Digital medicine is an interdisciplinary field, drawing together stakeholders with expertize in engineering, manufacturing, clinical science, data science, biostatistics, regulatory science, ethics, patient advocacy, and healthcare policy, to name a few. Although this diversity is undoubtedly valuable, it can lead to confusion regarding terminology and best practices. There are many instances, as we detail in this paper, where a single term is used by different groups to mean different things, as well as cases where multiple terms are used to describe essentially the same concept. Our intent is to clarify core terminology and best practices for the evaluation of Biometric Monitoring Technologies (BioMeTs), without unnecessarily introducing new terms. We focus on the evaluation of BioMeTs as fit-for-purpose for use in clinical trials. However, our intent is for this framework to be instructional to all users of digital measurement tools, regardless of setting or intended use. We propose and describe a three-component framework intended to provide a foundational evaluation framework for BioMeTs. This framework includes (1) verification, (2) analytical validation, and (3) clinical validation. We aim for this common vocabulary to enable more effective communication and collaboration, generate a common and meaningful evidence base for BioMeTs, and improve the accessibility of the digital medicine field.
Responses of motoneurons supplying muscles of the forelimbs, hindlimbs, back, and neck to stimulation of the medial pontomedullary reticular formation were studied with intracellular recording in cerebellectomized cats under chloralose anesthesia. Stimulation of the midline or of a reticular region consisting of nucleus reticularis (n.r.) pontis caudalis and the dorsorostral part of n.r. gigantocellularis produced monosynaptic excitation of ipsilateral motoneurons supplying axial muscles and flexor and extensor muscles in both proximal and distal parts of the limbs. This widespread excitation appears to have been produced by rapidly conducting medial reticulospinal fibers. Stimulation of a second region consisting of n.r. ventralis and the ventrocaudal part of n.r. gigantocellularis produced monosynaptic excitation of ipsilateral neck and back motoneurons but only longer latency, apparently multisynaptic excitation of limb motoneurons. Collision tests indicated that this monosynaptic excitation did not involve fibers descending along the midline. It therefore appears to have been produced by lateral reticulospinal fibers. Reticular stimulation also produced short latency, monosynaptic inhibition of neck motoneurons, long latency, apparently polysynaptic inhibition of limb motoneurons and intermediate latency inhibition of back motoneurons. The latencies and properties of inhibitory responses of back motoneurons indicated that they were produced either disynaptically by fast fibers or monosynaptically by slower fibers. The data indicate that the medial pontomedullary reticular formation can be divided into a number of different zones each with a distinct pattern of connections with somatic motoneurons. These include the dorsorostrally located medial reticulospinal projection area, from which direct excitation of a wide variety of motoneurons can be evoked, the ventrocaudally located lateral reticulospinal projection area from which direct excitation of neck and back and direct inhibition of neck motoneurons can be evoked and the dorsal strip of n.r. gigantocellularis which has direct excitatory and inhibitory actions only on neck motoneurons.
Extracellular microelectrodes were used to record the activity of reticulospinal neurons within the medial ponto-medullary reticular formation in the cat. In one series of experiments reticulospinal neurons were activated from electrodes in the ventro-medial reticulospinal tract (RSTm) and in the ipsi- and contralateral lateral reticulospinal tracts (RSTi, RSTc) at spinal levels C1--2, C4, Th1 and L1. RSTm neurons were found primarily in n.r. pontis caudalis and the rostro-dorsal part of n.r. gigantocellularis. 71% of these neurons projected as far as the lumbar spinal cord. RSTi neurons projecting to C4 and beyond were clustered in the caudo-ventral part of n.r. gigantocellularis, but those RSTi neurons projecting to the first three cervical segments were located more rostro-dorsally. In all, 63% of the RSTi neurons projected to the lumbar spinal cord. RSTc neurons, which comprised only 5% of the reticulospinal population, were found throughout n.r. gigantocellularis. RSTm neurons had a median conduction velocity of 101 m/sec whereas RSTi and RSTc had median conduction velocities on the order of 70 m/sec. In a second series of experiments microstimulation was used to activate branches of reticulospinal neurons within the gray matter of the cervical enlargement. Twenty-two of thirty-three neurons found to project to the cerivcal ventral horn were branching neurons that also sent axons to the lumbar spinal cord. Thus much of the teticulospinal activity reaching the cervical enlargement also acts at one or more other spinal levels. Detailed investigation of the course of reticulospinal axons within the cervical gray matter indicated that a single axon may traverse wide areas of the ventral horn including regions on both sides of the spinal cord.
A neural network model based on the anatomy and physiology of the cerebellum is presented that can generate both simple and complex predictive pursuit, while also responding in a feedback mode to visual perturbations from an ongoing trajectory. The model allows the prediction of complex movements by adding two features that are not present in other pursuit models: an array of inputs distributed over a range of physiologically justified delays, and a novel, biologically plausible learning rule that generated changes in synaptic strengths in response to retinal slip errors that arrive after long delays. To directly test the model, its output was compared with the behavior of monkeys tracking the same trajectories. There was a close correspondence between model and monkey performance. Complex target trajectories were created by summing two or three sinusoidal components of different frequencies along horizontal and/or vertical axes. Both the model and the monkeys were able to track these complex sum-of-sines trajectories with small phase delays that averaged 8 and 20 ms in magnitude, respectively. Both the model and the monkeys showed a consistent relationship between the high- and low-frequency components of pursuit: high-frequency components were tracked with small phase lags, whereas low-frequency components were tracked with phase leads. The model was also trained to track targets moving along a circular trajectory with infrequent right-angle perturbations that moved the target along a circle meridian. Before the perturbation, the model tracked the target with very small phase differences that averaged 5 ms. After the perturbation, the model overshot the target while continuing along the expected nonperturbed circular trajectory for 80 ms, before it moved toward the new perturbed trajectory. Monkeys showed similar behaviors with an average phase difference of 3 ms during circular pursuit, followed by a perturbation response after 90 ms. In both cases, the delays required to process visual information were much longer than delays associated with nonperturbed circular and sum-of-sines pursuit. This suggests that both the model and the eye make short-term predictions about future events to compensate for visual feedback delays in receiving information about the direction of a target moving along a changing trajectory. In addition, both the eye and the model can adjust to abrupt changes in target direction on the basis of visual feedback, but do so after significant processing delays.
We have investigated the ability of humans to stabilize their heads in space and assessed the influence of mental set and the relative importance of visual and vestibular cues. Ten normal subjects and 3 patients with bilateral vestibular loss were studied. Subjects were fixed firmly to the chair of a turntable facing a screen on which was projected a target spot. A 'gunsight' spot generated by a small projector fixed to the head provided feedback of head position. Four conditions were studied (1) Gunsight (GU): subjects were instructed to stabilize the head in space by superimposing the 'gunsight' spot on the fixed target spot while chair position was displaced according to a random pattern with a bandwidth from 0-1 Hz. (2) Imagined gunsight (IGU): identical to condition 1 except that the subject was blindfolded and so had to imagine the target position. (3) Mental arithmetic (MA): subjects did mental arithmetic while the chair was displaced. (4) Visual tracking (VT): subjects were instructed to track the target spot with the 'gunsight' spot while the chair was fixed and the target spot driven to follow the chair displacement trajectory used in conditions 1, 2 and 3. In GU normal subjects stabilized their head position extremely well (mean HEAD/CHAIR gain = 0.81). Significant stabilization was present in IGU although the gain (mean gain = 0.61) was reduced compared to GU. There was very little stabilization in MA (mean gain = 0.12). In VT, subjects tracked the target with about the same gain (mean gain = 0.68) as in IGU. By comparison, the vestibular patients could not perform IGU, for which their performance (mean gain = 0.08) was similar to MA (mean gain = 0.06). In GU (mean gain = 0.54), their performance was attributable to visual tracking (mean gain in VT = 0.50). For the frequency bandwidth in which subjects were tested, the results show that: When subjects were distracted by mental arithmetic, the contribution to head stability of the short latency cervico-collic (CCR) and vestibulo-collic (VCR) reflexes is negligible. As expected, vision plays an important role in stabilizing the head. Equally important are long latency stabilizing mechanisms whose onset times (140 ms) are shorter, but still comparable to that of vision. The latter mechanisms are of vestibular origin and their influence is under voluntary control so as to permit augmenting head stability compared to what it would be if vision acted alone.
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