for at least 10 min following the insult. Firing frequency, average burst interval and spikes within burst were assessed before and after injury. The electrophysiological responses to the insult were heterogeneous, although an increase in burst intervals and in the variability of the assessed parameters were common. This study provides a multi-faceted approach to elucidate the role of neuronal plasma membrane disruptions in TBI and its functional consequences.

A three-dimensional image processing program for accurate, rapid, and semi-automated segmentation of neuronal somata with dense neurite outgrowth.

Three-dimensional (3-D) image analysis techniques provide a powerful means to rapidly and accurately assess complex morphological and functional interactions between neural cells. Current software-based identification methods of neural cells generally fall into two applications: (1) segmentation of cell nuclei in high-density constructs or (2) tracing of cell neurites in single cell investigations. We have developed novel methodologies to permit the systematic identification of populations of neuronal somata possessing rich morphological detail and dense neurite arborization throughout thick tissue or 3-D in vitro constructs. The image analysis incorporates several novel automated features for the discrimination of neurites and somata by initially classifying features in 2-D and merging these classifications into 3-D objects; the 3-D reconstructions automatically identify and adjust for over and under segmentation errors. Additionally, the platform provides for software-assisted error corrections to further minimize error. These features attain very accurate cell boundary identifications to handle a wide range of morphological complexities. We validated these tools using confocal z-stacks from thick 3-D neural constructs where neuronal somata had varying degrees of neurite arborization and complexity, achieving an accuracy of ≥95%. We demonstrated the robustness of these algorithms in a more complex arena through the automated segmentation of neural cells in ex vivo brain slices. These novel methods surpass previous techniques by improving the robustness and accuracy by: (1) the ability to process neurites and somata, (2) bidirectional segmentation correction, and (3) validation via software-assisted user input. This 3-D image analysis platform provides valuable tools for the unbiased analysis of neural tissue or tissue surrogates within a 3-D context, appropriate for the study of multi-dimensional cell-cell and cell-extracellular matrix interactions.